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Kidney international, Vol. 29 (1986), pp. 108—119

Prostaglandins and other metabolites in the kidney

DETLEF SCHLONDORFF and RAYMOND ARDAILLOU

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, and Tenon Hospital, Paris, France

This review discusses the of arachidonic acid to Control of PG-synthesis (PG) and other metabolites and the site of activity. Changes in cell cyclooxygenase physiological action of these products along the nephron.activity (half-life 24 hr) may occur slowly under certain condi- Potential pathophysiological contributions of renal PG will betions and can chronically change the capacity for PG synthesis. briefly reviewed. The breakdown of prostaglandins will not beSuch alterations in total cyclooxygenase activity have been discussed and the reader is referred to several excellent articlesobserved, for example, in rats with congenital diabetes on the subject [1, 2]. insipidus after chronic administration of antidiuretic hormone [4]. A different mechanism may underlie the increase in cyclo- after unilateral ureteral ligation [5—8] or renal venous General principles of synthesis obstruction [91.Inthese instances it appears that the increase in does not occur in the renal cells, themselves, but is The biosynthetic pathway leading to the formation of theinstead due to proliferation of inflammatory cells [10]. unstable intermediate endoperoxides from arachidonic acid Substrate availability. Under normal physiological conditions the (AA) seems to be identical in all tissues investigated [1].amount of free intracellular AA, that is available for cyclooxygenase Subsequent conversion of the endoperoxides follows a tissue- specific pattern resulting in the formation of different PG by is negligible [1]. Apart from the activity of cyclooxygenase in a given tissue, the major factor controlling PG-synthesis is the availability of different tissues. The endoperoxides are synthesized by a singlefree AA. AA is esterified in the 2 position of the phospholipid, enzyme which is a glycoprotein with two enzymatic sites,predominantly in phosphatidylinositol but also in phosphatidyleho- cyclooxygenase and hydroperoxidase [II. The endoperoxidesline and phosphatidylethanolamine. can then be transformed by -synthase to PGI2, by Most likely both and synthase to TXA2, by PG to PGE2 andactivation are involved in the release of AA [11—12]. Agreement PGD2, and by endoperoxide reductase to yield PGF2,. (Fig. 1).exists that the enzymatic steps leading to the release of AA are There is, in addition, also some nonenzymatic decomposition of PGH2 into PGE2 and PGD2 [1]. It remains unclear at thiscalcium-dependent [1]. Phospholipase A2 in the renal medulla point whether the reduction from PGH2 to PGF2,. is an enzy-[12—14] may be a calcium-calmodulin-dependent enzyme, while phospholipase C appears to be calmodulin-independent [15, 161. matic reaction. Most crude homogenates contain enough thiol In the isolated kidney [17] and kidney slices [7] and cultured compounds and hemoproteins to generate significant amountsmesangial cells [181, there are specific pools of AA linked to of PGF2. by nonenzymatic reduction from PGH2 [1]. The different involved in the formation of thecyclooxygenase activity, while other AA pools are unrelated to PG-synthesis. Furthermore, metabolism of only a small per- various PUs have specific requirements (Table 1) socentage of the AA pool in phospholipids seems to be hormone that the pattern of PG production can change depending on the preparation and conditions used and need not at all reflect theresponsive [7, 181. The amount of membrane-bound AA converted to cyclooxy- pattern of PG formation in intact tissue. For example, thegenase or lipoxygenase products is only a small fraction of the relationship of the different PGs produced by kidneytotal. Only a few percent of the cellular AA is released even microsomes can be altered depending on the addition of variousafter maximal hormone stimulation, and of this, only a fraction cofactors [21. Also, the pattern of PG formed may vary with the(10 to 40%) is transformed by cyclooxygenase, while the rest enzyme/substrate ratio and substrate concentration [2]. Finally, may be reincorporated into phospholipids [17]. The fact that the the ratio of cyclooxygenase to may be different inhormone responsive AA pool is small compared to the total various tissues so that different results will be obtained depend-phospholipid-bound AA complicates studies which rely on the ing on whether AA or PGH2 are used as substrate (for example, prelabeling of phospholipids with exogenous AA, because see [3D. under most conditions the total phospholipid pool is labeled nonspecifically [7]. Prelabeling of the specific hormone respon- sive pool may be facilitated by prior hormone stimulation [19]. Received for publication June 12, 1985 Further complicating matters, different individual phospholip- © 1986 by the International Society of Nephrology ids also have different turnover rates and are represented to

108 Prostaglandins and metabolites in the kidney 109

Phosphoglyceride Triglyceride Cholesterol ester

(OOH) Acylhydrolase OH COOH COON COON 0 Arachidonic Acid (20:4) 2 5-HET 02 (HOO' Cyclo oxgenase 12-Het CHO CH2 r0H02 OH 0

PGG2 OOH [H)

6-keto-PGF1 OH

OH

°OH PGF2 PGD2

Fig. 1. Scheme of biologically active compounds derived from arachidonic acid. (Reprinted from [II with permission)

differing degrees within the cells. For example, phosphatidyl- Table 1. Some characteristics of enzymes involved in prostaglandin inositol only represent 5 to 10%, while phosphatidylcholine and synthesis phosphatidylethanolamine each account for about 30% of the Formation of Location Cofactors total phospholipids. Thus, small changes in the turnover of Cyclo- . phosphatidyicholine and phosphatidylethanolamine may re-AA PGG2 Hemin oxygenase lease as much AA as much more marked changes in phosphati- Particulate dylinositol turnover. For all these reasons, the exact source of Hydro- AA and the mechanism of its release have yet to be defined PGG2 . PGH2 Aromatic compounds (for peroxluase example, tryptophan) fully. as reducing substrate Inhibition of phospholipase. An endogenous inhibitor ofPGE2 Particulate Glutathione phospholipase has been described in neutrophils [20—22]and PGI2 Particulate None known renal medulla [22].Thisinhibitor is a protein that is synthetized Thromboxane Particulate None known PGD2 Soluble Glutathione (?) and released in response to glucocorticoids. It has been called albumin (?) macrocortin [20], lipomodulin [21], orrenocortin [22].Lipomod-PGF2 Enzymatic (?)Thiol compounds and ulin has been shown to inhibit both phospholipase A2 and C in hemoproteins vitro [21]. Other factors influencing AA availability. In addition to release of AA by phospholipase, factors that influence the AAmay be one explanation for increased PG synthesis observed availability include: during hypoxia [23—25]. (1) Binding of AA to protein. AA avidly binds to both extra (3) Competition forAA. In addition to cyclooxygenase, AA is and intracellular proteins and as such is no longer available foralso a substrate for lipoxygenase and epoxygenase. This com- cyclooxygenase. Thus, not all intracellular AA is "free" andpetition for free AA could influence PG-synthesis. Further- can be utilized for PG synthesis [1]. more, the products of these enzymes may in turn influence (2) Reincorporation of AA. AA released from thephospholipases and the cyclooxygenase system. These path- phospholipids may be reincorporated rapidly into phospholipidsways are only beginning to be explored in the kidney. [1, 17]. This reaction competes with cyclooxygenase for AA [7, 18]. As the reincorporation into phospholipids requires ATP, Lipoxygenase products and the kidney the reaction may be slowed during hypoxia, which, in turn, Formation of lipoxygenase products by the kidney. Arachi- could lead to higher concentrations of nonesterified AA. Thisdonic acid can also be metabolized via lipoxygenase pathways 110 Schlondorff and Ardaillou

