Effects of Adrenergic Nervous System and Catecholamines on Systemic and Renal Hemodynamics, Sodium and Water Excretion and Renin Secretion

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Kidney International, Vol. 6 (1974), p. 291—306

Effects of adrenergic nervous system and catecholamines on systemic and renal hemodynamics, sodium and water excretion and renin secretion

ROBERT W. SCHRIER

Department of Medicine, University of Colorado Medical Center, Denver, Colorado

The influences of the adrenergic nervous system on tion to the direct cardiac effect, in the increase in various organ systems in the body are protean. No cardiac output during i.v. administration of isopro- attempt will be made in this review to survey these terenol. On the other hand, if the rise in cardiac output many effects; but rather the focus will be on the specific during infusion of isoproterenol increases arterial influences that adrenergic tone and catecholamines blood pressure, then the fall in peripheral vascular re- exert on systemic and renal hemodynamics, the excre- sistance may be mediated both by the direct peripheral tion of sodium and water excretion and the secretion of vascular effect of the agonist and the baroreceptor- renin. Where possible, emphasis will be placed on the mediated reflex vasodilatation. Thus, several inter- integration of these functions intoa teleologically orien- related influences occur as a result of systemic ted system of control of systemic hemodynamics and of beta-adrenergic stimulation and the summation of body fluid volume and composition, including the im- these influences may result in different effects on mean plications for the pathogenesis of disease states. arterial blood pressure. In some instances isoproterenol Effect of adrenergic nervous system and catecho- administration may increase mean arterial pressure lamines on systemic and renal hemodynamics. The as a result of the predominant effect of the drug to endogenous catecholamines, norepinephrine and epine- increase cardiac output. In other circumstances the phrine, each exert a combination of alpha- and beta- peripheral vasodilatation associated with i.v. ad- adrenergic effects and the use of specific receptor ministration of isoproterenol may predominate and blocking agents has allowed pharmacological separa- cause a diminution in mean arterial pressure. In still tion of these two properties. When appropriate, there- other situations, the relative effect of beta-adrenergic fore, the separate effects of alpha- and beta-adrenergic stimulation to increase cardiac output and decrease stimulation will be discussed. peripheral vascular resistance may be such that arterial The primary cardiovascular effect of beta-adrener- pressure is unchanged. The extent to which either of gic stimulation relates to its inotropic and chrono- these effects of beta-adrenergic stimulation on syste- tropic action on the heart [1]. The increase in cardiac mic arterial pressure predominate appears to be related, output associated with the beta-adrenergic agonist, at least in part, to the amount of the stimulating agent isoproterenol, therefore is due to a rise in both heart administered. Because of these extrarenal effects of rate and stroke volume. An increase in 3'5'-adenosine beta-adrenergic stimulation on cardiac output and monophosphate (cyclic AMP) appears to be the intra- peripheral vascular resistance, it is difficult to isolate cellular hormonal mediator (secondary messenger) of the intrarenal effects of beta-adrenergic stimulation the increase in stroke volume produced by isopro- during the i.v. administration of these agonists. For terenol [2]. Beta-adrenergic stimulation has also been example, although i.v. administered isoproterenol demonstrated to exert a vasodilatory effect on the decreases total peripheral resistance, renal vascular peripheral vasculature [1]. This decrease in total peri- resistance may be unchanged or even increased if the pheral resistance may be a determining factor, in addi- net effect of the drug is to lower arterial pressure [3]. In this circumstance, the baroreceptor-mediated in- © 1974, by the International Society of Nephrology. crease in renal sympathetic tone may obscure any 292 Schrier direct intrarenal effect that isoproterenol may have to long t.4 value of this agent so that its accumulation may decrease renal vascular resistance. Since none of the lead to extrarenal hemodynamic alterations which known adrenergic agents exerts selective effects on the could obscure any intrarenal effects of beta blockade. kidney, neither the systemic administration of the In contrast to beta-adrenergic stimulation, changes agents nor the systemic blockade of their action per- in alpha-adrenergic tone definitely appear to exert mits delineation of any direct effects on the kidney. major physiological effects on renal hemodynamics. Moreover, due to the prolonged action of most beta- Norepinephrine, the adrenergic neurohumoral trans- and aipha-adrenergic blocking agents, systemic effects mitter, is primarily an alpha-adrenergic agonist; there- are observed even when these blocking agents are ad- fore, increases in renal sympathetic tone produce ministered into a renal artery. A selective intrarenal vasoconstriction of the renal vasculature. It appears adrenergic blockade, therefore, has been difficult to that several renal vascular sites for alpha-adrenergic obtain; thus, the intrarenal infusion of beta- and stimulation exist including the afferent and efferent alpha-adrenergic agonists has been the primary mode arterioles as well as the venules. With marked adren- of delineating the intrarenal effects of adrenergic ergic stimulation, an increase in renal vascular resist- stimulation. ance no doubt occurs as a result of vasoconstriction at In contrast to the effects of beta-adrenergic stimula- all of these locations and the result is a decrease in both tion, the primary cardiovascular effect of alpha- glomerular filtration rate and renal blood flow. Intra- adrenergic stimulation is vasoconstriction of the peri- renally administered norepinephrine and renal nerve pheral arterioles and venules [1]. This increase in stimulation, however, may exert a preferential vaso- peripheral vascular resistance results in an increase in constrictor effect on the efferent arteriole so that the arterial pressure which also may be secondarily modi- fall in glomerular filtration rate is less than the decrease fied by reflex changes in arterial baroreceptor tone. As in renal blood flow; thus, filtration fraction increases. with beta-adrenergic agonists, the intrarenal effect of With modest doses of norepinephrine, either infused alpha-adrenergic stimulation is best defined by direct i.v. or into the renal artery, mild constriction of the infusion of the agonist into the renal artery. Norepine- afferent arteriole may be counterbalanced by sufficient phrine possesses both alpha- and beta-adrenergic constriction of the efferent arteriole so that glomerular stimulating properties; therefore, the intrarenal alpha- filtration rate is maintained constant although renal adrenergic effect of the substance is best observed in blood flow decreases [12]. The counterpart of this the presence of beta-adrenergic blockade. Since the effect may occur during beta-adrenergic stimulation kidney has been demonstrated to be an effective site of with isoproterenol in which preferential vasodilatation inactivation of catecholamines, including isoproterenol of the efferent arteriole leads to a rise in renal blood [4] and norepinephrine [5], intrarenal effects of these flow as glomerular filtration rate remains constant agents can be produced in the absence of either syste- [6]. mic effects or effects in the contralateral kidney. The effect of alpha-adrenergic stimulation to