Comparison of renal actions of urodilatin and atria1 natriuretic peptide DREW A. HILDEBRANDT, MICHAEL W. BRANDS,

H. LELAND MIZELLE, AND JOHN E. HALL

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216 Hildebrandt, Drew A., H. Leland Mizelle, Michael W. Brands, and John E. Hall. Comparison of renal actions of urodilatin and atria1 natriuretic peptide. Am. J. Physiol. 262 (RegulatoryIntegrative Camp. Physiol. 31): R395-R399,1992.A 32-amino acid atria1 natriuretic peptide (ANP)-like peptide, putatively synthesizedby the kidney, has recently beenisolated from human urine. This peptide, urodilatin (Uro), is structurally similar to the 28amino acid ANP, suggestingthat they might have similar actions on renal fluid and electrolyte excretion. The purposeof this study was to characterize the direct renal actions of low dosesof Uro infusion and to comparethem with the effects of equimolarintrarenal infusions of either ANP or the 24-amino acid atriopeptin III (AP III). Synthetic Uro was infused into the renal artery of pentobarbital sodiumanesthetizedmongrel dogs(n = 8) at 0.14,0.28, and 1.43pmol kg-‘. min-’ while renal perfusion pressurewas servo-controlled at 100mmHg. Uro infusion at 1.43pmol. kg-l min-’ increased sodium excretion from an average control of 57.4 t 10.1 to 159.0 t 24.4 peq/min. Uro infusion at the highest dose also increasedpotassium excretion (28.0 t 4.5 vs. 40.4 & 7.4 peq/ min), chloride excretion (56 t 11 vs. 155 t 22 peq/min), and urine volume (0.54 t 0.12 vs. 1.22 t 0.25 ml/min). Fractional lithium excretion, a marker for proximal tubular sodium reabsorption, was not altered by Uro infusion, nor were urinary guanosine 3’,5’-cyclic monophosphateexcretion, glomerular filtration rate, or effective renal plasma flow changed. Equimolar infusions of these low dosesof either a-human ANP (n = 6) or AP III (n = 8) had no effect on any of the measured variables. Thus, within the range of dosesused in this study, Uro was a more effective natriuretic and diuretic agent than either ANP or AP III. Furthermore, the increasein renal fluid and electrolyte excretion with no changesin either renal hemodynamics or fractional lithium excretion supportsthe hypothesis that Uro inhibits tubular sodium reabsorption at a site beyond the proximal tubule. a-human atria1 natriuretic peptide; atriopeptin III; sodium; potassium; lithium; glomerular filtration; renal plasma flow; guanosine3’,5’-cyclic monophosphateexcretion; blood pressure l

YEARS after the discovery of atria1 natriuretic peptide (ANP), several structurally distinct peptides have been found in the atria and circulation, suggesting that there is actually a “family” of atria1 peptides having natriuretic and diuretic properties. Furthermore, the synthetic apparatus for ANP prohormone has been found in organs other than the heart (21), and other ANP-related peptides such as brain natriuretic peptide (17) have been discovered. Recently, a 32-amino acid ANP-like peptide was isolated from human urine (15). This peptide, named urodilatin, is identical in structure to the 2%amino acid a-human ANP (hereafter referred to as ANP) with the addition of four amino acids to the NH2 terminus (for review, see Ref. 3). Urodilatin apparently is cleaved in the kidney from a IN THE