(Figs. 1 and 2) [26]. To our knowledge, the formation of small COOH — amounts of 12-HETE by guinea pig kidney homogenates was Arachidonic acid first demonstrated by Hamberg [27]. Recently, Winokur and Morrison [28] demonstrated formation of 12-HETE and 15- I Lipoxygenase HOOH HOH HETE (identified by gas chromatography followed by mass — ---COOH spectrometry) by a cytosolic preparation from rabbit renal 5-HPETE 5-HETE medulla but not from the cortex. The lipoxygenase activity was OH increased in hydronephrotic kidneys, a finding similar to the Dehydrase HO COOH increase in cyclooxygenase activity in hydronephrotic kidneys Non- OH [5]. In the hydronephrotic kidney, it remains unclear whether enzymatic .OOH these products are truly of renal cell origin or are produced by A4(LTA4) Glutathione invading inflammatory cells [10]. The enzyme required calcium HvdrolaS>Z 'S- and was inhibited by the lipoxygenase inhibitors eicosatetray-H OH HOH HOH COOH noic acid (ETYA) and phenidone, but not by indomethacin [28]. COOH Lipoxygenase products have been identified lately by gas 5H1 ys-GIy chromatography-mass spectrometry as 12-HETE in rat (LTB4) c -Glu glomeruli [29, 301 and as 12- and 15-HETE in human glomeruli (LTC4) [30]. 1GGp It is to be expected that lipoxygenase products will be HO H identified in other renal structures, as more attention is directed LTD4 c_COOH toward these products and as analytical detection methods are Cys-Gly improving. The physiological significance of these lipoxygenase products in renal function remains to be determined but is HOH certain to attract much interest in the near future. Lately, it has LTE4 H SCOOH been postulated that lipoxygenase products may play a role in C5H11 Cys experimental immune injury to the glomerulus [31—33]. Metabolism of in the kidney. To date no evi- dence exists for 5-HETE formation and subsequent leukotriene HCOOH production by kidney tissue (Fig. 2). Systemic infusion of LTF4 leukotrienes, however, does influence renal function [34]. It is C5H11 Cys therefore reasonable to assume that leukotrienes released from c -Glu Fig. 2. Formationof leukotrienes via the 5-lipoxygenase pathway. inflammatory cells within the kidneys may influence renalGGTP is y-glutamyl transpeptidase. (Reprinted from [26] with hemodynamics and capillary permeability, as they do in otherpermission) systems [261. Also, the kidney may be involved in the metabo- lism of leukotrienes. Transformation of LTC3 to the biologically more active LTD3 by gamma-glutamyltranspeptidase has beenpossible that a P-450-linked epoxygenase system is demonstrated in the kidney [35]. Conversion of LTD to LTEinvolved in the formation of metabolites that previously were has also been demonstrated in the porcine kidney [36] and ismistaken for cyclooxygenase or lipoxygenase products. associated with a tenfold decrease in biological activity. In vivo An intriguing finding is the production of considerable the kidney may play a role in the metabolism and inactivation ofamounts of AA derivatives by the thick ascending loop of Henle leukotrienes as suggested by total body autoradiography ofthat derive from neither cyclo- nor lipoxygenase pathways and mice after of [3H]-labeled leukotriene C3 [37]. may be epoxygenase products [45—47]. The epoxygenase path- way is certain to attract considerable interest, especially as 5,6 Epoxygenase pathway , a product of a renal NADPH-depen- In addition to cyclooxygenase and lipoxygenase, the kidneydent pathway, can inhibit sodium transport in contains mixed function oxidases that are involved in theisolated collecting tubules [48] and 's hydroosmotic metabolism of fatty acids and also PG [38—41]. Recently, it hasaction in the toad urinary bladder [49]. been shown that AA can be converted by NADPH-dependent, cytochrome P-450 to oxidation products (Fig. 3); [42—44]. They PG-synthesis in the kidney include dihydroxyeicosatrienoic acids oxidized at the 5,6;the The kidney, and especially the renal medulla, is one of the 8,9; the 11, 12 and the 14,15 position as well as 19,20-most active PG-producing tissues. Homogenates or micro- hydroxyeicosatetraenoic acids, 19-oxoeicosatetraenoic acid,somes from the entire kidney produce PGE2, PGF2, 6 keto and eicosatetraen-l,20-dioic acid. The formation of these prod-PGF1,, TXB2, and PGD2 to varying degrees depending on the ucts by renal cortical microsomes depended on the pesence ofconditions used [2]. The isolated perfused kidney produces NADPH which cannot be substituted for NADH. 02 is alsopredominantly PGE2 [5, 50] but also can release PG!2 [51], and necessary for their formation [42—44]. The formation of the 11,under certain circumstances, TXB2 [52, 531. Table 2 lists factors 12- and the 14,15-dihydroxyeicosatetraenoic acid occurredinfluencing renal PG synthesis. probably via the intermediate epoxides 11(12)- and 14(15)- There are marked regional differences in the quantity and oxido-cis-5,8,14 eicosatrienoic acid. The dihydroxyacids can bepattern of PG production within the kidney. As PGs are locally metabolized further to trihydroxy acids [44] (Fig. 3). It isactive agents, the pattern of PGs produced by different nephron Prostaglandins and metabolites in the kidney 111 COOH / Arachidonic/\ acid w-oxidation w6 and w9 Epoxidation (w-1) Oxidation

/ Dehydro- genase OH 0

I I

HO OH HO OH

wand/1 (w-1) Oxidation and (w-1) Oxidation

COOH / COOH Dehydro- OOH 0r' genase HO OH HO OH OH HO OH HO OH OH HO OH 0 Fig.3. Tentative pathway of arachidonic acid metabolism leading to trihydroxy metabolites in fortfled rabbit kidney microsomes by the epoxy genase systems. (Reprinted from [44] with permission)

Table 2. Factors stimulating PG synthesis by the kidney in vivo or munofluorescence staining for cyclooxygenase activity gives perfused in vitro only a qualitative picture and a negative staining reaction does Stimulating factor Reference not rule out cyclooxygenase activity but could just indicate levels below the detection limit. Angiotensin II 7, 17, 23, 54—56 In the renal medulla both histochemical and immunofluores- Bradykinin 7, 17, 23, 55, 58—60 Vasopressin 61—63 cence methods show strongly positive staining in collecting Catecholamines and renal nerve tubule cells and interstitial cells [71—73]. stimulation 50, 60, 64 PG-synthesis by different nephron segments. (1) Renal cor- Converting 65 tex. To better characterize the source of PG synthesis in renal Mannitol 66 cortical tissue, isolated nephron segments have been examined Renal perfusion rate 67—69 for PG synthesis. PG!2 synthesis has been shown to be promi- nent in microdissected cortical arteries and arterioles [74]. Rat segments is important. PG synthesis increases from cortex toglomeruli produce mainly PGE2 and PGF2,, and less PGI2 and medulla [701 and has been examined recently in isolatedTXB2 [75—78]. Human glomeruli synthesize mainly PGI2 (deter- glomeruli, different tubular segments, interstitial cells, or cellsmined as 6 keto PGF1a,)andalso some TXB2, PGE2 and PGF2a derived from various nephron segments. [79, 80]. Localization of prostaglandin synthase by histochemical or Localization of PG synthesis within the glomerulus has been immunofluorescence methods. Localization of prostaglandinstudied using primary cultures of glomerular cells. Rat cultured synthase activity within the kidney has been performed bymesangial cells synthesize almost exclusively PGE2 [80, 811 histochemical staining for peroxidase activity [71, 72] andwhile mesangial cells from humans produce predominantly indirect immunofluorescence for cyclooxygenase [73]. BothPGI2, [82] similar to the isolated human glomerulus [83]. Rat methods have yielded remarkably similar results. In the renalglomerular epithelial cell cultures seem to have the same profile cortex of rabbit, cow, rat, sheep, and guinea pig, positiveas mesangial cells but the amount of PGs produced may be immunofluorescence for cyclooxygenase was observed in thesmaller [80, 84]. Kreisberg, Karnovsky, and Levine [85] have, endothelial cells of arteries and arterioles but not in the capil-however, reported considerable and predominant synthesis of 6 laries or venous tree [73]. Glomerular epithelial cells ofketo-PGF1, by epithelial cells in culture. The problem of Bowman's capsule stained positive in the rabbit only, whereasactually identifying the cultured cells to be of glomerular in bovine and ovine glomeruli, the fluorescence was present invisceral epithelial origin makes it difficult to assign an exact PG a mesangial distribution. Proximal tubules, the loop of Henle,profile to the epithelial cells. and distal convoluted tubules, including the macula densa, were In contrast to isolated glomeruli, cortical tubules, consisting negative by both immunofluorescence and peroxidase methodsof predominantly proximal tubules, produce very little PG [71, 72]. It should be considered, however, that the im-[76—78, 86] consistent with the absence of either peroxidase 112 Schlondorffand Ardaillou

Table 3.Factors stimulating PG synthesis in glomeruli years. The literature is extensive and shall not be reviewed in Tissue Stimulating factor Reference detail. Several excellent reviews dealing with the physiological and pathophysiological aspects of renal prostaglandins have Isolated glorneruli A23 187 16, 77 appeared. The reader is referred to them for a more extensive Angiotensin 11 76, 80, 87 treatment [I 15—I 17]. Converting enzyme inhibitor At present there is convincing evidence that prostaglandins Hydrogen peroxide 89 influence: (1) renal blood flow and glomerular filtration, (2) the Mercury chloride 90 release of , and (3) the urinary concentrating mechanism. A contribution of prostaglandins to NaCI and perhaps phos- Cultured glomerular A23 187 18 82 mesangial cells Angiotensin 11 18' 82 83' 92' 93phate and hydrogen ion handling by the kidney—independent of Vasopressin 82, 83 bloodflow—is likely, but not fully established. Finally, a role of activating factor 83, 94 prostaglandins in the control of renal erythropoeitin production Bradykinin has been postulated. Zymosan PG and the control of renal blood flow and glomerular Cultured glomerular A23 187 95 filtration. In general the importance of renal prostaglandins for epithelial cells Angiotensin II 84 the inaintenancc of blood flow and glomerular filtration can be Vasopressin 95 demonstrated only under conditions where the vasoconstrictor — systemis activated [118—119]. Similar to the vasculature in other organs PGE2 and PGI2 are vasodilators in the kidney Table 4. Factor stimulating PG synthesis in renalmedullary tissue ______[120].Occasional observed after PGE2 or PGI2 Tissue Stimulating factor Reference administration may be secondary to an increase in renin release and consequently angiotensin II formation [1211. When the Medullary slices and A 23187 14 47106107 medullary cell Vasopressin 14, 105, io formation of angiotensin II is blocked, both PGE2 and PG!2 act suspensions Angiotensin II II, 107, 109, 1 io as renal vasodilators. On the other hand, thromboxane is a Bradykinin 110 potent vasoconstrictor that also contracts isolated glomeruli Furosemide [122]. The physiological role of the vasodilatorprostaglandins is Hypertonic medium 14, 110,' 112 most likely to counteract the effect of vasoconstrictors. Renal (NaCI, mannitolj vasoconstrictors increase synthesis of vasodilatatory prosta- Isolated collecting A 23187 los glandins (see Tables 2 to 4) and thus act as a negative feedback. tubules Vasopressin 86, 105 Prostaglandins may affect renal blood flow to varying degrees Bradykinin 105 in different regions of the kidney [123, 124]. Inhibition of Cultured collecting Vasopressin 102,103 endogenous prostaglandin synthesis will preferentially decrease tubule cells Bradykinin 101, 103 medullary blood flow, possibly indicating that the high renal medullary PG synthesis maintains blood flow to this poorly Cultured renomedullary Angiotensin II 98,113 oxygenated and hypertonic region of the kidney. interstitial cells Vasopressin Prostaglandins also play a contributory role in renal autoreg- Bradykinin 98 Hypertonic medium 98, 114 ulation [125]. As modulators of renal vascular tone and mesan- gial contraction, prostaglandins also influence glomerular filtra- tion rate (GFR) [117, 121, 122, 125]. They may do so by stain or immunofluorescence for cyclooxygense in this tubularchanging the afferent and efferent arteriolar resistance [121, segment. Table 3 summarizes factors known to influence PG125], by influencing the renin-angiotensin system [117, 121, synthesis in isolated glomeruli and cultured glomerular cells. 125], and finally, by directly affecting the glomerular filtration (2) Renal medulla. In agreement with the histochemical andcharacteristics via changes in mesangial contraction [122]. The immunofluorescent studies, the major sources of PGE2 produc-glomerulus can decrease its size in response to various vasoac- tion within the medulla are collecting tubules and interstitialtive agents [122, 126], presumably by mesangial cell contraction cells. Both rabbit interstitial cells in culture [96—99] and isolated[82, 83, 94, 126—1281. This contraction is attenuated by concom- or cultured [100—103] collecting tubule cells very actively pro-itant increases in the synthesis of vasodilatory PGs [94, 122], duce PG, predominantly PGE2, and to a lesser extent, PGF2.Thus, locally produced prostaglandins may also directly influ- and PG!2. In addition the same pattern of prostaglandin synthe-ence the effective glomerular filtration surface. Micropuncture sis is observed in microdissected collecting tubules [86, 104,experiments have demonstrated that prostaglandins may also 105]. Other elements of the renal medulla, for example, the loopcontribute to tubuloglomerular feedback regulation [125]. In- of Henle, exhibit very little PG production [47, 104]. Thedeed, the local production of renin, angiotensin II and thick-ascending loop of Henle may, however, have consider-prostaglandin and their respective interactions would be suited able epoxygenase activity [45, 46]. Table 4 indicates agents that ideally for regulation of individual glomerular function. alter PG synthesis in collecting tubules and medullary intersti- The role of intrarenal prostaglandins in the maintenance of tial cells. renal blood flow and GFR is even more evident in various renal diseases. PG synthesis may contribute to maintain renal func- Physiological and pathophysiological considerations tion in patients with systemic lupus erythematosus, congestive The physiological role of prostaglandins in modifying variousheart failure, chronic renal failure, liver cirrhosis, diabetes renal functions has become increasingly apparent over the lastmellitus, volume depletion, , or old age. (For a corn- Prostaglandins and metabolites in the kidney 113