con- Evidence has been obtained that the kidney possesses strict renal venules is another component of the in- both alpha- and beta-adrenergic receptors. The intra- crease in renal vascular resistance and, in the presence renal infusion of the beta-adrenergic agonist, isoprote- of drug-induced renal vasodilatation, may be primarily renol, has been demonstrated to produce vasodilata- responsible for the observed increase in deep renal tion of the kidney [6]. In quantitative terms this effect venous pressure with a norepinephrine infusion [13]. of isoproterenol appears to be less potent than other In addition to these renal vasoconstrictor effects of renal vasodilators such as acetylcholine [7, 8], brady- alpha-adrenergic stimulation, there have been reports kinin [7, 8] and prostaglandin E1 [9]. In the presence of that aipha-adrenergic stimulation may not produce the beta-adrenergic blocker, propranolol, large doses homogeneous vasoconstriction throughout all of the of isoproterenol can be associated with renal vasocon- nephrons. Using the 85krypton washout method, striction, an alpha-adrenergic effect [6]. Whether Pomeranz, Birtch and Barger [14] suggested that renal either the intrarenal beta- or aipha-adrenergic effect of nerve stimulation induced either by bilateral carotid isoproterenol is of physiological importance remains ligation or splanchnic nerve stimulation decreased to be determined. In this regard, the intrarenal infusion outer cortical and increased medullary blood flow. In of the beta-blocking agent, propranolol, has not been contrast to these results, estimation of renal blood dis- found to produce any detectable unilateral alterations tribution by investigators using radioactive micro- in renal hemodynamics in anesthetized dogs which are spheres has failed to demonstrate any effect of renal known to have an increase in renal sympathetic tone nerve stimulation [15] or norepinephrine infusion [16] [11]. The interpretation of these results must be tem- to redistribute renal cortical blood flow. However, pered, however, by the knowledge of the relatively several investigators using either the inert gas or radio- Responses to adrenergic stimulation 293 active microsphere method have found a decrease in jects the same dose of metaraminol exerts profound outer cortical blood flow during hemorrhage [15—18]. renal vasoconstriction so that glomerular filtration Norepinephrine has been suggested to be important in rate and renal blood flow decrease. On the other hand, this effect of hemorrhage on cortical blood flow but the renal vasodilatation which accompanies volume attempts to reverse this redistribution with alpha- expansion is much more pronounced in patients with adrenergic blockade have produced conflicting results essential hypertension and increased renal vascular [15, 17, 18]. The results of recent studies using the resistance than in normal subjects [25]. The exagger- radioactive microsphere technique suggest that the ated response of arterial pressure and renal hemodyna- fall in arterial pressure during hemorrhage may be re- mics to volume expansion in patients with autonomic sponsible for the associated decrease in outer cortical insufficiency may be related primarily to an ineffective blood flow. In these studies, the lowering of renal per- arterial baroreceptor mechanism [26]. Finally, alpha- fusion pressure [15], but not the infusion of norepine- adrenergic stimulation with norepinephrine may inter- phrine or angiotensin [16], was shown to mimic the fere with renal autoregulation but the exact mechanism effect of hemorrhage to decrease fractional blood flow has not been defined [27]. to the outer cortical nephrons. Effects of adrenergic nervous system and catecho- Adrenergic stimulation also has been suggested to lamines on sodium reabsorption and excretion. Altera- cause a redistribution of blood flow away from the tions in adrenergic neural tone may influence sodium renal cortex in humans with heart failure and experi- reabsorption and excretion by several pathways. mental models of sodium retention [19]. These results Changes in sympathetic neural tone might alter extra- were obtained using the inert gas technique to estimate renal mechanisms which in turn mediate changes in the distribution of renal blood flow. The administra- renal sodium excretion. Effects of adrenergic stimulation of alpha-adrenergic blockers into the renal artery tion on renal hemodynamics may also affect renal also has been found to reverse the increase in renal sodium excretion. Finally, a direct effect of alpha- or vascular resistance which occurs in patients [20] and beta-adrenergic stimulation on active sodium trans- experimental animals [21] with heart failure. There is port mechanisms by the renal epithelial cell may alter also other evidence suggesting that increased renal renal sodium excretion. There are several investiga- adrenergic tone, occurs in patients with cardiac failure. tions which bear on the role of these potential path- As with renal nerve stimulation and norepinephrine ways whereby adrenergic pathways affect renal sodium infusion, an increase in filtration fraction is a consistent excretion. occurrence in patients with severe heart failure [22]. Spinal cord section [28, 29] and cardiac denervation Moreover, high concentrations of endogenous catecho- [30, 31] both have been used to incriminate extrarenal lamines have been measured in patients with heart adrenergic mechanisms in the regulation of sodium failure [23]. The renal vasoconstriction which occurs excretion. The interruption of sympathetic afferent and during heart failure may be mediated both by an in- efferent pathways by cervical spinal section has been crease in renal sympathetic efferent tone, as well as demonstrated to impair the natriuretic response to elevated concentrations of endogenous catecholamines. volume expansion with both isotonic saline [28] and Renal vasoconstriction observed in patients with ad- artificial whole blood [29]. The demonstration that vanced liver disease [24] also may be mediated, at least cardiac denervation is associated with a similar blunt- in part, by an increase in renal adrenergic tone and ing of the natriuretic response to volume expansion elevated concentrations of endogenous catecholamines. [30, 31] led to the suggestion that an intracardiac Of course, an additional importance of other circulat- volume receptor is involved in the regulation of sodium ing vasoconstrictor agents, such as angiotensin II, also excretion. This hypothesis was supported by the ob- may be involved in the renal vasoconstriction associ- servation that spinal cord section at the cervical, but ated with cardiac or hepatic failure. not at the sixth thoracic, level was associated with an The baseline level of renal vascular tone also may be impaired natriuretic response to volume expansion [28]. an important determinant of renal responses to various On the basis of these results [29—3 1], the thoracic sym- stimuli. For example, in the presence of a high control pathetic afferent pathways were thought to transmit level of renal vascular resistance, alpha-adrenergic signals arising from alterations in extracellular fluid stimulation may be less effective but any vasodilating volume to the central nervous system. However, since response may be accentuated. For example, patients cord section and cardiac denervation interrupt both with hepatorenal syndrome actually increase their sympathetic afferent and efferent pathways, further glomerular filtration rate and renal blood flow in re- studies were necessary to document this hypothesis. sponse to pressor doses of the alpha-adrenergic The hypothesis was found not to be tenable when agonist, metaraminol [24]. In contrast, in normal sub- selective interruption of thoracic sympathetic afferent 