The Renal Action of Atrial Natriuretic Peptide During Control of Glomerular Filtration

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Kidney International, Vol. 30 (1986), pp. 16—19

The renal action of atrial natriuretic peptide during control of glomerular filtration

JOHN C. BURNETT, JR., TERRY J. OPGENORTH, and JOEY P. GRANGER

Departments of Medicine andPhysiology,Mayo Medical School, Rochester, Minnesota, USA

The renal action of atrial natriuretic peptide during control of glomer- of glomerular filtration rate in the natriuretic response to the ular filtration. Studies were performed in anesthetized dogs (N =7)to peptide glucagon [6, 7]. determine the effects of synthetic atrial natriuretic peptide (ANP) on sodium excretion in the presence and absence of control of glomerular filtration rate produced by suprarenal aortic clamping. Intrarenal infu- Methods sion of synthetic atrial natriuretic peptide (0.3 g/kg/min) significantly increased glomerular filtration rate from 29.3 3.0to 43.2 4.4 Experiments were performed on seven mongrel dogs of either ml/min, urinary sodium excretion from 20.1 10.3to 223.3 52.3 sEq/min, fractional sodium excretion from 0.47 0.19to 3.75 sex (16 to 22 kg body wt). The dogs were fasted overnight prior 0.59%. Incontrast, aortic clamping blocked the incrcase in glomerularto the acute experiment but allowed access to water. Dogs were filtration rate in association with an attenuated natriuresis. Urinaryanesthetized with sodium pentobarbital (30 mg/kg) and main- sodium excretion increased from 6.3 2.3to 68.3 23.4jzEq/min and tained with supplemental doses as necessary. The trachea was fractional sodium excretion increased from 0.15 0.04to 0.90 0.30%.Despite this differential response in glomerular filtration rate and intubated with a cuffed endotracheal tube and the dogs were sodium excretion, whole kidney fractional delivery of sodium from the ventilated with a Harvard Apparatus respirator. A femoral vein proximal tubule as estimated by the fractional excretion of lithiumwas cannulated for infusions and obtaining blood samples. Two increased during both unclamped (17.7 1.8to 30.4 0.8%)and catheters were inserted via the femoral artery and placed below clamped (12.9 2.1to 23.9 2.7%)periods. These studies demonstrate that atrial natriuretic peptide—induced natriuresis is importantly and above the aortic clamp to assess systemic blood pressure mediated by an increase in glomerular filtration rate and decrease in and renal perfusion pressure. The left kidney and left renal tubular reabsorption. artery were isolated via a retroperitoneal flank incision. The dogs were supported in a metal frame that held them in a position approximating their normal upright posture. A noncan- nulating flow probe (Carolina Medical Electronics, King, North Recent investigations employing both crude atrial extract andCarolina, USA) was placed around the left renal artery and a newly available synthetic atrial natriuretic peptide have repeat-small needle was inserted into the artery distal to the flow edly demonstrated that the natriuretic response to this peptideprobe. The left ureter was cannulated for collection of urine is associated with an increase in glomerular filtration rate 1—3].from the left kidney only. An infusion of saline (1 mI/mm) was While some investigations have suggested an effect of atrialinitiated to maintain the patency of the needle. A peptides on tubular reabsorption [1, 4, 16], most studies supportvariable—resistance Blalock clamp was placed around the aorta the hypothesis that atrial natriuretic peptide—induced natriure-just proximal to the renal arteries without causing any constric- sis is mediated by an enhancement of the filtration processtion. 1—3]. No studies have been performed, however, to establish After the surgical preparation, an inulin infusion was begun in the dependency of atrial natriuretic peptide—induced natriuresisthe femoral vein at I mi/mm at a concentration calculated to on glomerular filtration rate in the normally functioning kidneyproduce a plasma concentration of 50 mg/dl. At the end of this employing a specific synthetic atrial natriuretic peptide frag-equilibration period, two 15 mm clearances were performed, ment. with a blood sample obtained either in the middle of a single The present study was therefore designed to elucidate theclearance or between the two clearances. I'he saline infusion contribution of glomerular filtration rate in the mechanism ofinto the renal artery was then replaced by an infusion of atrial natriuretic peptide—induced natriuresis. Aortic clampingsynthetic ANP (8-33, Peninsula Lab., Belmont, California, was used to block the predicted increase in glomerular filtrationUSA) at a rate of 0.3 g .kg1.min for a total of 45 mm. rate during administration of synthetic atrial natriuretic peptideFifteen mm after initiation of synthetic ANP infusion, two 15 in anesthetized dogs. This experimental maneuver has beenmm clearances were obtained. The infusion was stopped. employed in previous investigations which established the roleFollowing a 45 mm washout period, two 15 mm recovery clearances were obtained. After the recovery clearance, the clamp was tightened to decrease renal blood flow to the lowest Received for publication May 17, 1985 level of renal blood flow autoregulation determined by that and in revised form September 16, 1985 pressure at which renal blood flow began to fall. Following a 30 © 1986 by the International Society of Nephrology mm equilibration period, the above protocol was repeated. In