plete review of the effects of PG-synthesis inhibitors on renalsegment is central to the generation and maintenance of the function refer to [129, 130].) The possibility that imbalancesmedullary hypertonicity, these data suggest that PGE2 can also between vasodilatory PG and the vasoconstrictor thromboxaneaffect the urinary concentration mechanism by modifying the play a role in renal diseases has also been raised based onaction of vasopressin in the thick ascending limb of Henle's results with experimental unilateral ureteral obstruction [5, 6,loop. 131], acute renal failure [52, 91, 132], renal transplant rejection The major effect of PG in the concentrating mechanism is its [133], and experimental nephrotoxic serum nephritis [134].interference with the cellular mechanism of action of ADH. Changes in intraglomerular hemodynamics can significantlyStudies in the toad urinary bladder [153, 154] in segments of the influence the filtration, deposition, and subsequent handling ofthick ascending loop of Henle and in isolated collecting tubules macromolecules (for example, proteins and immune com-[151, 152, 155, 1561, and in vivo [157] have shown that PGE2 plexes) by the glomerulus [135]. Thus, vasoactive agents couldinterferes with the ADH-induced cyclic AMP generation prob- hfluence glomerular immune-injury; this process could, in turn,ably via an inhibitory subunit of the adenylate cyclase. While be modulated by intraglomerular production of PGs [94]. this effect can be shown in intact tissue, an inhibitory action of PG and the control of renin release. PGs, particularly PGE2PG on ADH-stimulated adenylate cyclase in broken cell prep- and PGI2, have been demonstrated to enhance plasma reninarations has not been uniformly found [1581. Furthermore, activity in vivo and directly increase renin release in vitro andPGE2 at concentrations of 10-6 Mandupward may even thus represent one of the multiple factors controlling renin (forincrease cellular cyclic AMP concentrations [14, 153, 1541. review, see [1361). Therefore, the possibility of an additional inhibitory action of In vitro studies showed that locally produced PGs act onPG at a site distal to the generation of cyclic AMP has been renin secretion by renal cortical preparations [1361. Stimulationpostulated [154]. Finally, it has been proposed that thrombox- of renin release also occurs in isolated glomeruli superfusedane may directly enhance vasopressin's action [159] though with arachidonic acid PGE2 or PG!2 [137], and this is blocked bythese findings remain controversial [160]. PG synthesis inhibition. The mechanism of action of PGs on The second question, that is, whether ADH directly enhances renin release seems to involve cyclic AMP as second messengerthe synthesis of prostaglandins in its target organ thereby [138] and both PGE2 and PGI2 stimulate cyclic AMP generationclosing a negative feedback loop as originally proposed by in rat [139] and human glomeruli [140]. Zusman, Keiser, and Handler [161], has resulted in some PG in the urinary concentrating mechanism. Ever since theseemingly contradictory answers. In the toad urinary bladder original observation that PGE1 inhibits the effect of antidiureticstimulation of PGE2 and thromboxane synthesis after ADH has hormone in the toad urinary bladder [1411 and in the mammalianbeen reported [159, 161]. Other groups were unable to detect a collecting tubule [142], the interaction of ADH with PG hassignificant effect of ADH on PGE2 synthesis in the toad bladder attracted much interest. Multiple studies have confirmed thator toad bladder epithelial cells [162—164]. At present it appears PGE1 and PGE2 antagonize the antidiuretic action of ADH boththat the reason for the differences may in part relate to in vitro and in vivo. [143—1451. differences in the preparation of the tissue [165, 166]. Two major questions that have attracted considerable inter- In studies with mammalian tissue, interstitial cells in culture, est are: (1) How does PG interfere with the renal concentratingmedullary slices and cell suspensions, collecting tubule cells in mechanism? (2) Does ADH directly enhance the synthesis ofculture, and microdissected collecting tubules have been used. prostaglandins in its target organ closing a negative feedbackIn medullary slices and cell suspensions ADH usually stimu- loop? lates PGE2 synthesis to some extent (see Table 4). These Concerning the first question, several possible mechanismspreparations do, however, contain both interstitial and collect- exist. PG could interfere with the renal concentrating mecha-ing tubule cells, and thus, do not allow one to attribute the nism by increasing renal medullary blood flow leading to theincrease in PGE2 synthesis to a specific cell. In primary cultures washout of solute and dissipation of the osmotic gradientof medullary collecting tubule cells ADH increased cyclic AMP required for water reabsorption. PG may also influence medul-concentration but did not stimulate PGE2 synthesis [101]. On lary solute composition by decreasing sodium transport andthe other hand, in cultures of cortical collecting tubules ADH urea accumulation in the medulla. Both of these effects could beincreased PGE2 synthesis [102, 103]. Similarly, ADH and DD independent of ADH. Consistent with this formulation, medul-AVP were found to increase PGE synthesis in isolated cortical lary NaCI concentration increases after inhibition of PG syn-collecting tubules [86]. Studies carried out in our laboratory thesis and decreases after administration of PGE2 [146, 147].indicate that some of the differences may be due to the in vitro Thus, PG could influence medullary solute composition andincubation conditions and that, under certain conditions, ADH hence urinary concentrating ability even in the absence of ADHcan increase PGE2 synthesis in both cortical and medullary [148]. Also, urea permeability of the toad urinary bladder [149]collecting tubules [105]. and the mammalian collecting tubule [150] increases after A number of points have to be considered to explain these inhibition of PG synthesis while exogenous PG decreases ureadiscrepant results. For example, PGE2 synthesis by toad uri- permeability. It has been shown that vasopressin stimulatesnary bladder, medullary slices, and isolated collecting tubules adenylate cyclase and enhances NaCI reabsorption via cyclicdecreases progressively with incubation time [14, 105, 163]. The AMP in the medullary thick ascending limb of Henle. More-absence of a stable baseline makes it difficult to unequivocably over, two laboratories independently have shown that PGE2demonstrate stimulation, unless this occurs to a very marked inhibits adenylate cyclase and NaCI reabsorption in this neph-degree. Demonstration of ADH-induced PGE2 synthesis may ron segment in a dose-dependent manner in response to vaso-be complicated further by the fact that cyclic AMP can decrease pressin [151, 152]. Since NaCI reabsorption in this nephronPG production probably by inhibiting phospholipase activity. 114 Schlendorffand Ardaillou