294 Schrier pathways by posterior rhizotomy did not impair the effect of renal neural tone on tubular sodium reab- natriuretic response to expansion of the extracellular sorption. fluid volume [28]. Since interruption of vagal path- There is considerable evidence that an increase in ways also was found not to influence the natriuresis renal adrenergic tone may be partially responsible for associated with volume expansion [28, 31], the inter- the increased retention of sodium associated with low- ruption of sympathetic efferent pathways seemed the output cardiac failure in humans and experimental primary mediator of the impairment in sodium excre- animals. The intrarenal injection of alpha-adrenergic tion following cervical spinal cord section [28, 29] or blocking agents has been demonstrated not only to de- cardiac denervation [30, 31]. Support for this conclu- crease renal vascular resistance but to increase urinary sion is provided by the observation that selective in- sodium excretion in humans [201 and experimental terruption of adrenergic or sympathetic efferent path- animals [21] with low-output heart failure. Alpha- ways by pharmacologic depletion of catecholamines is adrenergic blockade also abolishes the effect of acute associated with a similar impairment in sodium excre- constriction of the thoracic inferior vena cava to in- tion as cord section or cardiac denervation [32]. Dur- crease tubular sodium reabsorption, specifically the ing volume expansion the primary hemodynamic con- component of this enhanced sodium reabsorption sequence of interruption of adrenergic pathways is a which occurs independent of changes in renal arterial diminution in total peripheral resistance and arterial and renal venous pressures [38]. While this anti- pressure which occurs in the absence of any effect on natriuretic effect of vena caval constriction seems to be the cardiac output [28, 32]. In this situation the diminu- partially due to changes in circulating catecholamines tion in renal perfusion pressure, which occurs in the [38], the effect of hemorrhage to increase tubular absence of detectable changes in glomerular filtration sodium reabsorption has been demonstrated to be rate, may mediate the increased tubular reabsorption mediated primarily by increased renal adrenergic tone of sodium [8, 32]. [39]. When the renal nerves of a hemorrhaged animal In the absence of alterations in systemic arterial were left intact but the blood perfusing the same pressure, the intrarenal effect of diminished adrenergic animal's kidneys was derived from another animal, an tone may predominate and be associated with an in- antinatriuresis in the hemorrhaged animal occurred in crease, rather than a decrease, in sodium excretion. the absence of a detectable change in filtration rate [39]. For example, when tested in the supine position, indi- This finding seems to focus on the importance of renal viduals with idiopathic [26] or pharmacologically in- nerves and to exclude the need for changes in circulat- duced [33] autonomic insufficiency have been found to ing concentrations of catecholamines, angiotensin or excrete a saline load more rapidly than normal sub- other vasoactive substances in the antinatriuretic jects. An earlier escape from the sodium-retaining effect of hemorrhage. While the authors suggested that effect of mineralocorticoid hormones has also been this effect of renal nerve stimulation during hemorrhage demonstrated to occur in the presence of adrenergic might enhance sodium reabsorption by a direct effect impairment secondary to guanethedine administra- on the active transport of sodium by the renal tubule tion [34]. Taken together, these results suggest that cell, it is important to note that the antinatriuresis was renal adrenergic impairment may enhance sodium ex- associated with a consistent decrease in renal blood cretion unless the fall in total peripheral resistance and flow and increase in filtration fraction. In fact, in arterial pressure associated with extrarenal adrenergic virtually all in vivo experiments demonstrating an effect impairment obscures this intrarenal effect. When the of alterations in adrenergic tone on sodium excretion, extrarenal effect of adrenergic impairment predomin- the results do not differentiate between a direct effect ates, renal sodium retention occurs. Such is generally on active sodium transport and an indirect effect the situation with the use of sympatholytic agents, for mediated by some alteration in intrarenal hemodyna- the treatment of hypertension and the concomitant mics. administration of diuretics is necessary to avoid ex- As already alluded to, the intrarenal hemodynamic cessive sodium retention. consequences of alpha-adrenergic stimulation which Renal denervation has been known for some time to could be involved in the resultant decrease in sodium be associated with a natriuresis in the anesthetized excretion include a diminution of glomerular filtration dog [35]. Although this natriuretic effect of renal de- rate or renal cortical blood flow, or both, and an innervation may be partially related to the concomitant crease in filtration fraction. A decrease in glomerular increase in glomerular filtration rate [36], prevention filtration rate due to adrenergic stimulation, even in the of this increase in filtration rate by injection of micro- presence of glomerulotubular balance, would certainly spheres has failed to abolish this "denervation natri- be expected to somewhat decrease urinary sodium ex- uresis" [37], thus suggesting some direct or indirect cretion. There is considerable clearance [8, 13, 40, 41] Responses to adrenergic stimulation 295 and micropuncture [42—44] evidence that a decrease in [20, 23] may contribute to edema formation by caus- postglomerular hydrostatic pressure and an increase in ing venoconstriction and impeding lymphatic flow. postglomerular oncotic pressure, as might occur with As with aipha-adrenergic stimulation, any effect of the increased renal vascular resistance and filtration beta-adrenergic stimulation to decrease tubular sodium fraction during alpha-adrenergic stimulation, might reabsorption [50] could be related either to alterations lead to increased proximal tubular sodium reabsorp- in intrarenal hemodynamics or to a direct effect on the tion. It should, however, be mentioned that some re- active transport of sodium. Injection of large doses of cent micropuncture investigations [45, 46] have failed isoproterenol into the renal artery has been shown to to demonstrate a substantial effect of these peritubular cause renal vasodilatation [6]; however, redistribution Starling forces on tubular sodium reabsorption. The of cortical blood flow has not been found to occur dur- mechanism whereby a redistribution of renal blood ing beta-adrenergic stimulation with isoproterenol [51]. flow away from outer cortical to juxtamedullary ne- In addition to the aforementioned extrarenal and phrons might increase the tubular reabsorption of intrarenal hemodynamic effects of adrenergic stimula- sodium also remains to be explained [19]. It has been tion on the renal excretion of sodium, there is some proposed that since juxtamedullary nephrons possess evidence that beta- and alpha-adrenergic stimulation longer loops of Henle than outer cortical nephrons, may directly alter active sodium transport. In this re- more avid sodium reabsorption may occur in the gard, norepinephrine has been demonstrated to in- juxtamedullary nephrons. Results of recent experi- crease the short circuit current in the toad bladder [52], ments, however, have cast doubt on whether such and frog skin [53], thus suggesting an increase in redistribution in renal blood flow occurs during alpha- active sodium transport. A direct effect of alpha- and adrenergic stimulation [15, 