prohormone with the same sequence of amino acids as the ANP prohormone found in the atria. However, the prohormone from which urodilatin is cleaved is synthesized in the kidney and is not merely sequestered from circulating prohormone of cardiac origin (6, 15). Immunohistochemical evidence suggests that urodilatin is synthesized in the distal nephron, and it has been postulated that urodilatin is secreted into the lumen of the nephron and acts to inhibit sodium transport in the distal tubule (3). Urodilatin activates guanylate cyclase to the same extent as does ANP (7), and urodilatin has been shown to increase plasma guanosine 3’,5’-cyclic monophosphate (cGMP) concentration when administered intravenously (14). Like ANP, urodilatin increases urine flow and sodium excretion when infused intravenously (9,14); however, intravenous urodilatin increases renal sodium and water excretion in dogs with congestive heart failure at infusion rates at which infused ANP has no effect on renal function (14). Although high doses of ANP have been reported to alter renal excretory function in heart failure (4, 13), the report of Riegger et al. (14) suggests that urodilatin is either a more potent natriuretic agent or acts through a different mechanism than ANP. Although urodilatin has been synthesized and characterized biochemically, the direct renal actions of urodilatin, particularly as they compare with the renal actions of ANP, have not been elucidated. The purpose of this study therefore was to characterize the renal actions of urodilatin and to compare the effects of intrarenal urodilatin infusion to the effects of equimolar intrarenal infusions of ANP and of atriopeptin III. METHODS Animal preparation. Conditioned mongrel dogsof either sex, weighing 18.2-25.9 kg (22.0 t 2.3, mean & SE) were used for all experiments. The dogs were fed a standard kennel ration (Purina Pride, Purina Mills, St. Louis, MO) until 16-18 h before the experiment, when they were given one can (477 g) of low-sodium dog food (H/D no. 5640, Hill Pet Products, Topeka, KS) with 10 g NaCl and 300 mg lithium carbonate added. The dogswere then fasted until the time of the experiment but were given free accessto water. On the morning of the experiment, anesthesia was induced with pentobarbital sodium (30 mg/kg), and the dogswere intubated and ventilated with room air (model 607 respiration pump, Harvard Apparatus, South Natick, MA). Arterial blood gaseswere measured with a blood gas analyzer (model 213, Instrumentation Laboratories, Lexington, MA), and the ventilation was adjustedto maintain a systemic arterial blood pH between 7.35 and 7.40. Both the right and left femoral arteries were cannulated, and the catheters were advanced into the aorta. One catheter was advanced so that its tip was above the renal arteries and was usedto measuresystemicarterial blood pressureand to collect

0363-6119/92 $2.00 Copyright 0 1992 the American Physiological Society

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arterial blood samples. The other arterial catheter was advanced so that its tip was at the level of the renal arteries and was used to measure renal perfusion pressure. One femoral vein also was catheterized, and the catheter was advanced into the vena cava. During surgery, a 1:l mixture of lactated Ringer solution and 5% dextrose in 0.9% saline was infused intravenously at 2 ml/min with a roller pump (Minipuls 2, Gilson Medical Electronics, Middleton, WI). The left kidney was exposed via a retroperitoneal flank incision, and an inflatable Silastic cuff-occluder wasplaced on the aorta above the renal arteries and connected to a servocontrolled pump (8). The left ureter wascatheterized and used to measureurine flow rate and to collect urine samplesfor determination of renal excretory function. A curved 23-gauge needlewasplacedin the renal artery and maintained patent by infusing isotonic salineat 0.2 ml/min. A curved 20-gaugeneedle was placed in the renal vein and used to obtain renal venous blood samples.Rectal temperature was monitored and maintained at 37-38°C by warming the dog table with a heat lamp. Experimental protocol. After completion of surgery, the intravenous infusion rate was decreasedto 1 ml/min and a mixture (4:l) of lactated Ringer solution and 5% dextrose in 0.9% saline was substituted for the 1:1 mixture that had been infused during surgery. Pentobarbital sodium (5 mg kg-’ gh-l) was addedto this solution to maintain an appropriate level of anesthesia.[1251]iothalamate (0.005 PCi. kg-‘. min-l, Isotex Diagnostics,Friendswood, TX) also was added to this infusion mixture. A priming doseof [1251]iothalamate(0.5 &i/kg) was administeredintravenously at this time. The aortic cuff-occluder was inflated, and renal perfusion pressurewas maintained constant throughout the experiment at 100 mmHg. Servocontrolling renal perfusion pressureat 100 mmHg prevents the kidneys from being exposed to the elevated arterial pressure induced by anesthesia and allows for renal function to be determined at normal renal perfusion pressures.Furthermore, maintaining renal perfusion pressureconstant throughout the experiment prevents changesin systemic renal pressurethat could occur during the experiment from influencing renal function. The dogswere then allowed to stabilize for 75-90 min. After stabilization, two 20-min urine collections were obtained. Then, either synthetic urodilatin (n = 8), ANP (n = 6), or atriopeptin III (n = 8) was infused via the renal arterial catheter at 0.14 pmol .kg-‘. min-l (the synthetic urodilatin and ANP were purchased from Peninsula Laboratories, Belmont, CA, and the atriopeptin III was generouslydonated by Dr. E. H. Blaine, Searle Researchand Development, St. Louis, MO). After a 15-min stabilization period, another 20-min urine collection was obtained, and the peptide infusion rate was increasedto 0.28 pmol kg-l min-l and then to 1.43 pmol kg-‘. min-’ with 20-min urine samplestaken at each rate of infusion. The peptide infusion was then terminated, and the animals were allowed to recover for 60 min. After stabilization, two 20min recovery urine collections were made. Systemic arterial and renal venous blood sampleswere taken at 7 and 15 min of each urine collection period. Experimental measurements. During the experiment, both arterial catheters were connectedto pressuretransducers (Statham, Gould, Oxnard, CA) and arterial pressureswere recorded continuously on a polygraph (model 7D, Grass Instruments, Quincy, MA). Plasmaand urine sodiumand potassiumconcentrations were determined with ion-selective electrodes (Nova 1, Nova Biomedical, Waltham, MA), chloride concentrations were determined by coulometric titration (model4-2500,Haake-Buchler Instruments, Fort Lee, NJ), lithium concentrations were determined by flame photometry (model 943, Instrumentation Laboratories), and [1251] iothalamate concentrations were determined by counting 12!jIactivity with a gammacounter (Searle l