Based on the observation that 8 bromo cyclic AMP can inhibithas been reported [48] and will have to be examined further. PGE2 synthesis in renal medullary cells and toad bladderConceivably, the effect of PGE2 on NaCI transport observed in epithelial cells under basal and ADH-stimulated conditions, itisolated tubules may be an indirect one secondary to an has been proposed recently that ADH and PGE2 may interact ininfluence of the added PGE2 on the formation of a dual feedback loop [1661. In this scheme ADH would increasenoncyclooxygenase products. PGE2 synthesis by activating phospholipases in a cyclic AMP- Role of PG in renal phosphate excretion. Published reports independent manner as originally proposed by Zusman, Keiser,on the effects of PGs on renal phosphate transport are also and Handler [161]. The resulting increase ofPGE2 will, in turn,conflicting. Beck et al [175] showed that PGE1 alone was mildly inhibit ADH's hydroosmotic effect, to a large extent by inter-antiphosphaturic but that it markedly inhibited the phosphaturic fering with cyclic AMP generation. On the other hand, theresponse to PTH in intact dogs. In contrast, Strandhoy et al increase in cyclic AMP could inhibit phospholipase activation[1761 reported that PGE1 increased the fractional excretion of and the resulting synthesis of PGE2, representing a secondphosphate in intact dogs whereas PGE2 was inactive. In further feedback loop that would tend to prevent an overshoot of bothstudies Fragola et al [177] confirmed that PGE2 by itself had no the ADH and PGE2 effect in either direction. effect on phosphate excretion in thyroparathyroidectomized Contribution of PG to renal NaC1 excretion. Despite adogs, but abolished the phosphaturic action of PTH in vivo. considerable amount of experimental data from both in vivo andThis effect occurred only if PGE2 infusion preceded the admin- in vitro studies, the evidence for a blood-flow independent roleistration of PTH. More recently, the same group using the for prostaglandins in renal NaCI excretion remains controver-microperfusion technique showed a dual role for PGE2. PGE2, sial. In vivo, depending on the experimental conditions (forlike PTH, inhibited phosphate transport in the proximal straight example, prior NaCI content of diet, volume status, watersegment of the rabbit nephron, but also antagonized the effect diuresis, or antidiuresis, awake or anesthesia, and so forth),of PTH [178]. Taken together, these results could suggest that intrarenal administration of PGE or inhibition of renal PGthe interaction of PTH and PGE in vivo could represent tubular production has provided results that indicate: (1) renal PG dodesensitization to PTH by PGE2. not influence renal NaCI excretion; (2) PG inhibit NaCI excre- In rabbit cortical collecting tubules, Holt and Lechene [174] tion, or (3) PG increase renal NaCI excretion [115, 116, 1671.demonstrated that ADH inhibited calcium and phosphorus These conflicting results are not overly surprising as the phys-reabsorption and that pretreatment with meclofenamate iological status of the animal can alter the effect of prostaglan-blocked this effect of ADH whereas PGE2 mimicked the effect. dins on renal blood flow and its distribution. Though someFrom these studies, the authors concluded that phosphate studies attempt to minimize or exclude changes in blood flow, itreabsorption in the cortical collecting tubule may be decreased remains doubtful whether this factor can ever be eliminatedby PGE2 synthesized in response to ADH. adequately during in vivo studies. Studies using urinary PGE2 In summary some evidence supports a role for PG to inhibit excretion as an index of renal PG synthesis have occasionally,tubular phosphate transport. It should be recalled however, that but not always, shown a correlation between urinary PG andthe proximal tubule, the major site of phosphate transport, has NaCI excretion. very little capacity to produce PG [76, 77, 86]. Also to date, no Studies using the isolated perfused tubule have resultedunequivocal effect of PG inhibition on proximal tubular phos- similarly in conflicting results [1671. While several groups havephate transport has been demonstrated. shown inhibition of NaCI transport by PGE2 or PGI2 in the Role of PG in renal erythropoeitin production. A role for cortical collecting tubule [168—1 70] or the thick ascending looprenal PG in the production and release of erythropoeitin by the of Henle [171] from rabbits, another group has been unable tokidney has been postulated based on some indirect experimen- show such an effect [172, 173]. The reason for these discrepan-tal evidence [179, 180]. Unfortunately, our knowledge of the cies remains unclear and cannot be explained easily by differ-synthesis of erythropoeitin by the kidney and its control is too ences in hormonal status, basal NaCI transport, or buffers used.scanty at this point to allow a critical evaluation of this issue. If PGE2 produced by the collecting tubule inhibits NaCl trans- port, it remains unclear why inhibition of collecting tubular PG Role of prostaglandins in various renal diseases synthesis does not result in enhancement of NaCI transport. Because of the multiple contributions of prostaglandins to Holt and Lechene [1741 did, however, report that PG-inhibitionvarious renal functions, it is not surprising that abnormal prevented the vasopressin-induced changes in Na-transport inprostaglandin synthesis has been invoked to contribute to a cortical collecting tubules. Studies using simultaneous measure-variety of disease states. In cases of threatened renal function, ments of NaCI transport and PGE2 synthesis by isolated col-the enhanced PG synthesis may help to maintain renal blood lecting tubules might be helpful in resolving the role of PGE2 inflow and glomerular filtration (see Renal blood flow above). The NaCI transport by this segment. Also, it is possible thatpossible role of prostaglandins in systemic hypertension of noncyclooxygenase products of arachidonic acid influencevarious etiologies continues to attract considerable interest. NaCI transport. For example, PGE2 has been postulated toChanges in renal PG synthesis have been described in several inhibit NaCl transport in the thick ascending limb of Henle'smodels of hypertension, Again, it remains unclear whether the loop [171]. The thick ascending loop of Henle, however,changes in PG synthesis represent a primary contributing factor produces only very small amounts of prostaglandins [104, 122,or a secondary reaction [1811. 125]. On the other hand, cells from this segment seem to have Surprisingly, a possible contributory role of inhibition of a high capacity to metabolize arachidonic acid to noncycloox-prostaglandin synthesis to the etiology of analgesic nephrop- ygenase products possibly via the epoxygenase pathway [45,athy has not been investigated extensively. Nonsteroidal 661. The possibility that such products influence NaCI transportantiinflammatory drugs, all of which are PG-synthesis inhibi- Prostaglandins and metabolites in the kidney 115 tors, are, however, associated With a variety of abnormalities of References renal function [129, 130]. Abnormalities of renal PG synthesis have also been observed I. LANDS WEM: The biosynthesis and metabolism of prostaglan- dins. Ann Rev Physiol 41:633—642, 1979 in experimental hypokalemia [182—184], experimental hypercal- 2. SUN FF, TAYLOR BM, MCGLFF JC, WONG PK: Metabolism of cemia [185], and hypothyroidism [186] and were related to the prostaglandins in the kidney. Kidney mt 19:760—770, 1981 associated inability to maximally concentrate urine. However, 3. SHENG WY, WYCHE A, LYSZ T, NEEDLEMAN P: Prostaglandin these findings have been questioned [187, 188] and the urinary endoperoxide E2 isomerase is dissociated from prostaglandin concentrating defect appears independent of changes in PG endoperoxide synthetase in the renal cortex. J Biol Chem 257:14632—14634, 1982 synthesis [189, 190]. Also, a contributory role of enhanced 4. BECK TR, HA55ID A, DUNN Mi: Desamino-D-Arginine Vasopres- prostaglandin synthesis in Bartter syndrome has been discussed sin induces fatty acid cyclooxygenase activity in the renal medulla [191]. of diabetes insipidus rats. J Pharmacol Exp Ther 221:269—274, 1982 5. Nisi-iiw.s. K, MORRISON A, NEEDLEMAN P: Exaggerated Summary prostaglandin biosynthesis and its influence on renal resistance in the isolated hydronephrotic rabbit kidney. J Clin Invest This very brief summary of the various possible contributions 59:1143—1150, 1977 of PG to normal and abnormal renal function should highlight 6. MORRISON AR, MORITZ H, NEEDLEMAN P: Mechanism of enhanced the problem of assigning a specific role to PG in overall renal renal prostaglandin biosynthesis in ureter obstruction. Role of de novo protein synthesis. J Biol Chem 253:8210—8212, 1978 physiology and pathophysiology. PG produced in specific seg- 7. SCHWARTZMAN M, LIBERMAN E, RAZ A: Bradykinin and angio- ments of the nephron will affect specific functions occurring in tensin IL activation of arachidonic acid deacylation and this segment. These effects need not necessarily be reflected in formation in rabbit kidney. Hormone-sensitive the overall renal function. Also in some cases, the determinant versus hormone-insensitive lipid pools of arachidonic acid. J Biol may not be prostaglandins, that is, cyclooxygenase derivatives Chem 256:2329—2333, 1981 8. SHENG WY, LYSz TA, WYCHE A, NEEDLEMAN P: Kinetic com- of AA, but perhaps lipoxygenase or epoxygenase products that parison and regulation of the cascade of microsomal enzymes influence the functional parameters of the specific segment. involved in renal arachidonate and endoperoxide metabolism. J Despite the multitude of renal functions that may be influ- Biol Chem 258:2I88—2192, 1983 enced by PG, we would like to propose a teleological hypoth- 9. ZIPSER RD. MYERS SI, NEEDLEMAN P: Exaggerated prostaglandin and thromboxane synthesis in the rabbit with renal vein constric- esis for an overall role of PG in the kidney, that is, that of tion. Circ Res 47:23 1—237, 1980 cytoprotective agents. Renal vasodilatatory prostaglandins will 10. OKEGAWA J, DESCHRYVER EK, KAWASAKI A, NEEDLEMAN P: maintain renal blood flow when the latter is challenged, thus, Metabolic and cellular alterations underlying the exaggerated preventing hypoxic injury to the tissue. Endogenous prosta- renal prostaglandin and thromboxane synthesis in ureter obstruc- glandins may also protect tubular cells from extreme environ- tion in rabbits. J Clin Invest 71:81—90, 1983 11. BENABE JE, SPRY LA, MORRISON AR: Effect of angiotensin II on mental changes as may occur on both the luminal and phosphatidylinositol and polyphosphoinositide turnover in rat contraluminal sides. For example, tubular cells may be exposed kidney. J Biol Chem 257:7430—7434, 1982 to luminal fluid that may vary from hypotonic to hypertonic, 12. CRAVEN PA, DERUBERTIS FR: Ca2 calmodulin-dependent re- from alkaline to acid, and so forth. Similarly, the interstitial lease of arachidonic acid for renal medullary prostaglandin syn- thesis. J Biol Chem 258:4814—4823, 1983 fluid osmolality and solute composition is subject to consider- 13. CRAVEN PA, DERUBERTIS FR: Effects of vasopressin and urea on able variations which may be opposite to those existing on the Ca2 +-calmodulin-dependentrenal (abstract). Am urinary side. The role of PG might be to maintain the internal J Physiol 241:F649, 1981 milieu of the cells exposed to such extreme changes in environ- 14. CRAVEN, PA, STUDER RK, DERUBERTIS FR: Renal inner medul- ment. This could be accomplished by changing the permeability lary prostaglandin synthesis. J C/in Invest 68:722—732, 1981 15. WALENGA RW, OPAS EE, FEINSTEIN MB: Differential effects of characteristics of the membranes and the function of pumps. calmodulin antagonists on phospholipases A2 and C in thrombin- Thus, specific PGs could dampen the hormonal response to stimulated . J Biol Chem 256:12523—12528, 1981 protect the specific nephron segment, which might otherwise 16. FOLKERT VW, YUNIS M, SCHLONDORFF D: Prostaglandin synthe- suffer injury. This hypothesis might also help to explain why the sis linked to phosphatidylinositol turnover in isolated rat glomeruli. Biochim Biophys Acta 794:206—217, 1984 effect of PG administration or inhibition of PG synthesis may 17. NEEDLEMAN P, WYCHE A, BRONSON SD, HOLMBERG 5, vary considerably depending on the overall physiological state MORRISON AR: Specific regulation of peptide-induced renal of the subject: Maintenance of a local internal milieu may prostaglandin synthesis. J Biol Chem 254:9772—9779, 1979 require different responses from those required for total body 18. SCHLONDORFF D, PEREZ J, SATRIANO iA: Differential stimulation homeostasis. of PGE2 synthesis in mesangial cells by angiotensin and A23 187. Am J Physiol 248:Cl19—C126, 1985 19. MONACO ME: The phosphatidylinositol cycle in WRK-l cells. Evidence for a separate hormone-sensitive phosphatidylinosil Acknowledgments pool. J Biol Chem 257:2137—2139, 1982 Supported by a grant from the National Institute of Health AM-22036 20. BLACKWELL GJ, CARNUCCIO R, DIROSA M, FLOWER Ri, IVANJI (Schiondorif) and by the Institut National de Ia Sante et de la Recherche i, LANGHAM CSJ, PARENTE L, PERsico P, WOOD i: Suppression Medicale (Ardaillou) and by a North Atlantic Treaty Organization grant of arachidoniate oxidation by glucocorticoid-induced antiphospho- for international collaboration in research (Schlondorff and Ardaillou). lipase peptides. Adv PG. Thrombox Leukotr Res 11:65—72, 1983 We thank Mrs. G. O'Sullivan for secretarial assistance. 21. HIRATA F: Lipomodulin, a possible mediator of the action of glucocorticoids. Adv PG, Thrombox Leukotr Res 11:73—78, 1983 22. ROTHHUT B, CLOIX iF, RUSSO-MARIE F: Dexamethasone induces Reprint requests to Dr. D. Schlondorff, Room 615 UI/mann, Division the synthesis on "renocortins," two antiphospholipase proteins in of Nephrology, Department of Medicine, Albert Einstein College of rat renomedullary interstitial cells in culture. Adv PG Thrombox Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA LeukotrRes 12:51—56, 1983 116 Schlondorffand Ardaillou