16 Effects of ANP during control of GRE 17 four of the seven dogs, the clamping protocol preceded the Table 1. Renal hemodynamic and excretory responses to intrarenal unclamped protocol. infusion of synthetic atrial natriuretic peptide in the presence and Glomerular filtration rate was measured hy the clearance of absence of control of glomerular filtration rate (N =7) inulin. Inulin concentrations were measured by the anthrone Unelamped method [8]. Concentrations of sodium and potassium were AN F measured using ion-selective electrodes (Beckman E2A ana- Baseline (0.3 j.cglkg/min) Recovery lyzer, Beckman Instruments, Fullerton, California, USA). MAP,mmHg 119±3 109±3* 112±3* Whole kidney proximal tubular reabsorption of sodium wasRBF, ml/min 168 21 175 23 159 18 estimated by the lithium—clearance technique. This technique GFR, mI/mm 29.3 3.0 43.2 44** 30.6 3.3 has been shown to be a reliable method for estimating deliveryRVR, ' of sodium from the proximal tubule, since lithium is reabsorbed mm Hg(ml/mmn1 0.76 0.060.68 0.06* 0.73 0.05 FF 0.33 0.050.46 0.060.35 0.03 exclusively by the proximal tubule [9, 10]. This method is basedV, ml/min 0.37 0.172.46 0.68* 0.44 0.14 on evidence indicating that lithium is rcabsorbed almost exclu-Uosmoi, mOsmol/kg H20932 265 383 58* 702 155 sively in the proximal tubule, including the pars recta, inUNV, p.Eq/min 20.1 10.3223.3 52.3***51.9 12.9** parallel with sodium and water. Micropuncture studies haveFENa, % 0.47 0.173.75 0.59***1.31 0.62 shown that fractional lithium reabsorption correlates very wellFEL, % 17.7 1.8 30.4 0.8***22.5 14.4* with proximal sodium reabsorption over a wide range of prox- Clamped imal reabsorption rates. In addition, diuretics that predomi- ANF nantly inhibit sodium transport in the ascending limb of the loop Baseline (0.3 gg/kg/min) Recovery of Henle and the distal tubule and collecting duct do notMAP,mmHg 128±8 121 7* 128±5 increase urinary lithium excretion [5]. In contrast, maneuvers RBF, mI/mitt 182 21 173 19 149 14** known to inhibit proximal sodium reabsorption, such asGFR, ml/mmn 27.4 1.9 28.0 1.5 31.2 4.0 acetazolamide and osmotic diuretics, increase lithium excretionRVR, mm Hg' (ml/minf'1 0.79 0.110.79 0.11 0.93 0.l1** [11]. The dogs were given 300 mg of lithium (orally) the nightFF 0.27 0.040.33 0.04* 0.39 0.07 before each experiment. Lithium concentration in plasma andV, mI/mitt 0.18 0.060.56 0.16* 0.24 0.38 urine was measured by flame emission spectrophotometryU051, mosmllkg 1120 841 194 665 137 742 148 (model 357, Instrumentation Laboratory, Lexington, Massa-UNV, jzEq/min 6.3 2.3 68.3 23.4* 12.3 4.0 FENa, % 0.15 0.040.90 0.30* 0.31 0.11 chusetts, USA). FE1, % 12.9 2.1 23.9 2.7** 16.7 2.6** All data from the two clearances at baseline, atrial natriuretic peptide, and recovery periods were averaged and arc expressed Values are means 5E. Ahbreviations are: MAP, meanarterial pressure; RBF, renal blood flow; GFR, glomerular filtration rate; RVR, as means 5E. The data were analyzed using Dunnett's pairedrenal vascular resistance; FF, filtration fraction; V, urine flow; Uosnioj, t-test for simultaneous multiple comparisons. urinary osmolality; UNaV, urinary sodium excretion; FENa, fractional excretion of sodium; FEL, fractional excretion of lithium. P values Results compare results with baseline: *PC 0.05; **PC 0.02, PC 0.005. Table 1 and Figure 1 summarize the renal hemodynamic and excretory response data during control, intrarenal infusion of synthetic atrial natriuretic pcptidc, and recovery for seven dogs 2.7%, P <0.02. Increases were observed in urine flow from in the presence and absence of control of glomerular filtration0.18 0.06 to 0.56 0.16 mI/mm (P < 0.05), urinary sodium rate. excretion from 6.32.3 to 68.3 23.4 ,aEq/min, P <0.05, and In the absence of suprarcnal aortic constriction, intrarenalfractional excretion of sodium from 0.15 0.04 to 0.90 ANP infusion resulted in a significant increase in glomerular0.30%. Urine osmolality was unchanged at 841 194 filtration rate (29.33.0 to 43,2 4.4 mI/mm, P <0.02), urinemOsmol/kg H20. Renal blood flow and renal vascular resist- flow (0.37 0.17 to 2.46 0.68 mI/mm, P < 0.05), urinaryance also did not change. Filtration fraction, however, in- sodium excretion (20.1 10.3 to 223.3 52.3 jzEq/min, P