18]. Moreover, such a re- beta-adrenergic stimulation to alter net sodium trans- distribution in renal blood flow has been dissociated port in the proximal tubule has also been suggested on from changes in renal sodium excretion [15, 45]. the basis of results obtained in the dog during water Specifically, this alteration in renal blood flow distri- diuresis [50, 54]. Since norepinephrine and isopro- bution has been observed during sodium restriction in terenol have been reported to decrease and increase man using radioxenon washout measurements, but renal cortical tissue cyclic AMP, respectively, in the restoration to a normal blood flow pattern did not dog [55] and rat [56], it has been proposed that the occur with the administration of large doses of alpha- effect of adrenergic stimulation on proximal tubular adrenergic blocking agents into the renal artery [47]. sodium reabsorption may involve a cyclic-AMP- Similarly, using the technique of radioactive micro- mediated mechanism. In this regard, dibutyryl cyclic spheres to estimate cortical blood flow distribution, AMP has been shown to increase urine flow in the dog the decreased fractional blood flow to outer cortical during water diuresis in a manner similar to intrarenally nephrons which occurs during hemorrhage is not re- administered isoproterenol [57]. However, although versed by alpha-adrenergic blockade [15]. Other studies the dibutyryl cyclic AMP was infused into one renal using the same microsphere method have been unable artery, a bilateral renal effect was observed; thus, an to correlate distribution of renal cortical blood flow extrarenal mechanism mediating this effect of the with changes in sodium excretion but have found a nucleotide could not be excluded. correlation between sodium excretion and total renal Infusion of cyclic guanosine 3'5'-monophosphate vascular resistance [48]. (cyclic GMP) has also been reported in a preliminary There is another potential extrarenal effect of communication to produce a similar decrease in urine alpha-adrenergic stimulation on sodium excretion. flow as norepinephrine [58]. Since guanyl cyclase and cy- Alpha-adrenergic stimulation is known to cause vaso- clic GMP are known to be present in the kidney [59—61], constriction of venules and veins [1]. This venocon- it has been proposed that enhanced sodium reabsorp- striction could impede the return of lymph flow into tion in the proximal tubule during alpha-adrenergic the thoracic veins and there is some experimental stimulation may be mediated by increased intracellular evidence that such an impedance to lymphatic flow concentrations of cyclic GMP [54, 58]. Thus, increased may initiate renal sodium retention. Specifically, the cyclic AMP and cyclic GMP have been proposed to resultant sodium retention and ascites formation mediate the effect of beta- and alpha-adrenergic stimu- associated with chronic constriction of the thoracic in- lation on proximal tubular sodium reabsorption. A ferior vena cava may be attenuated by shunting the similar effect of these nucleotides on renal gluconeo- thoracic duct across the vena caval constriction into a genesis and ammonia formation has also been pro- thoracic vein [49]. It is thus possible that the increased posed [62, 63]. While such a hypothesis remains adrenergic neural tone and catecholamine concentra- attractive, it should be noted that two recent groups of tions which are present in patients with cardiac failure investigators using micropuncture techniques in the 296 Schrier dog have failed to detect any effect of either alpha- or in renal arterial pressure during the norepinephrine beta-adrenergic stimulation on proximal tubular infusion in earlier studies could have contributed to the sodium reabsorption [64, 65]. A small effect of adren- water diuresis. The results of more recent investiga- ergic stimulation on tubular sodium reabsorption, tions, however, have demonstrated that this water which is not detectable by micropuncture techniques, diuresis occurs in spite of maintenance of a constant however, cannot be excluded. Such a modest effect, if renal perfusion pressure [12]. present, could be of considerable physiological signi- Isoproterenol administered i.v. may quantitatively ficance over a period of hours or days. diminish total peripheral resistance to a greater degree Effects of the adrenergic nervous system and catecho- than it enhances cardiac output; thus, a diminution in lamines on renal water excretion. There is considerable systemic arterial pressure frequently occurs [3, 7 1—73]. evidence in both man and experimental animals that The antidiuretic effect of beta-adrenergic stimulation alterations in adrenergic neural tone may influence the therefore could be partially attributed to changes in osmotic movement of water in the mammalian ne- renal arterial pressure. However, as with i.v. admini- phron. The i.v. infusion of norepinephrine has been stration of norepinephrine, the antidiuretic effect of known for some time to be associated with a solute- beta-adrenergic stimulation has been dissociated from free water diuresis in both man [66—68] and animals alterations in renal arterial pressure [3]. These effects [69, 70]. This diuresis has been demonstrated to occur of systemic alpha- and beta-adrenergic stimulation on in the absence of changes in two of the main deter- renal water excretion have also been demonstrated not minants of renal water excretion, namely glomerular to be dependent on renal sympathetic innervation [3, filtration rate and solute excretion [66—68]. Other re- 12]. Thus, taken together, these results suggest that an suits also indicate that this effect of norepinephrine on adrenergic influence on renal water excretion appears water excretion is related to its aipha-adrenergic to occur independent of changes in renal hemo- stimulating properties since the diuresis is abolished by dynamics, renal innervation and renal perfusion pres- alpha- but not beta-adrenergic blockade [69]. In con- sure. A direct effect of adrenergic stimulation on the trast, beta-adrenergic stimulation with i.v. admini- water-permeability of the renal tubule epithelium or on stered isoproterenoi has been shown to be associated the release of vasopressin therefore was implicated. with a consistent antidiuresis [3, 7 1—73] which also There is some in vitro evidence which suggests that may occur independent of alterations in the rate of alpha-adrenergic stimulation with norepinephrine glomerular filtration or solute excretion [3]. This anti- antagonizes the effect of vasopressin on water trans- diuretic effect with i.v. administered isoproterenol is port [52, 76]. It has been suggested that this antagon- abolished by beta- but not aipha-adrenergic blockade ism by norepinephrine of the action of vasopressin [70]. On the basis of these results, it is evident that on osmotic water movement in the toad bladder alpha- and beta-adrenergic stimulation exert con- may be mediated by interference with the effect of sistent and competing effects on renal water excretion. vasopressin to increase cyclic AMP [52]. Recent in There are several investigations which bear on the vitro results using dissected medullary collecting mechanism(s) whereby adrenergic stimulation alters ducts support this hypothesis, since addition of renal water excretion. Alpha- and beta-adrenergic norepinephrine abolished the effect of vasopressin to stimulation may decrease [54] and increase [51] distal enhance cyclic AMP generation [56]. In contrast, the tubular fluid delivery, respectively; therefore, these in vitro results examining the effect of isoproterenol on effects would, if anything, modify both the diuretic water transport and cyclic AMP, however, have not effect of norepinephrine and the antidiuretic effect of been consistent [52, 76]. While the in vitro