23. MCGIEFJC, CROWSHAW K, TERRAGNONA,LONIGROAJ,STRA MCGIFF JC:Vasopressinstimulates -related JC,WILLIAMSONGA,LEE JB, NaKKF:Prostaglandin-like arachidonic acid metabolism in renalmedullarycells. Nature substancesappearing in caninerenal venousblood during renal 314:620—622,1985 ischemia (abstract).Circ Res 27:765, 1970 47.SCHLONDORFF D,ZANGERR,SATRIANOJA,FOLKERT VW, 24. HERMAN CA, ZENSER TV, DAVIS BB: Prostaglandin E2 produc- EVELOFFJ:Prostaglandinsynthesis by isolated cells from the tion by renal inner inedullary tissue slices, effect of metabolic outermedulla and fromthethick ascending loopof Henleof rabbit inhibitors. Prostaglandins14:679—687,1977 kidney. JPharmacol Exp Ther 233:120—124,1982 25.ZIPSERR,SPECKARETP.HAt-INJ,BOSWELL W, HORTON R: 48.JAcoBsoN HR. CORONAS.CAPDEVILLAJ,CHACOSN, MANNA S. Releaseof immunoassayable POE by the human ischaemic kid- WOMACKA,FALCKJR:5, 6epoxyicosatrienoicacidinhibits ney. JC/in Endocrinol Metab 47:914—917,1978 sodiumabsorption and potassium secretioninrabbitcortical 26. SAMUELSSON B: Leukotrienes, mediators of immediate hypersen- collectingtubule (abstract).Kidney ml25:330, 1984 sitivity reactions and . Science220:568—575,1981 49. SCHLONDORFI' D,PETTYE, OATES J,LEVINESD:Effects of 27. HAMBERG M: On the formation of and 12 5,6-epoxyeicosatrienoicacid on osmotic water flow in toad urinary L-hydrox-5,8,lO,l4 eicosatetraenoic acid in tissues from the bladder (abstract).C/in Res 33:588A,1985 guinea pig. BiochemBiophys Acta 431:651—654,1976 50. MCGIFF JC,TERRANONONA, MALIK KU,L0NIGR0AJ: Release 28. WIN0KuR TS, MORRISON AR: Regional synthesis of monohy- of a prostaglandin E-like substance from canine kidney by brady- droxy by the kidney. JBiol Chem 256:10221—10223, kinin. CircRes 31:36—42,1972 1981 51.NEEDLEMANP,BRONSONSD, WYCHE A, SIVAKOFF M, 29. JIM K, HASSID A, SUN F, DUNN MJ: Lipoxygenase activity in rat NICOLAOU KC: Cardiac and renal prostaglandin 12, biosynthesis kidney glomeruli and glomerular epithelial cells. JBio/ Chem and biological effects in isolated perfused rabbit tissues. JC/in 257:10294—10299,1982 Invest61:839—849,1978 30. SRAER J, RIGAUD M, BENS M, RABINOVITCH H, ARDAILLOU R: 52.BENABEJE, KLAHR 5, HOFFMAN MK,MORRISONAR:Produc- Metabolism of arachidonic acid via the lipoxygenase pathway in tionof by the kidney in glycerol-induced acute human and murine glomeruli. JBio/ Chem 258:4325,1983 renal failure in the rabbit. Prostag/andins19:333—347,1980 31. LIAN0S EA, DUNN Mi: Glomerular arachidonate lipoxygenation 53. MYERS SI, ZIPSER R, NEEDLEMAN P: Peptide-induced in nephrotoxic serum nephritis (abstract).Kidney mt 23:186A, prostaglandinbiosynthesis in the renal-vein-constricted kidney. 1983 BiochimJ 198:357—363,1981 32. SRAER J,BAUDL,BENSM,PODJARNYE, SCHLONDORFF D, 54.AuJW, VANE JR: Intrarenal prostaglandin release attenuates ARDAILLOU R,SRAER JD: Glomeruli cooperatewith macrophages the renal vasoconstrictor activity of angiotensin. JPharmacol Exp in converting arachidonic acid to prostaglandins and hydroxyeico- Ther 184:678—687,1981 satetraenoic acids. Prostagi,Leukotr Med 13:67—74,1984 55.FROHLICHJC,WILSONTW,SWEETMANBJ,SMIGEL M, NIES AS, 33. BAUD L, HAGEGE J, SRAFR J, RONDEAU E, PEREZ J, ARDAILLOU CARRKJ,WATSONJT,OATESJA:Urinaryprostaglandins: iden- R: Reactive oxygen production by cultured rat glomerular mesan- tificationand origin. JCl/n In vest 55:763—770,1975 gial cells during phagocytosis is associated with stimulation of 56.NEEDLEMANP. KAUFFMAN AH, DOUGLAS JR J, JOHNSON EM lipoxygenase. JExp Med 158:1836—1852,1983 JR.MARSHALL OR:Specificstimulation and inhibition of renal 34. BADR KF, BAYLIS C, PFEFFER JM, PFEFFER MA, SOBERMAN Ri, prostaglandin release by angiotensin analogs. AmJ Physio/ LEWISRA, AUSTEN KF, COREY EJ, BRENNER BM: Renal and 224:1415—1419,1973 systemic hemodynamic responses to intravenous infusion of 57.DUNNMi,LIARDJF,DRAYF:Basal and stimulated rates of renal leukotriene C4 in the rat. CircRes 54:492—499,1984 secretion and excretion of prostaglandinsE2, F2,and 13, 14 35.HAMMARSTROMS: Metabolism of leukotriene C3 in the guinea pig. dihydro-15-ketoF2in the dog. KidneyInt 13:136—143,1978 JBiol Chem 256:9573—9578,1981 58.IASAKSON PC,RAz A, DENNYSE,WYCHEA,NEEDLEMANP: 36. BERNSTROM K, HAMMARSTROM S: Metabolism of leukotriene D Hormonal stimulation of arachidonic release from isolated by porcine kidney. JBiol Chein 256:9579—9582, 1981 perfusedorgans. Relationship to prostaglandin biosynthesis. Pros- 37. APPELGREN LE, HAMMARSTROM 5: Distribution and metabolism taglandins 14:853—871,1977 of 3H-labeled leukotriene C3 in the mouse. JBiol Chem 59.C0uNA-CHoUIuoJ, McGIFF JC,MILLER MP,NASJLETTIA: 257:531—535,1982 Possible influence of intrarenal generation of kinins on 38. ELLIN A, JAKOBSSON SV, SCHENKMAN JB,ORRENIUSS: prostaglandin release from the rabbit perfused kidney. BrJ Cytochrome P450K of rat kidney microsomes, its involvement in Pharmacol 58:165—172,1976 fatty acid W- and (W-l)-hydroxylation. ArchBiochem Biophys 60. NEEDLEMAN P,DOUGLASJR. JAKSCHIK B,STOECKLEINPB, 150:64—71,1972 JOHNSONEM: Release of renal prostaglandin by catecholamines, 39. ICHIHARA K, KUSUNOSE E, KUSUNOSE M: A fatty acid W- relationship to renal endocrine function. JPharmacol Exp Ther hydroxylation system solubilized from porcine kidney cortex 188:453—460,1974 microsomes. BiochemBiophysActa239:178—189,1971 61.WALKERLA,WHORTONAR, SMIGEL M,FRANCER,FROLICHJC: 40. ZENSER TV, MATTAMMAL MB, DAVIS BB: Differential distribu- Antidiuretic hormone increases renal prostaglandin synthesis in tion of the mixed-function oxidase activities in rabbit kidneys. J vivo. AmJ Physio/ 235:Fl80—F185,1978 Pharmacol Exp Ther 207:719—725,1978 62. ZIPSER RD.MYERSSI,NEEDLEMANP:Stimulation of renal 41. NAVARO J,PIccoLo DE,KUPFER D: Hydroxylation of prostaglandinsynthesis by the pressor activity of vasopressin. by kidney cortex microsomol monooxygenase in Endocrinology108:495—499,1981 theguinea pig.ArchBiochim Biophys 191:125—133,1978 63. WALKER LA,FROLICHJC:Dose-dependentstimulation of renal 42. MORRIsON AR,PASCOE N: Metabolismof arachidonic acid prostaglandinsynthesis by deamino-8-D arginine vasopressin in through NADPH-dependentoxygenaseof renal cortex. ProcNail rats with hereditary diabetes insipidus. JPharmacol Exp Ther Acad Sci USA 78:7375—7378,1981 217:87—91,1981 43. MANN S. FALCK JR. CHACOS N, CAPDEVLLA J: Synthesis of 64. DIz Dl, BAERP0,NASJLETTIA:Effectof norepinephrine and arachidonic acid metabolites produced by purified kidney cortex renal denervation on renal POE2 andkallikrein in rats. AmJ microsomal cytochrome P-450. TetraLet 24:33—36,1983 Physiol 241:F477—F481, 1981 44. OLIw EH, OATES JA: Rabbit renal cortical microsomes metabo- 65. JoHNsLi, MURDOCK R,SINGERB:The effect of angiotensin I lize arachidonic acid to trihydroxyeicosatrienoic acids. Prosta- converting enzyme inhibitor (SQ 20881) on therelease of prosta- glandins 22:863—871,1981 glandinsby rabbitkidney, in vivo. BrJ Pharmacol 60:573—581, 45. FERRERI NR, SCHWARTZMAN M, EBRAHAN NG, CHENDER DN, 1977 MCGIFF JC: Arachidonic acid metabolism in a cell suspension 66. JOHNSTONPA,BERNARDDB,PERRINNS,LEVINSKYNG:Pros- isolated from rabbit renal outer medulla. JPharm Exp Therap taglandins mediate thevasodilatory effect of mannitol in the 231:441—448,1984 hypoperfused rat kidney. JCl/n Invest 68:127—133,1981 46. SCHWARTZMAN M, FERRaRI NR, CARROL MA, SONGU MIZE E, 67.OLSEN UB: Perfusion rate dependent prostaglandin release from Prostaglandins and metabolites in the kidney 117