l

OF

URODILATIN

model 1185,TM Analytic, Brandon, FL). Urinary cGMP concentrations were measuredby radioimmunoassaywith a commercially available kit (New England Nuclear, Billerica, MA). Plasmaprotein concentration wasdeterminedby refractometry (model l0400A TS meter, Cambridge, Instruments, Buffalo, NY). Renal iothalamate clearance and renal excretion rates of sodium,potassium,chloride, and lithium were calculated using standard formulas.The renal clearancerate of iothalamate was equated with glomerular filtration rate, and renal plasmaflow wascalculated from the renal clearanceand renal extraction of iothalamate. Fractional lithium excretion wasusedto estimate proximal tubular sodium reabsorption. Although criticized recently (lo), lithium clearanceis still consideredto be a generally valid technique to estimate proximal tubular sodiumreabsorption as long as the experimental animals are not in a state of extreme antidiuresis or sodiumdepletion (10, 19). Statistical analysis. All data are reported as meanst SE. Within each group of dogs, analysis of variance for repeated measuresand Dunnett’s test for multiple comparisonswith a control (2) were usedto assessthe effects of peptide infusion on individual variables. Differences in selectedvariables between groups were tested using one-way analysis of variance. P < 0.05 was consideredto be statistically significant. RESULTS

The effects of peptide infusion on absolute and fractional sodium excretion and fractional lithium excretion are shown in Fig. 1. Intrarenal urodilatin infusion increased sodium excretion in a dose-related fashion, but the increase in sodium excretion achieved statistical significance only during the 1.43 pmol. kg-’ min-’ infusion rate, when sodium excretion increased from an average control of 57.4 t 10.1 to 159.0 t 24.4 peq/min. When the urodilatin infusion was terminated, sodium excretion returned to a level not different from control. In contrast, neither atriopeptin nor ANP significantly increased sodium excretion at any dose, although there was a tendency for sodium excretion to increase at the highest dose of each peptide. Sodium excretion averaged 61.1 t 14.5 and 55.8 t 13.4 peq/min during control and 75.2 t 13.7 and 73.6 t 15.8 peq/min during 1.43 pmol kg-‘. min-’ ANP and atriopeptin infusion, respectively. Urodilatin infusion at each dose increased fractional sodium excretion, but the change reached statistical significance only during I.43 pmol . kg-’ min-’ urodilatin, when fractional sodium excretion increased from 1.0 t 0.2% during control to 2.6 t 0.4%. Fractional sodium excretion was not significantly altered by either atriopeptin or ANP infusion, averaging 1.0 t 0.2 and 1.1 t 0.3% during control and 1.2 t 0.2 and 1.3 t 0.3% during ANP and atriopeptin III infusion at 1.43 pmol kg-‘. min-l, respectively. Fractional lithium excretion was not altered at any dose of any of the peptides, averaging 25 t 3, 19 t 3, and 21 t 3%, respectively, during control for urodilatin, ANP and atriopeptin III. There were no significant differences during control for any measured variable among the three groups of dogs. Urodilatin increased chloride excretion and urine volume in a pattern similar to sodium excretion (Fig. 2). Chloride excretion increased from an average control of 56 t 11 to 155 t 22 peq/min during the 1.43 pmol kg-‘. min-l urodilatin infusion rate. Urine volume increased l