addition of isoproterenol rather than account for them. Since the isoproterenol to dog kidney tissue has been found to i.v. infusion of norepinephrine is associated with an increase medullary cyclic AMP [55], this finding was increase in systemic arterial pressure, the possibility not confirmed in the rat kidney [56]. .Recent studies existed that the resultant water-diuresis was mediated from our laboratory, however, have demonstrated that by the increase in renal perfusion pressure. A so- the i.v. infusion of isoproterenol is associated with an called "druck-diuresis" or pressure diuresis had been increased renal medullary tissue concentration of cyclic previously described in association with an increase in AMP in water-diuresis intact rats but not in rats suffer- renal arterial pressure to a perfused kidney [74, 75]. ing from pituitary diabetes insipidus [77]. Although the level of renal arterial pressure was Beta-adrenergic stimulation with isoproterenol has greater in these previous studies [74, 75] than the renal been found, however, to directly activate adenyJate arterial pressure which occurred during the i.v. infu- cyclase and increase cyclic AMP in several nonrenal sion of norepinephrine [12, 66—69], a water diuresis tissues of the body [78, 79]. If vasopressin and isopro- was observed in both circumstances. Thus, the increase terenol increase osmotic water movement in the mam- Responses to adrenergic stimulation 297 malian nephron via the same cyclic AMP-mediated renal mechanisms. Since the time of onset and nature mechanism, then beta-adrenergic blockade with pro- of the effect of both systemic alpha- and beta-adren- pranolol might be expected to abolish both antidiuretic ergic stimulation on renal water excretion mimicked responses. In this regard, propranolol administration the action of vasopressin, the role of alterations in has been found to abolish the antidiuretic effect of iso- endogenous vasopressin release in these responses has proterenol but not the antidiuretic effect of vasopres- been investigated. sin [70]. In view of these findings, the proposal has In recent studies, acutely hypophysectomized dogs been presented that an intermediate receptor in the undergoing a water diuresis during glucocorticoid renal tubule cell might be involved in the antidiuretic hormone replacement were used to investigate the role effect of beta-adrenergic stimulation [70]. of vasopressin release in mediating the effect of adren- In many in vivo studies which have suggested a direct ergic stimulation on renal water excretion. In the intrarenal effect of the adrenergic nervous system on absence of water loading, these hypophysectomized water transport, a role of endogenous vasopressin re- animals have been found to excrete urine with a mean lease unfortunately has not been excluded [66—73]. osmolality less than 100 mOsm and to respond to the Moreover, the use of the bioassay for vasopressin has administration of exogenous vasopressin [12]. In con- failed to allow definitive conclusions, since i.v. ad- trast to results in the intact animal, beta-adrenergic ministered isoproterenol has been reported to increase stimulation with i.v. administered isoproterenol in endogenous vasopressin in man [80] but not in dogs these hypophysectomized dogs was not associated [70]. A small antidiuretic effect of i.v. administered iso- with an antidiuresis although the systemic and renal proterenol has been demonstrated to occur in rats hemodynamic responses were similar [3]. Moreover, in suffering from hereditary diabetes insipidus [81]. How- acutely hypophysectomized animals receiving a con- ever, although arterial pressure and renal hemodyna- tinuous infusion of either a large or small dose of exo- mics were not measured in these studies [81], the genous vasopressin, i .v. administered norepinephrine dose/body weight ratio was such as to expect rather was found not to be associated with a water diuresis profound changes in these hemodynamic indexes [3]. [12]. These results in intact and hypophysectomized If present, intrarenal hemodynamic alterations, such as animals, during systemic alpha- and beta-adrenergic a decrease in renal arterial pressure or glomerular stimulation are shown in Figs. 1 through 3. Taken filtration, or both [82, 83], could entirely account for together, these findings provide substantial evidence the small increase in urinary osmolality (120 to 180 that the primary effect of both alpha- and beta- mOsm) which occurred with beta-adrenergic stimula- adrenergic stimulation on renal water excretion is tion in these rats with pituitary diabetes insipidus [81]. mediated by alterations in endogenous vasopressin There is some recent experimental evidence which release. The previous results in man [68] and dog [69] fails to support a direct in vivo effect of either alpha- or which demonstrated a diuretic effect of i.v. adminis- beta-adrenergic stimulation on the permeability of the tered norepinephrine during an infusion of sub- distal nephron to osmotic water movement [3, 12]. In maximal doses of vasopressin are best explained by these experiments norepinephrine [12] or isoproterendi failure of complete suppression of endogenous vaso- [3] was infused directly into the renal artery in a dose pressin or the effect of the concomitant increase in estimated to deliver an amount of the drug to the renal renal perfusion pressure to produce a "druckdiuresis" circulation which was equal to or greater than that or both. Recent results in patients with diabetes reaching the kidney during the i.v. infusion of the insipidus indicate that the primary cause may have agents. Although both the water diuresis with fore- been failure of suppression of endogenous vasopressin pinephrine and the antidiuresis with isoproterenol con- [84]. Intravenous infusion of norepinephrine into sistently occurred during i.v. infusion of these hor- patients suffering from pituitary diabetes insipidus, mones, these effects on water excretion could not be and receiving the same dose of vasopressin as used in duplicated by the intrarenal infusion of the sub- the previous study [68], was not associated with a stances [3, 12]. Since the doses of norepinephrine and water diuresis. Moreover, the i.v. infusion of isopro- isoproterenol which were infused into the renal artery terenol into the same patients with diabetes insipidus were associated with either minimal or no detectable failed to produce an antidiuresis. changes in renal hemodynamics or solute excretion There are several pathways whereby alpha- and [3,12], it was unlikely that any effect of the adrenergic beta-adrenergic stimulation may result in the altered agents on tubular water transport was obscured by rate of release of endogenous vasopressin. Although such alterations. These results thus suggested that the the effect of adrenergic stimulation on renal water effect of both alpha- and beta-adrenergic stimulation excretion has been dissociated from changes in renal on water excretion may be primarily mediated by extra- perfusion pressure, consistent alterations in systemic 298 Schrier

hemodynamics occur both during alpha and beta- No,ysimpfl,u C,SI,.,I uRucd,.. CO.I,M COM,M adrenergic stimulation [3, 121. The increase in mean Ot,.r/kgluft, O.SpgjkrfrH, arterial pressure during the i.v. administration of 600 norpinephrine or the decrease in mean arterial pressure .5 during the i.v. administration of isoproterenol, there- .0 500 0.: 400

300

Norntl hypophyaeal.hypothaIamc Ablat,oo of hypopbyeoal.ltypolhalun,ic —0.5 200 neural System neural system

Control 7°1consro Cotstrol lsOpro1reflot Control —1.0 too