isolated rabbit kidneys. Prostaglandins15:645—649,1978 91. SRAER JD, MOULONGUET-DOLERIS L, DELARUE F, SRAER J, 68. NEEDLEMAN P, MINKES MS, DOUGLAS JR JR: Stimulation of ARDAILLOU R: Prostaglandin synthesis by glomeruli isolated from prostaglandin biosynthesis by adenine nucleotides. Profile of rats with glycerol-induced acute renal failure. CircRes prostaglandin release by perfused organs. CircRes 34:455—462, 49:775—783,1981 1974 92. SRAER J, FOIDART J, CHANSEL D, MAHIEU P, ARDAILLOU R: 69. JACKSON ED, GERKENS JF, BRASH AR, BRANCH RA: Acute renal Prostaglandin synthesis by rat isolated glomeruli and glomerular artery constriction increases renal prostaglandin '2biosynthesis cultured cells. mtjBiochem12:103—107,1980 and renin release in the conscious dog. JPharmacol Exp Ther 93. UGLESITY A, KREISBERG JI, LEVINE L: Stimulation of arachi- 222:410—413,1982 donic acid metabolism in rat kidney mesangial cells by bradykinin, 70. LARSSON C, ANGGARD E: Regional differences in the formation antidiuretic hormone and their analogues. ProstagLeukotr Med and metabolism of prostaglandins in the rabbit kidney. EurJ 10:83—93,1983 Pharmacol 21:30—36,1973 94. SCHLONDORFF D, SATRIANO JA, HAGGEGE J, PEREZ J, BAUD L: 71. JANSZEN FHA, NUGTEREN DH: Histochemical localization of Effect of platelet-activating factor and serum-treated zymosan on prostaglandin synthetase. Histochemie27:159—164,1971 prostaglandin E2 synthesis, arachidonic acid release, and contrac- 72. CAVALLO T: Cytochemical localization of endogenous peroxidase tion of cultured rat mesangial cells. JClin Invest 73:1227—1231, activity in renal medullary collecting tubules and papillary mucosa 1984 of the rat. Labinvest 34:223—228,1976 95. LIEBERTHAL W, LEVINE U: Stimulation of prostaglandin produc- 73. SMITH WL, BELL TG: Immunohistochemical localization of the tion in rat glomerular epithelial cells by antidiuretic hormone. prostaglandin-forming cyclooxygenase in renal cortex. AmJ Phys- KidneyIn! 25:766—770,1984 iol 235:F451—F457,1978 96. MUIRI-IEAD EE, GERMAIN G, LEACH BE, PITCOCK JA, 74. TERRAGNO NA, TERRAGNO A, EARLY JA, ROBERTS MA, MCGIFF STEPHENSON P, BROOKS B, BRO5IUs WL, DANIELS EG, KINMAN JC: Endogenous prostaglandin synthesis inhibitor in the renal JW: Production of renomedullary prostaglandins by renomedul- cortex. ClinSci Mol Med 55(suppl4): 199s—202s, 1978 lary interstitial cells grown in tissue culture. CircRes 30—31(suppl 75. FOLKERT VW, SCHLONDORI'F D: Prostaglandin synthesis in iso- II):161s—172s, 1972 lated glomeruli. Prostaglandins17:79—86,1979 97. DUNN MJ, STALEY RS, HARRISON M: Characterization of 76. SCHLONDORFF D, ROCZNIAK S, SATRIANO JA, FOLKERT VW: prostaglandin production in tissue culture of rat renal medullary Prostaglandin synthesis by isolated rat glomeruli, effect of angio- cells. Prostaglandins12:37—49,1976 tensin II. AmJ Physiol 239:F486—F495,1980 98. ZUSMAN RM, KELSER HR: Prostaglandin biosynthesis by rabbit 77. HASSID A, KONIECZKOWSKI M, DUNN MJ: Prostaglandin synthe- renomedullary interstitial cells in tissue culture. Stimulation by sis in isolated rat kidney glomeruli. ProcNail Acad Sci USA angiotensin II, bradykinin, and arginine vasopressin. JClin invest 76:1155—1159,1979 60:215—223,1977a 78. SRAER J, SRAER JD, CHANSEL D, RUSSO-MARIE F, 99.BECK TR,HASSIDA, DUNN MJ:The effectof arginine vasopressin KOUZNETZOVA B, ARDAILLOU R: Prostaglandin synthesis by andits analogs on the synthesis of prostaglandin E2 by rat renal isolated rat renal glomeruli. MolCell Endocrinol 16:29—37,1979 medullary interstitial cells in culture.JPharmacol Exp Ther 79. STAHL RA, PARAVICINI M, SCHOLLMEYER P: Angiotensin 11 215:15—19,1980 stimulation of PGE2 and 6 keto PGF1,. formation by isolated 100.BOHMAN SO: Demonstration of prostaglandin synthesis in collect- human glomeruli. Kidneymt 26:30—34,1984 ing duct cells and other cell types of the rabbit renal medulla. 80. SRAER J, FOIDART J, CHANSEL D, MAHIEU P, KOUZNETZOVA B, Prostaglandins14:729—744,1977 ARDAILLOU R: Prostaglandin synthesis by mesangial and epithe- 101. GRENIER FC, ROLLINS TE, SMITH WL: Kinin-induced hal glomerular cultured cells. FEBSLeti 15:420—424,1979 prostaglandin synthesis by renal papillary collecting tubule cells in 81. SCHARSCHMIDT LA, DUNN MJ: Prostaglandin synthesis by rat culture. AmJ Physiol 24l:F94—F104,1981 glomerular mesangial cells in culture. Effects of angiotensin II and 102. GARCIA-PEREZ A, SMITH WL: Use of monoclonal to arginine vasopressin. JClin invest 71:1756—1764,1983 isolatecortical collecting tubule cells: AVP induces PGE release. 82. ARDAILLOU N, HAGEGE Y, NIvEz MP, ARDAILLOU R, AmJ Physiol 244:C211—C220,1983 SCHLONDORFF D: Vasoconstrictor-evoked prostaglandin synthe- 103.GARCIA-PEREZA, SMITH WL: Apical-basolateral membrane sisincultured human mesangial cells. AmJ Physiol asymmetryin canine cortical collecting tubule cells. JClin Invest 248:F240—F246,1985 74:63—74,1984 83. SRAER J, ARDAILLOU N, SRAER JD, ARDAILLOU R: In vitro 104. JACKSON BA, EDWARDS RM, DousA TP: Vasopressin- prostaglandin synthesis by human glomeruli and papillae. Prosta- prostaglandin interactions in isolated tubules from outer medulla. glandins 23:855—864,1983 JLabCliii Med96:119—128, 1980 84. PETRULIS AS, AIKAWA M, DUNN MJ: Prostaglandin and throm- 105. SCHLONDORFF D, SATRIANO JA, SCHWARTZ GJ: Synthesis of boxane synthesis by rat glomerular epithelial cells. Kidneymt prostaglandin PGE2 in different segments of isolated collecting 20:469—474,1981 tubules from adult and neonatal rabbits. AmJ Physiol 85.KREISBERGJI, KARNOVSKY MJ, LEVINE L: Prostaglandin produc- 248:Fl34—Fl44,1985 tion by homogenous cultures of rat glomerular epithelial and 106.ZENSERTV, HERMAN CA, DAVIS BB: Effectsof calcium and mesangial cells. Kidneymt 22:355—359,1982 A23187 on renal inner medullary prostaglandin E2 synthesis. AmJ 86. KIRSCHENBAUM MA, LOWE AG, TRIZNA W, FINE LG: Regula- Physiol 238:E371—E376,1980 tion of vasopressin action by prostaglandins. Evidence for 107.KNAPPHR, OELZ 0, ROBERTS U, SWEETMAN BJ, OATES JA, prostaglandin synthesis in the rabbit cortical collecting tubule. J REED P: lonophores stimulate prostaglandin and thromboxane Clin invest 70:1193—1204,1982 synthesis. ProcNatl Acad Sci USA 74:4251—4255,1977 87. FOLKERT VW, SCHLONDORFF D: Altered prostaglandin synthesis 108. KALISKER A, DYER DC: In vitro release of prostaglandins from the by glomeruli from rats with unilateral ureteral ligation. AmJ renalmedulla. JPharmacol 19:305,1972 Physiol 241:F289—F299, 1981 109.DANON A, CHANG LC, SWEETMAN BJ, NIES AS, OATES JA: 88. GALLER M, BACKENROTH R, FOLKERT VW, SCHLONDORFF D: Synthesis of prostaglandins by the rat renal papilla in vitro. Effect of converting enzyme inhibitors on prostaglandin synthesis Mechanism of stimulation by angiotensin II. BiochimBiophys by isolated glomeruli and aortic strips from rats. JPharmacol Exp Ada 388:71—83,1975 Ther 220:23—28,1982 110. DANON A, KNAPP HR. OELZ 0, OATES JA: Stimulation of 89. BAUD L, NIVEZ MP, CHANSEL D, ARDAILLOU R: Stimulation by prostaglandin biosynthesis in the renal papilla by hypertonic oxygen radicals of prostaglandin production by rat renal mediums.AmJ Physiol 234:F64—F67,1978 glomeruli. Kidneymt 20:332—339,1981 111. CRAVEN PA, DERUBERTIS FR: Calcium-dependent stimulation of 90. SRAER JD, BAUD L, SRAER J, DELARUE F, ARDAILLOU R: Stimulation renal medullary prostaglandin synthesis by furosemide. JPharm of PGE2 synthesis by mercuric chloride in rat glomeruli and glomerular Exp Ther 222:306—314,1982 cells in vitm. Kidneymt 21:563—568,1982 112.ZENSER TV, LEVITT MJ, DAVIS BB: Effect of oxygen and solute 118 Schlondnrffand Ardai/lou