Baseline ANP Recovery lar resistance increased [1]. Preliminary micropuncture studies 50 in the rat by Ichikawa et al are in agreement with such an 40— interpretation [14]. A separate mechanism may involve a direct GFR action of atrial natriuretic peptide to increase the coefficient for 30 mI/mm ultrafiltration, Kf, recognizing the demonstration of atrial natri- 20= uretic peptide—induced generation of cGMP within the glomerulus [15]. The present studies are similar to previous investigations FELl 25 which employed aortic clamping to define the mechanism of 15 glucagon—induced natriuresis [6, 7]. Such previous studies definitively demonstrated by the maneuver used in the present - study that the natriuretic response to the peptide glucagon is 225 dependent on an increase in glomerular filtration rate with no UNV pEq/min 150= ,,//fN evidence for a tubular effect. In contrast to the glucagon 75 studies, the present studies demonstrate that despite the aboli- —# tion of atrial natriuretic peptide—induced increase in glomerular 1_ :: filtration rate, a proximal tubular action of atrial natriuretic 3.75 peptide as estimated by the clearance of lithium may contribute FEN2.50 to the attenuated natriuresis. The fractional delivery of sodium / from the proximal tubule as estimated by the increase in 1.25 fractional lithium excretion occurred in both the presence and — —, absence of control of glomerular filtration rate. The decrease in Fig. 1.Theeffect of atrial natriuretic peptide (ANP) on renal function in whole kidney proximal tubule reabsorption, despite a blunted the presence and absence of control of glomerularfiliration rate (GFR). increase in glomerular filtration rate during aortic clamping, Symbols are: (0) absence of control of GFR; (•) control of GFR. Abbreviations are: FELl, fractional excretion of lithium; UNaV, urinary would support the conclusion that the decrease in proximal sodium excretion; FENa,fractionalexcretion of sodium (N 7). tubule reabsorption of superficial and/or deep nephrons in response to synthetic atrial natriuretic peptide is not dependent on an increased filtered load of this ion. Such a conclusion is peptide—induced natriuresis and glomerular filtration rate, butsupported by the recent report from Hammond and colleagues establishes a natriuretic response independent from increases inthat sodium co-transport is inhibited in proximal tubular brush the filtration process. border vesicles harvested from rats undergoing atrial natriuretic Recent studies have reported an important relationship be-peptide—induced natriuresis [161. The present studies demon- tween atrial natriuretic peptide natriuresis and glomerular fil-strate a dissociation between glomerular filtration rate and tration rate. In the isolated perfused kidney preparation, intra-whole kidney proximal tubule reabsorption as estimated by the renal infusion of crude atrial extract resulted in a significantclearance of lithium, such that whole kidney proximal tubule increase in both glomerular filtration rate and sodium excretionreabsorption decreases in response to atrial natriuretic peptide [12]. Beasley and Malvin extended earlier studies and reportedduring aortic clamping, despite the absence of an increase in the that continuous infusion of crude atrial extract in rats resultedfiltration process. Thus, the present findings support the con- in significant increases in both glomerular filtration rate andclusion of a proximal tubular action of atrial natriuretic peptide. sodium excretion, in contrast to ventricular extracts which Aortic clamping blocked the decrease in urinary osmolality as failed to augment glomerular filtration rate or sodium excretionwell as the increase in glomerular filtration rate, suggesting [3]. Recent purification, sequencing, and synthesis