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from an average control of 0.54 t 0.12 to 1.22 t 0.25 ml/ min during the highest urodilatin infusion rate. Potassium excretion also increased significantly, from an average control of 28.0 t 4.5 to 40.4 t 8.4 peq/min at the highest urodilatin infusion rate. Neither ANP nor atriopeptin significantly increased either chloride or potassium excretion or urine volume at any infusion rate. Average control values for potassium excretion, chloride excretion, and urine volume were 21.7 t 3.1 peq/min, 46 respectively, for + 9 peq/min, and 0.59 t 0.13 ml/min, ANP infusion, and 24.7 t 6.0 peq/min, 54 t 13 peq/min, and 0.43 t 0.08 ml/min, respectively, for atriopeptin III infusion. There were no changes in either glomerular filtration rate or renal plasma flow during infusions of any of the peptides (Fig. 3). Mean systemic arterial blood pressure decreased gradually with time in all three groups, but these changes did not appear to be related to the peptide infusions because arterial pressure did not recover after the peptide infusions were terminated (Fig. 3). Furthermore, even though there was a decrease in systemic arterial blood pressure during the experiments, arterial pressure did not decrease below 100 mmHg. Thus at no time during these experiments did renal perfusion change from the servo-controlled value of 100 mmHg.

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Fig. 1. Absolute and fractional renal sodium excretion and fractional renal lithium excretion during control (Cl-(X), intrarenal infusion of urodilatin (open squares, n = 8), atria1 natriuretic peptide (ANP, closed triangles, n = 6), or atriopeptin III (closed squares, n = 8), and postinfusion recovery (Rl-R2) periods. Peptides were infused at 0.14 (El), 0.28 (E2), and 1.43 pmol kg-‘*min-’ (E3). Each point represents average excretion during 20-min collection period. *P < 0.05 vs. C2 period within same group. “P < 0.5 urodilatin vs. ANP and atriopeptin III for that period.

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Fig. 2. Renal chloride and potassium excretion and urine volume during control (Cl-C2), intrarenal infusion of urodilatin (open squares, n = 8), ANP (closed triangles, n = 6), or atriopeptin III (closed squares, n = 8), and postinfusion recovery (Rl-R2) periods. Peptides were infused at 0.14, 0.28, and 1.43 pmol. kg-l. min-‘; each point represents average excretion during 20-min collection period. *Fp < 0.05 vs. C2 period within same group. V < 0.05 urodilatin vs. atriopeptin III. #P < 0.05 urodilatin, vs. ANP and atriopeptin III.

Urinary cGMP excretion was measured in the urodilatin- and ANP-infused groups of dogs but was not changed during either urodilatin or ANP infusion (Table 1). DISCUSSION

The results of this experiment demonstrate that direct intrarenal infusions of urodilatin increase renal excretory function at concentrations below which neither ANP nor atriopeptin III is effective and support the hypothesis that urodilatin, over the infusion range used in this study, is a more effective natriuretic agent than either of the other two peptides. Because urodilatin increased renal fluid and electrolyte excretion with no change in either glomerular filtration rate or effective renal plasma flow, these data suggest that urodilatin inhibits renal tubular reabsorption. Whether this inhibition is due to a direct action of urodilatin on tubular transport or is secondary to subtle changes in renal hemodynamics and intrarenal physical forces not detectable by measurements of total renal blood flow and glomerular filtration rate is not clear. It is possible that urodilatin may alter renal medullary hemodynamics and interstitial physical forces, but further studies are needed to test this idea. The fact that urodilatin did not alter fractional lithium excretion,