on PGEand PGF productionby rat kidney slices. Prostagandins 137. BEIERWALTESWH,SCHRYVERS.SANDERSE, STRAND J, 13:143—151,1977 ROMEROIC:Reninrelease selectively stimulated by prostglandin 113. BROWNCA,ZUSMANRM,HABERF:Identification of an angio- 12 in isolated rat glomeruli. A,nJ Physiol 243:F276—F283,1982 tensinreceptor in rabbit renomedullary interstitial cellin tissue 138. WEBERP. LARSSON E, ANGGARD E, HAMBERG M,COREYE, culture.Correlation with prostaglandin biosynthesis. CircRes NICOLAOUC, SAMUELSSON B: Stimulation of renin release from 46:802—807,1980 rabbit renal cortex by arachidonic acid and prostaglandin 114. ZUSMANRM,KEIsERFIR:Regulationof prostaglandin E2synthe- endoperoxides. CircRes 39:868—874,1976 sis by angiotensin 11, potassium, osmolality and dexarnethasone. 139.SCHLONDORFF D, Yoo P. ALPERT BE: Stimulation of adenylate Kidneymt 17:277—283,1980 cyclasein isolated rat glomeruli by prostaglandins AmJ Physiol 115.HORTON R, DUNN Mi: Prostaglandins and the kidney. Miner 235:F458—F464,1978 Electrolyte Metab 6-5—90, 1981 140. FRIEDLANDERG. CI-IANSEL D,SRAERJ,BENSM,ARDAILLOUR: 116.DUNN Mi: Renal prostaglandins, in ContemporaryIVephrology, PGE2 Binding sites andPG-stimulated cyclic AMP accumulation editedby KLAI-IR S, MASSEY SG, New York, London. Plenum inrat isolated glomeruli andglomerular cultured cells. MolCell Medical Book Company, 1983, pp 145—192 Endocrinol 30:20l—2l4,1983 117. DWORKIN LD, ICHIKAWA I, BRENNER BM: Hormonal modulation 141. ORLOFFJ,HANDLERIS, BERGSTROM S:Effect of prostaglandin of glomerular function. AmJ Physiol 244:F95—Fl04,1983 PGE on the permeabilityresponse of toad bladder to vasopressin, 118. I-IENRJCHWL, BERLT,MCDONALDKM. ANDERSON Ri,SCHELER theophylline and adenosine 3',5'-monophosphate, Nature(Lon- RW: Angiotensin II, renal nerves and prostaglandins in renal hemody- don) 205:397—398,1965 naniics during hemorrhage. AmJ Physiol23S:F46-.F51, 1978 142.GRANTHAM JJ, ORLOFF J: Effects of prostaglandin E1 on the 119.OLIVER JA, SciAccA RB, PINTo J, CANNON P1: Participation of permeability response of the isolated collecting tubule to vaso- the prostaglandins in the control of renal blood flow during acute pressin, adenosine 3'S'-nionophosphate, and theophylline. JC/in reduction of cardiac output in the dog (abstract).J C/in Invest Invest 47:1154—I161, 1968 67:229,1981 143. GROSS PA,SCHRIERRW. ANDERSON RJ: Prostaglandins and 120. JACKSON EK, HEIDEMANN HT, BRANCH RA, GERKENS JF: Low watermetabolism: A review with emphasis on in vivo studies dose intrarenal infusions of PGE2, PGI2 and 6-keto-PGE1 vasodi- (abstract).Kidney tnt 19:839,1981 late the in vivo rat kidney. CircRes51:67—72, 1982 144. HANDLERiS: Vasopressin-prostaglandin interactions in the regu- 121. SCHOR N, IcHIKAwA 1, BRENNER BM: Mechanisms of action of lation of epithelial cell permeability to water(abstract). Kidney In! various hormones and vasoactive substances on glomerular ultra- 19:831,l98l filtration in the rat (abstract).Kidney mt 20:442,1981 145. STOKES JB: Integrated actions of renal medullary prostaglandins 122. SCHARSCLIMIDT LA, LIANOS E, DUNN Mi: Arachidonate metab- in the control of water excretion (abstract).Am J Physio/ olites and the control of glomerular function. FedProc 240:F47l,1981 42:3058—3063,1983 146.GANGULIM, TOBIAN L, AZAR S,O'DONNELLM: Evidence that 123.KIRSCHENBAUM MA, WHITE N, STEIN JH, FERRIS TF: Redistri- prostaglandin synthesis inhibitors increase the concentration of bution of renal cortical blood flow during inhibition of sodium and chloride in rat renal medulla. CircRes 40:1135—1139, prostaglandin synthesis. AmJ Physiol 227:801—805,1974 1977 124. BILL A: Effects of indomethacin in regional blood flow in con- 147.HAYLOR J.LOTECJ:The influence of prostaglandinE2and scious rabbits—a microsphere study. ActaPhysiol Scand indomethacinon the renal corticomedullary solute gradient in the 105:437—442,1979 rat.JPharmaco/ 35:299—305,1983 125. SCHNERMAN I, BRIGGS JP,WEBERPC:Tubuloglomerularfeed- 148.WALKER RM, BROWN RS, STOFF iS: Role of renal prostaglandins back, prostaglandins and angiotensin in the of during antidiuresis and water diuresis in man. KidneyInt glomerular filtration rate. Kidneytnt 25:53—64, 1984 21:365—380, 1981 126. SRAER J, SRAER JD, ARDAILLOU R, MIMOUNE D: Evidence for 149.CARVOUNIS CP, FRANKI N,LEVINESD,HAYSRM: Membrane renal glomerular receptors for angiotensin 11. Kidneymt pathways for water and solutes in the toad bladder. I. Independent 6:241—246,1974 activationof water and urea transport. JMembr Biol 49:253—268, 127.MAHIEU PR, FOIDART JB, DUBOIS CH,DECHENNECA, DENEFFE 1979 J: Tissue culture of normal rat glomeruli. contractile activity of the ISO. ROMANRI,LECHENEC: Prostaglandin E2reducesurea reabsorp- cultured mesangial cells. InvestCell Pathol 3:121—128,1980 tion from the rat collecting duct (abstract).Am J Physiol 241:F53, 128. AUSIELLO DA, KREISBERG ii, ROY C, KARNOVSKY Mi: Contrac- 1981 tion of cultured rat glomerular cells of apparent inesangial origin 151.CULPEPPERRM,ANDREOLITE:Interactions among prostaglandin after stimulation with angiotensin 11 or arginine vasopressin. JC/in E2, antldiuretic hormone and cyclicadenosine monophosphate in Invest 65:754—760,1980 modulating Cl absorption in single mouse rnedullary limbs of 129. CLIVE DM, STOFF IS: Renal syndromes associated with nonsteroidal Henle. JC/in Invest 71:1588—1601,1983 anti-inflammatory drugs. New EngIJ Med 310:563—572, 1984 152. TORIKAI S,KUROKAWAK: Effect of PGE2 on vasopressin- 130.DUNN Mi, ZAMBRASKI EJ: Renal effects of drugs that inhibit dependent cell cAMP in isolated single nephron segments. AmJ prostaglandin synthesis. Kidneymt 18:609—622,1980 Physio/ 245:F58—F66,1983 131.YARGER WE, SCHOCKEN DD, HARRIS RH: Obstructive nephrop- 153. OMACI-II RS,ROBBIEDE, HANDLER iS,ORLOFFJ:Effects of athy in the rat. Possible roles for the renin-angiotensin system, ADHand other agents on cyclic AMP accumulation in toad prostaglandins and in post-obstructive renal func- bladderepithelium. AmJ Physiol 226:1152—1157,1974 tion. JClin Invest 65:400—412,1980 154.SCHLONDORFF D,CARVOUNISCP,JACOBYM,SATRIANOJ,LEVINE 132.TORRESUE, STRONG CU, ROMERO JC, WILSON DM: Indometh- SD:Multiple sites forinteraction of prostaglandin and vasopressin in acm enhancement of glycerol-induced acute renal failure in rab- toad urinary bladder. AmJ Physiol 241:F625—F631, 1981 bits. Kidneytnt 7:170—178,1975 155.MOREL F,IMBERT-TEBOULM, CI-IABARDES D: Cyclic nucleotides 133. FOEGH ML,ZMUDKAM,COOLEYC,WINCHESTERJF,HELFRICII and tubule functions (abstract).Adv Cyclic Nuc/ Res 12:301,1980 GB,RAMWELLPW: Urine i- TXB2 in renal allograft156. rejectionEDWARDSRM,1ACK50NBA,DOUSATP:ADH-sensitivecAMP (abstract).Lancet 2:431,1981 systemin papillary collecting duct and effect of osmolality and 134. LIANOS EA, ANDRES GA, DUNN MJ: Glomerular prostaglandin PGE2.Amf Physiol 240:F311—F3l8,1981 and thromboxane synthesis in rat nephrotoxic serum nephritis. 157. LUM GM, AISENBERG GA, DUNN Mi,BERL T, SCHRIERRW, Effects on renal hemodynamics. JC/in Invest 72:1439—1448,1983 MCDONALD KM:In vivoeffect of indomethacin to potentiate the 135. STEIN HD, FEDDERGREEN W, KASHGARIANM,STERZELRB: Role of renal medullary cyclic AMP response to vasopressin. JC/in Invest angiotensin 11-induced renal functional changes in mesangial deposition 59:8—13, 1977 of exogenous ferritin in rats. LabInvest 490:270—280,1983 158.DOUSA TP, NORTHRUP TE:Cellular interactions between vaso- 136.HENRICHWL: Role of the prostaglandins in renin secretion. pressinand prostaglandins in the mammalian kidney. Contrib KidneyIn! 19:822, 1981 Nephrol 12:106—115,1978 Prostaglandins and metabolites in the kidney 119