600 Fig. 3. Absence of eJfect of i.v. administration of norepinephrine on 500 free waler clearance (left) and urinary osmolality (right) in hypophysectomized dogs receiving 20 to 40 (i.U/kg/min of vasopressin. Each point is the mean of three to five collections. Solid lines 400 denote results in innervated kidneys and dotted lines in denervated kidneys. The open circles represent experiments in which 40 U/ 300 kg/mm of vasopressin was infused and the closed circles represent experiments in which 20 sU/kg/min of vasopressin was infused (reproduced with permission of publisher, Ref. 12). 200

100 fore, could be involved in the alterations in vasopressin release. Such an effect could be due to a direct effect of changes in cerebral arterial pressure or changes in cervical parasympathetic afferent tone on vasopressin I) 1.) release [85]. Since beta-adrenergic stimulation with i.v. to to administered isoproterenol increases renin release [86], t;C) — the resultant antidiuretic effect also could be mediated by an effect of antiotensin II to increase vasopressin release. Such a mechanism is possible, since some C) investigators have suggested that angiotensin II stimulates vasopressin release [87]. Other workers have failed, however, to confirm this observation using Fig. 1. Effect of i.v. administration of isoproterenol on urinary similar bioassay techniques [88], and moderate hemor- osmolality and free water clearance in the intact dog (left) vs. the dog with ablation of the hypothalamo-neurohypophysial system rhage also has been shown to stimulate renin but not (right). The broken lines indicate the results in the denervated vasopressin release [89]. In recent studies in dogs kidneys, and the solid lines indicate the results in the innervated undergoing a water diuresis, neither i.v. nor intra- kidneys. Each point is the mean of three to five periods (reproduced with permission of publisher, Ref. 3). carotid infusion of antiotensin 11 was found to alter renal water excretion [90]. Taken together, these results thus suggest that increased antiotensin II concentrations during beta-adrenergic stimulation are not involved in the resultant antidiuresis. Since i.v. administered norepinephrine stimulates renin release [91—93] and, yet, is associated with a water diuresis, angiotensin II appears to be unimportant in this effect of aipha-adrenergic stimulation to suppress vasopressin release. In an effort to demonstrate a direct effect of catecholamines on vasopressin release, both isoproterenol [94] and norepinephrine [95] have been infused into the carotid artery of dogs at doses estimated to deliver Fig. 2. Effect of i.v. adminstration of norepinephrine on free water clearance (left) and urinary osmolality (right) in the hydropenic dog. an amount of the drug comparable or greater than Each point represents the mean of three to five collection periods. that reaching the cerebral circulation during the i.v. Solid lines denote results in innervated kidneys and dotted lines in denervated kidneys (reproduced with permission of publisher, infusion of these adrenergic agents. The intracarotid Ref. 12). infusion of neither alpha- nor beta-adrenergic agonists Responses to adrenergic stimulation 299 has been found to alter renal water excretion [94, 95]. Sham-operated Denervated baroreceptors Also, no evidence for a direct effect of changes in PrnoonlrolImfO:dt1tOIPontoonttol cerebral arterial pressure on vasopressin release was obtained in experiments in which the carotid arteries >n of animals with denervated baroreceptors were pump- perfused at different levels of arterial pressure [95]. Ii — Since alterations in arterial baroreceptor tone may - influence vasopressin release [85], the effect of i.v. p administration of norepinephrine on renal water - excretion was compared in sham-operated animals vs. animals with denervated arterial baroreceptors. Alpha-adrenergic stimulation with i.v. administered +6.0 norepinephrine was associated with a water diuresis only in the sham-operated animals (Fig. 4) [95]. Similarly, i.v. administration of isoproterenol was associated with a consistent antidiuresis in sham- 0 I operated animals but not in the animals with denervated arterial baroreceptors (Fig. 5) [94]. ! These results thus suggest that the effect of both Fig. 5. Effect of i.v. administration of isoproterenol on urinary osniolality (above) and free-water clearance (below) in animals alpha- and beta-adrenergic stimulation on vasopressin with cervical sham-operation (left) and denervation of barore- release involves alterations in arterial baroreceptor ceptors (right). Each point represents the mean value of three to tone. It also is possible that this same pathway may be five urine collections from a single kidney (reproduced with per- involved in other circumstances in which renal water mission of publisher [94]). excretion is altered by nonosmotic influences. In this regard, the antidiuretic effect of nicotine recently has been demonstrated to be dependent on intact cervical emotional status, endocrine dysfunction, cardiac or parasympathetic pathways [96]. Whether alterations in hepatic failure and administration of various drugs renal water excretion during changes in volume or such as barbituates and opiates involve this baroreceptor-mediated pathway of vasopressin release remains to be determined. Effect of adrenergic nervous system on renin secretion. Sham-operated Denervated baroreceptors There is considerable evidence that increased activity No,epinephrine Norepinrphrinr precuntrol infused jo. Posteontrol Prroontrol infused i.e. Posteontrot of the adrenergic nervous system provides a potent nun OSegfkgf O.Seelkelmlo stimulus to increase renin secretion. Several maneuvers 2000 --- - are known to stimulate both sympathetic neural path- 1500 —--— ways and renin release including hemorrhage [97—100], -:— carotid occlusion [98], direct stimulation of renal -— nerves [91, 101, 102], infusion of catecholamines or II ganglionic stimulating agents [91, 98], hypoglycemia _____ [103, 104] and stimulation of the midbrain [105—107]. It has been proposed that either circulating catecholamines from the adrenal medulla or norepinephrine liberated at renal adrenergic nerve terminals, or a combination thereof, may mediate these responses. I' Evidence in support of a role of circulating catechol- ______; amines from the adrenal medulla is derived from experiments in which adrenal, but not renal, denerva- Fig. 4. Effect of i.v. administration of norepinephrine on urinary tion abolished the effect of hypoglycemia to increase osmolality (above) and free water clearance (below) in animals plasma renin activity [104]. It is not known, however, with cervical sham operation (left) and denervation of baroreceptors (right). Denervation of baroreceptors abolished the whether release of norepinephrine from nonadrenal diuretic effect of i.v. administered norepinephrine. Each point extrarenal adrenergic nerve endings can substantially represents the mean value of three to five urine collections for a alter circulating levels of norepinephrine so as to single kidney. The broken lines represent results from denervated kidneys and the solid lines represent results from innervated mediate effects on renin secretion. A local effect of kidneys (reproduced with permission of publisher [95]). norepinephrine release at renal sympathetic nerves is 300 Schrier suggested by the finding that increased plasma renin earlier, although results using radioxenon washout activity associated with midbrain stimulation can be curves suggested that adrenergic stimulation might attenuated or abolished by renal denervation [107]. produce such a redistribution of cortical blood flow There are several mechanisms whereby adrenergic [14, 17], more recent studies using the radioactive stimulation might cause an increase in renal secretion microsphere method failed to demonstrate such an of renin. The renal vasoconstriction association with effect on cortical blood flow distribution