of atrialanother contributing mechanism to the attenuated natriuretic natriuretic factor have resulted in the availability of syntheticresponse to atrial natriuretic peptide during control of glomer- peptide fragments with pure biological activity. Synthetic atrialular filtration rate. Previous studies have suggested that med- peptides have permitted further elucidation of the precise actionullary washout, due to increased papillary plasma flow charac- of this peptide system on renal function, Several studies haveteristic of renal vasodilators, may occur during ANP infusion now consistently demonstrated an important association between urinary sodium excretion and glomerular filtration rate[171. The present studies suggest that aortic clamping may prevent medullary washout, and that without decreases in the during infusion of synthetic atrial peptide fragments [1, 2, 13]. The present studies importantly extend previous studies em-medullary gradient, the natriuretic response to atrial natriuretic ploying synthetic atrial natriuretic peptide, and establish anpeptide is prevented [1, 2, 17]. important relationship between atrial natriuretic peptide— In summary, the present findings suggest that reduction in induced natriuresis and glomerular filtration rate. renal artery perfusion pressure to the lowest levels of renal The mechanism by which atrial natriuretic peptide increasesbloodflow autoregulation preventsatrialnatriuretic glomerular filtration rate remains to be defined. Based on thepeptide—induced increases in glomerular filtration rate, and significant increase in filtration fraction with no significantattenuate the subsequent natriuresis supporting a role for increase in renal blood flow, we reported in previous studiesglomerular filtration rate in the natriuretic response to this that the increase in glomerular filtration rate may be mediatedpeptide hormone. The observation, however, of a natriuretic by a balanced action on segmental renal vascular resistances, inresponse and increase in fractional excretion of lithium during which preglomerular resistance is decreased and postglomeru-aortic clamping, despite the absence of an increase in glomer- Effi'cts of ANP during control of GRF 19 ular filtration rate, supports a direct or indirect action of atrial 233:F61—F66, 1977 natriuretic peptide on proximal tubular reabsorption. 8.FUHR J, KACHZMARCZYK J, KRUTTGEN CD:Eine einfache eolorimetrische Methode zur Insulinbestimmung für Nierenclearanceuntersuchungen bei Stoffwechselgesunden und Acknowledgments Diabetikern. Kim Wochenschr 33:729—730, 1955 The authors thank Denise Heublein for her technical assistance and 9.HAYSLETT JP, KASUGARIAN M: A mieropuncture study of the renal June M. 1-lanke for secretarial assistance. These studies were supported handling of lithium. P,fluigers Arch 380:159—163, 1979 by the Hearst and Rappaport Foundations and by a Grant—in—Aid 10. THOMSEN K, HOLSTEIN—RATHLOW NH, LEYSSAC VP: Comparison (83-964) from the American Heart Association. of three measures of proximal tubular reabsorption: Lithium clearance, occlusion time, and micropuncture. Am J Physiol Reprint requests to John C. Burnett, Jr., M.D.,Divisionof Cardio- 241:F348—F355, 1981 vascular Diseases, Department of Internal Medicine, Mayo Medical 11. THOMSEN K, Scuow M: Renal lithium excretion in man. Am J School, Rochester, Minnesota 55905, USA. Physiol 215:823—827, 1968 12.CAMARGO MJF, KLEINERT HD, ATLAS SA,SEALEYGE, LARAGH References JH, MAACK T: Ca-dependent hemodynamic and natriuretic effect of atrial extract in isolated rat kidney. Ant J Physiol 246:F447—F456, 1. BURNETT JC, GRANGER JP, OPGENORTH TJ: Effects of synthetic 1984 atrial natriuretic factor on renal function and renin release. Ant J 13. 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