159. BURCH RM, HALUSHKA PV: Thromboxane and stable JB, DAVIS BB: Effect of prostaglandin E1 on certain renal actions prostaglandin endoperoxide analogs stimulate water permeability of parathyroid hormone (abstract). J C/in Invest 51:2352, 1972 in the toad urinary bladder (abstract). J C/in Invest 66:1251, 1980 176.STRANDHOY JW, OTT CE, SCHNEIDER EG, WILLIS LR, BECK 160. LUDENS JH, TAYLORCJ:Inhibition of ADH-stimulated water flow NP, DAVIS BB, KNOX FG: Effects of prostaglandins E1 and E2 on by stable prostaglandin endoperoxide analogues. Am J Physiol renal sodium reabsorption and Starling forces. Am J Physio/ 242:Fl19—F125, 1982 226:1015—1021,1974 161. ZUSMAN RM, KEISERHR,HANDLER JS: Vasopressin-stimulated 177.FRAGOLA J, PUSCHETT JB, DOMINGUEZ JH, CHAN TC: Inhibition prostaglandin E biosynthesis in the toad urinary bladder. J C/in of the renal tubular effects of PTH on phosphate transport by Invest 60:1339—1347, 1977 PGE2. Endocrinology 109:2267—2269,1981 162. WONGPYD,BEDWANIJR,CUTHBERT AW: Hormone action and 178. DOMINGUEZ JH, PITT5 TO, BROWN T, PUSCHETT DB, SCHULER the levels of cyclic AMP and prostaglandins in the toad bladder. F, CI-IEN TC,PUSCHETTJB: PGE2 and parathyroid hormone: Nature New Bio/ 238:27—3 1, 1972 comparison of their actions on the rabbit proximal tubule. Kidney 163. BI50RDI JE, SCHLONDORFF D, HAYS RM: Interaction of vaso- mt 26:404—410,1984 pressin and prostaglandins in the toad urinary bladder. J C/in 179.ARCE JM, NAUGHTON BA, K0LK5 GA, LIu P, GORDON AS, Invest 66:1200—1210,1980 PILIEROSJ: The effect of prostaglandins on erythropoiesis. Pros- 164.FORREST iN, SCHNEIDER CT, GOODMAN DBP: Role of tag/andins 21:367—377, 1981 prostaglandin E2 in mediating the effect of pH on the hydroosmotic 180. RADTKE HW, JUBIZ W, SMITH JB, FISHERJW: Albuterol-induced response to vasopressin in the toad urinary bladder (abstract). J erythropoietin production and prostaglandins release in the iso- C/in Invest 69:499, 1982 lated perfused dog kidney. J Pharmacol Exp Ther 214:467—471, 165.BURCH RM, HALUSHKA PV: Vasopressin stimulates prostaglandin 1980 and thromboxane synthesis in toad bladder epithelia cells. Am J 181. SMITH MC, DUNN MJ: Renal kallikrein, kinins and prostaglandins Physiol 243:F593—F597, 1982 in hypertension, in Hypertension, edited by BRENNER B, STEIN J, 166. SCHLONDORFF D, SATRIANO JA: Interaction of vasopressin, New York, Churchill Livingston, 1981, p 168 cAMP and prostaglandins in toad urinary bladder. Am J Physio/ 182. GALVEZ OG, BAY WH, ROBERTS BW, FERRIS TF: The hemody- 248:F454.-.F458,1985 namic effects of potassium deficiency in the dog. Circ Res 40:1—Il, 167.KOKKO JP: Effect of prostaglandins on renal epithelial electrolyte 1977 transport. Kidney Int 19:791—796, 1981 183. ATTALLAHAA, STAHL RA, BLOCH DL, AMBRUS JL, LEE J' 168. STOKES JB, K0KK0 JP: Inhibition of sodium transport by Inhibition of rabbit renal prostaglandin E2 biosynthesisby chronic prostaglandin E2acrossthe isolated, perfused rabbit collecting potassiumdeficiency. J Lab C/in Med 97:205—212, 1981 tubule. J C/in Invest 59:1099—1104, 1977 184.BECKN, SHAW JO: Thromboxane B2 and prostaglandin E2 in the 169. IlNo Y, IMAI M: Effects of prostaglandins on Na transport in K-depleted rat kidney. Am J Physiol 240(2):F151—F157, 1981 isolated collecting tubules. Pflugers Arch 373:125—132, 1978 185. SERROS ER, KIRSCHENBAUM MA: Prostaglandin-dependent poly- 170. IlNo Y, TROY J, BRENNER BM: Influence of prostacyclin (PGI2) on uria in hypercalcemia. Am J Physiol 24l:F224—F230,1981 transepithelial potential difference (PD) in isolated perfused rabbit 186. ZENSER TV, ROBINSON AG, SElF SM, DAVIS BB: Impaired inner cortical collecting tubule (CCT) (abstract). Kidney Int 16:822, medullary production of prostaglandin E2 in the kidney of the 1979 myxedematousrat. Endocrinology102:884—888,1978 171. STOKES JB: Effect of prostaglandin E2 on chloride transport across 187. HooD VL, DUNNMJ:Urinary excretion ofprostaglandin F2_ in the rabbit thick ascending limb of Henle. Selective inhibition of potassium-deficient rats. Prostaglandins15:273—280,1978 the medullary portion. J C/in Invest 64:495—502, 1979 188. DUSINGR,ATTALLAHAA,PREZYNAAP,LEEJB: Renal biosyn- 172. FINE LG, TRIZNA W: Influence of prostaglandins on sodium thesis of prostaglandin E2and F2 alpha, dependence on extracel- transport of isolated medullary nephron segments. Am J Physiol lularpotassium. J Lab C/in Med 92:669—677,1978 232:F383—F390, 1977 189. BERL T, AISENBREY GA, LINAS SL: Renal concentrating defect in 173. FINE LG, KIRSCHENBAUM MA: Absence of direct effects of the hypokalemic rat is prostaglandin independent. Am J Physiol prostaglandins on sodium chloride transport in the mammalian 283:F37—F41, 1980 nephron. Kidney Int 19:797—801, 1981 190. BERL T,ERICKSONAE: Calcium-prostaglandin interaction on the 174. HOLT WF, LECHENE C: ADH-PGE2 interactions in cortical col- action of antidiuretic hormone in the dog (abstract). Am J Physiol lecting tubule. I. Depression of sodium transport. Am J Physio/ 242:F313,1982 241:F452—F460,1981 191. DUNNMi:Prostaglandins and Bartter's syndrome.Kidney mt 175.BECK NP, DERUBERTIS FR, MICHELIS MF, Fusco RO, FLELD 19:86—102,1981