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Table

1. Effects of intrarenal urodilatin or ANP infusion on renal cGMP excretion Peptide n

Infusion,

pmol

- kg-’ - min-’

Control

Recovery 0.14

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537-1-100 497t97 543tlOO 479t99 ANP 6 447t49 Uro 7 408t116 446t121 422zk139 4891t122 402t119 Values, expressed in units of pmol cGMP/min, are means k SE. ANP, atria1 natriuretic peptide; Uro, urodilatin. Control and recovery are means of 2 values during control and postinfusion recovery periods, respectively.

which is a marker for proximal tubular sodium transport, but did increase fractional sodium excretion, is consistent with the hypothesis that urodilatin acts to inhibit sodium reabsorption at a nephron segment beyond the proximal tubule. The reason that urodilatin is a more effective natriuretic agent than either ANP or atriopeptin III is not known. One possibility is that urodilatin inhibits sodium reabsorption to a greater extent than does ANP because of a greater receptor-binding affinity, which has been shown to be true for urodilatin binding to adrenal cortical ANP receptors (7). Thus, for a given amount of peptide delivered to the distal tubule, more urodilatin would bind to its receptors and generate a grea .ter response than ANP. Although microcatheteriza tion studies have dem-

OF URODILATIN

onstrated that urodilatin and ANP inhibit medullary collecting duct serum transport to the same degree (16), the doses of urodilatin and ANP used were not equivalent, and both peptides were administered at supraphysiological concentrations. Use of these excessively high, unequ al in fusion rates might have obscured any differences that existed in the tubular response to urodilatin and ANP; therefore, despite those-data, it would be premature to discard a role for a greater urodilatin receptor-binding affinity in mediating the differential renal response to ANP and to urodilatin. It is also possible that urodilatin exerts a more potent renal excretory effect because more of this peptide reaches the distal tubule for a given amount filtered than does ANP. Urodilatin is not degraded by the endopeptidase that is known to inactivate ANP (5). Because of this, urodilatin could traverse the renal tubule without significant degradation occurring, whereas ANP would be inactivated to some degree, and less ANP than urodilatin would be available to bind to the receptors in the distal nephron. However, direct evidence for this hypothesis is lacking. It is interesting to note that urodilatin did not alter urinary cGMP excretion. ANP infusion increases urinary cGMP excretion (20), and urodilatin has been shown to stimulate particulate guanylate cyclase activity to the same extent as ANP (7). However, in our study, picomolar concentrations of the three peptides were used compared with the micromolar concentrations used in previous studies (7, 20). Thus it is possible that at the low infusion rates used in this study, urinary cGMP excretion does not directly reflect renal cGMP production. It is also possible, as postulated by Blaine et al. (l), that ANP-induced changes in urinary cGMP excretion may be more a reflection of changes in systemic arterial cGMP concentration than in renal cGMP production. The low infusion rates used in this study would be expected to have only minimal extrarenal actions and thus probably did not alter systemic arterial cGMP concentrations. In the search for the circulating form of ANP, several peptides of various len .gths, later shown to be isolation artifacts derived from the same parent molecule, were isolated and purified, and their relative potencies were tested in several different in vivo and in vitro bioassays (11, 18). Although biological activity decreased when the length of the peptide was reduced below 24 amino acids, peptides ranging in length from 26 to 35 amino acids differed very little in their binding activity, their ability to relax precontracted smooth muscle, their ability to inhibit aldosterone secretion from adrenal cells in culture, or thei .r ability to increase sodium excretion in anesthetized rats. This latter observation m ay seem puzzling in light of the results of this study. However, it should be noted that these early bioassays were done with very high, supraphysiological concentrations of the peptides, and the many systemic actions of the peptides, such as a profound reduction in arterial pressure, most probably functioned to counteract any natriuretic actions of the peptides. In summary, direct intrarenal infusion of urodilatin increase renal fluid and electrolyte excretion at concen-