during either aipha-adrenergic stimulation could increase renin norepinephrine infusion [16] or renal nerve stimula- release by either diminishing the rate of sodium tion [15]. delivery to [108], or transport at [109], the macula There is some evidence that beta-adrenergic stimu- densa. Such an effect could be caused by either a lation may provide a more important pathway for diminished filtration rate of sodium, an increase in control of renin release than aipha-adrenergic stimula- sodium reabsorption in the proximal tubule, or a tion. Several of the maneuvers known to stimulate combination thereof. Adrenergic stimulation could renin release including hypoglycemia [104], renal also increase renin secretion by diminishing the pres- nerve stimulation [101, 102] and midbrain stimulation sure at an intrarenal vascular receptor site which in- [107] have been found to be attenuated or abolished fluences renin release [110, 111]. Although systemic by the administration of the beta-adrenergic blocking arterial pressure may increase during renal nerve agent, propranolol, but are either enhanced or un- stimulation [101, 102], carotid occlusion [98] and mid- affected by aipha-adrenergic blockade. In contrast to brain stimulation [105—107]; it may remain unchanged these results, however, are the findings of Winer, during moderate hemorrhage [98] and hypoglycemia Chokshi and Walkenhorst [117], which demonstrated [103, 104] or decrease during severe hemorrhage [97]; that both propranolol and the aipha-adrenergic yet, in all these situations the concomitant renal nerve antagonist phentolamine blocked the effects of nore- stimulation and renal vasoconstriction could diminish pinephrine to increase renin secretion. The beta- pressure at some intrarenal pressure-sensitive receptor adrenergic blocker propranolol also abolished the and stimulate renin release from the juxtaglomerular effect of cyclic AMP to stimulate renin secretion [117]. cells. These authors therefore suggested that phentolamine In addition to the importance of these so-called and propranolol suppress renin secretion at a site macula densa [108, 109] and baroreceptor mechanisms distal to cyclic AMP production, rather than by block- [110, ill], some investigators have suggested that ade of plasma membrane alpha- or beta-adrenergic renal nerve stimulation may increase renin release by receptors or inhibition of adenyl cyclase. Winer et a! a direct effect on the juxtaglomerular cells [101, 102, [117] also have reported that both the D-andL-isomerS 112, 113]. This possibility has been considered tenable of propranolol block the effect of norepinephrine to since juxtaglomerular cells of the afferent arteriole are increase renin release, even though only the L-iSomer richly innervated by postganglionic neural fibers [114, possesses beta-adrenergic blocking properties. Since 115]. Moreover, it has been reported that stimulation lidocaine, a local anesthetic, did not prevent the of renal nerves increases the release of renin in both isoproterenol-induced rise in renin secretion, the the normal [112] and nonfiltering kidney [113] in authors concluded that the anesthetic properties of which vascular reactivity has been diminished by a propranolol did not account for the capacity of these renal arterial infusion of papaverine. Since the respon- agents to block the effect of isoproterenol to stimulate siveness of any intrarenal vascular receptor governing renin secretion [117]. Renal denervation also has renin release may be abolished by the papaverine in- failed to abolish the effect of i.v. administered isopro- fusion and any effect of sodium delivery to, or trans- terenol to increase renin secretion [86]. port at, the macula densa is presumably precluded by As yet there is no adequate explanation for the use of the nonfiltering kidney, these results have been reported different effects of alpha-adrenergic blocking interpreted in support of a direct effect of adrenergic agents on the effect of various adrenergic stimuli to pathways on renin release. Other support for a direct increase renin secretion. It is known, however, that action on the juxtaglomerular cells is the observation aipha-adrenergic blockade alone is a potent stimulator that catecholamines may increase production or of renin secretion [101]. In this regard, most investiga- release of renin from renal cortical slices in vitro [116]. tors who have failed to attenuate the increases in A redistribution of blood flow away from the outer plasma renin activity during various adrenergic portion of the renal cortex, which contains the highest stimuli by alpha-adrenergic blockade, have used large renal concentration of renin, is another potential doses of blockers. These larger doses of alpha- mechanism whereby renal nerve stimulation might adrenergic blocking agents are associated with a de- cause an increased release of renin. As discussed crease in systemic arterial pressure, and this hypo- Responses to adrenergic stimulation 301

tensive effect may account for the rise in renin secretion hypothesis is the finding that norepinephrine, epine- observed during their administration. Thus, the inde- phrine and cyclic AMP have been reported to stimulate pendent effect of the aipha-adrenergic blockers to renin release in vitro [116]. Other investigators, how- stimulate renin secretion may have obscured any effect ever, have not been able to demonstrate similar in that these aipha-adrenergic blockers may have had to vitro effects of catecholamines in renin release [125, inhibit renin release caused by the primary stimulus. 126]. Moreover, in vitro results may not be readily Studies are therefore needed to examine whether transferable to in vivo conditions. smaller doses of aipha-adrenergic blocking agents, It has been suggested that since either propranolol which do not independently stimulate renin secretion administration or renal denervation abolishes the but produce effective alpha-adrenergic blockade, effect of midbrain stimulation to increase plasma renin exist. activity, the effect must involve an intrarenal beta- Not only are the results of studies using alpha- and receptor [107]. Such an interpretation, however, can beta-adrenergic blockers difficult to synthesize into be accepted only with some reservation. Although firm conclusions, but the results of investigations using renal hemodynamics were not measured in these alpha- and beta-adrenergic stimulators also do not experiments [107], it is known from other studies that conclusively favor the predominance of either an midbrain stimulation is associated with a marked alpha- or beta-adrenergic receptor in the regulation of diminution in glomerular filtration rate [127]. Such an renin secretion. Both relatively specific beta-adrenergic effect of midbrain stimulation on renin secretion agonists, such as isoproterenol [3, 118, 119], and could be mediated, therefore, by either a baroreceptor aipha-adrenergic agonists, such as metaraminol and or macula densa mechanisms in the absence of any methoxamine [120, 121], have been shown to stimulate direct effect on the juxtaglomerular cells. In this regard, renin release. Some authors have found that with the effect of renal denervation to abolish the effect of similar doses of epinephrine and norepinephrine, midbrain stimulation to increase plasma renin activity epinephrine provides the more potent stimulation of could be related to the attenuation of these renal renin release, thus favoring the predominance of a hemodynamic alterations [107]. Moreover, the extra- beta-adrenergic receptor [97]. Recent studies by renal hemodynamic effects of midbrain stimulation Johnson, Davis and Whitty [113], however, have were markedly altered by systemic beta-adrenergic shown that the effect of epinephrine, but not fore- blockade with propranolol. Specifically, the rise in pinephrine, to stimulate renin release in the nonfilter- arterial pressure with midbrain stimulation was much ing kidney is blocked by papaverine. This finding less after administration of propranolol. These results would suggest that any direct effect of these catechol- with midbrain stimulation [107], therefore, do not amines on the juxtaglomerular cells may involve establish the presence of an intrarenal beta-adrenergic alpha-adrenergic receptors. The finding that cyclic receptor which regulates renin secretion. AMP [117] and theophylline (a phosphodiesterase The studies which more directly investigate the inhibitor, which increases tissue concentrations of presence of an intrarenal adrenergic receptor involve cyclic AMP) [122, 123], increase renin secretion has either renal nerve stimulation [101, 102, 113] or been used to support a predominant role of beta- infusion of catecholamines into the renal artery [91— receptors in the control of renin release. The basis for 93]. Since the doses of norepinephrine which stimulate this argument is that beta-, but not alpha-, adrenergic renin secretion may also produce renal vasoconstric- stimulation increases renal cortical tissue concentration, a direct effect of this catecholamine on the juxta- tions of cyclic AMP [55, 56]. It must be emphasized, glomerular cells to release renin is difficult to assess. however, that conflicting results as to the effect of The infusion of the beta-adrenergic agonist isopro- cyclic AMP on renin secretion have been reported terenol into the renal artery has been shown to [117, 124]. stimulate renin secretion in the absence of renal The exact location of an alpha- or beta-adrenergic vasoconstriction, but in some of these studies the receptor for regulation of renin release also has been doses of isoproterenol used may have produced extra- a matter of some debate. Evidence has been presented renal alterations [118, 119]. A comparison of the effect for the existence of an intrarenal beta-receptor which of isoproterenol on renin secretion in the infused and affects renin secretion [101, 102]. The histologic contralateral kidneys was also not examined in these findings previously mentioned [114, 115] which demon- studies in an effort to document an intrarenal effect. strated many adrenergic nerve endings among the The study by Ayers, Harris and Lefer [118] has juxtaglomerular cells provide the anatomical setting provided some evidence for the presence of an intra- for an intrarenal receptor site whereby adrenergic renal beta-adrenergic receptor which regulates renin stimulation influences renin release. In support of this secretion. In this study the intrarenal infusion of iso- 302 Schrier proterenol into the constricted renal artery of animals ever, in a recent study in the isolated perfused rat with renal vascular hypertension produced a more kidney, large doses (per g of kidney wt) of isoproterenol pronounced effect on renin secretion than an i.v. were found to stimulate renin secretion [128]. Whether infusion of the same dose of the drug. The renal this effect is of pharmacologic or physiologic signi- arterial infusion, however, was begun one hour after ficance, however, remains to be determined. the i.v. infusion, and no control studies were performed As previously mentioned, the effect of renal nerve to examine whether a continuous i.v. infusion of iso- stimulation to increase plasma renin activity has been proterenol for the same duration of time would have reported to be abolished by propranolol administration produced similar results. A recent study in dogs also [101, 102]. Since renal hemodynamics were not has compared the effect of the same dose of isopro- measured in these studies [101, 102] and propranolol terenol infused i.v. and into a renal artery on renin administration could alter the renal hemodynamic secretion [86]. Because of the capacity of the kidney response to renal nerve stimulation, further studies are to inactivate isoproterenol [4], the intrarenal infusion necessary to differentiate between a direct effect of was not associated with extrarenal hemodynamic renal nerve stimulation on the juxtaglomerular cells alterations [86]. Only the i.v. infusion of isoproterenol and an effect on renin release mediated by either a was found to exert a significant effect on plasma renin baroreceptor or macula densa mechanism. The studies activity and renin secretion (Fig. 6). These results of Johnson et al [113] have demonstrated that renal therefore suggested that an extrarenal mechanism was nerve stimulation increases renin secretion in the non- responsible for the effect of isoproterenol to increase filtering kidney receiving a papaverine infusion. While renin secretion. The dose of isoproterenol used in these results suggest a direct effect of renal nerve these dog studies was sufficient to produce a 50% stimulation on the release of renin by the juxta- increase in cardiac output when infused i.v. and, yet, glomerular cells, they do not differentiate between an did not affect renin secretion when infused into the alpha- or beta-adrenergic receptor. As previously renal artery [86]. If present, therefore, any intrarenal discussed, the finding that papaverine administration beta-receptor influencing renin release must be con- abolished the effect of epinephrine but not norepine- siderably less sensitive than the extrarenal cardio- phrine to increase renin secretion in the nonfiltering vascular beta-receptors. kidney suggested an importance of an intrarenal In intact animals the effect of larger intrarenal doses alpha-receptor [113]. of isoproterenol to stimulate renin release is difficult In summary, there seems little doubt that adrenergic to evaluate with respect to an intrarenal beta-receptor, stimulation provides a potent stimulus to renin secre- since these large doses of isoproterenol may produce tion by both extrarenal and intrarenal mechanisms. extrarenal hemodynamic alterations [118, 119]. How- This effect on renin secretion may be mediated by several pathways including a direct effect on the juxtaglomerular cells, a change in pressure at an intrarenal vascular receptor or a change in sodium delivery to, or transport at, the macula densa. Whether there is a predominant role of alpha- or beta-adrenergic receptors, or whether this pharmacologic approach used to define the mechanism is even appropriate, awaits further investigations. A primary or secondary .5 S role of adrenergic stimulation in the increased renin secretion observed in clinical circumstances including salt restriction and hypovolemia; adrenal insufficiency; 0 congestive failure; hepatic cirrhosis; nephrotic syndrome; anesthesia; and high renin, accelerated hyper- C tension seems likely and must be investigated further.

Acknowledgments Some of the studies reported in this review were supported by Public Health Service grants HL 15467 Fig. 6. Effect of i.v. administered but not intrarenal isoproterenol and 15629 from the National Institutes of Health, and (iso) to increase renin secretion rates. Results in denervated and innervated kidneys are shown by broken and solid lines, respec- a grant from the Hoechst Pharmaceutical Company. tively (reproduced from data published in [86]). Ms. Linda Benson and Ms. Diana LaRocco provided Responses to adrenergic stimulation 303 secretarial assistance in the preparation of the manu- hemorrhagic hypotension in the dog. J C/in Invest 52:39— script. The advice collaboration and work of the 47, 1973 following individuals was instrumental in the perfor- 16.RECTOR JB, STEIN JH, BAY WH, OSGOOD RW, FERRIS TF: Effect of hemorrhage and vasopressor agents on distribu- mance of many of the studies described in this review: tion of renal blood flow. 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