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ACTIONS

trations at which neither atriopeptin III nor a-human atria1 natriuretic peptide had any effect. Urodilatin appears to exert its effects at a site beyond the proximal tubule because there were no changes in either renal hemodynamics or fractional lithium excretion. Thus the results of this study are consistent with the hypothesis that urodilatin inhibits sodium reabsorption mainly in the distal nephron. Fu rther ‘more, these results demonstra te tha t urodilatin, over the range of doses used in this stu .dy, is a mo re effectiv #e natriure tic and diuretic peptide than A NP 9 al though the exact m.echanism for this enhanced effectiveness remains to be elucidated. We thank Arun Patel, Beth Miller, Calvin Torrey, and Ken McDill for expert technical assistance. This study was funded by National Heart, Lung, and Blood Institute (NHLBI) Grants HL-11678, HL-23502, and HL-39399. D. A. Hildebrandt and M. W. Brands are recipients of NHLBI Individual National Research Service Awards HL-07931 and HL-08171, respectively. Address for reprint requests: D. A. Hildebrandt, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216. Received 18 January 1991; accepted in final form 25 September 1991. REFERENCES 1. Blaine, Napier.

E.

H.,

A.

A.

Seymour,

E.

A.

Marsh,

and

M.

A.

R399

OF URODILATIN ulate guanylate cyclase. Biochem. 41, 1989. 8. Hester, R. L.,

J. P. Granger,

Biophys.

J. Williams,

J. Physiol. 1983. 9. Kentsch,

244 (Renal M.,

Fluid

D. Ludwig,

Electrolyte

Physiol.

R. Gerzer,

and

latin: a newly described member of the ANP macol. Sci. 10: 93-94, 1989. 4. Freeman, R. H., J. 0. Davis,

Urodi-

Forssmann. family. Trends

28: S-22-S-25, 1990. 11. Misono, K. S., R. T. Grammer,

Renal response to atria1 natriuretic factor in conscious dogs with caval constriction. and

R. C. Vari.

Am. J. Physiol. 248 (Regulatory Integrative Comp. R495-R500,1985. 5. Gagelmann, M., D. Hock, and W.-G. Forssmann. (CDD/ANP-95-126) is not biologically inactivated

Physiol.

17):

Urodilatin by a peptidase from dog kidney cortex membranes in contrast to atria1 natriuretic peptide/cardiodilatin (cu-hANP/CDD-99-126). FEBS Mt. 233: 249-254,1988.

6. Greenwald, Schriener.

J.

E.,

P.

Needleman,

M.

Wilkins,

and

G.

Renal synthesis of atriopeptin in physiology pathophysiology (Abstract). Kidney Int. 37: 339, 1990.

7. Heim,

J.-M.,

Urodilatin

S. Kiefersauer,

H.-J.

Fulle,

and

R.

F.

and

Gerzer.

and @-ANF: binding properties and activation of partic-

(95-126 3: 88A,

H. Fukumi,

and

T. Inagami.

Rat atria1 natriuretic factor: isolation, structure and biological activities of four major peptides. Biochem. Biophys. Res. Commun. 123: 444-451,1984. 12. Navar, L. G.,

and J. A. Schafer. Comments on “Lithium clearance: a new research area.” News Physiol. Sci. 2: 34-35, 1990.

13. Redfield, Burnett,

M. Jr.

M.,

B. S. Edwards,

D. M.

Hublein,

and

J. C.

Restoration of renal response to atria1 natriuretic factor in experimental low-output heart failure. Am. J. Physiol.

257 (Regulatory Integrative Comp. Physiol. 26): R917-R923,1989. 14. Riegger, G. A. J., D. Elsner, W.-G. Forssmann, and E. P. Kromer. Effect of ANP-(95-126) in dogs before and after induction of heart failure. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H1643-H1648,1990. 15. Schulz-Knappe, P., K. Forssmann, F. Herbst, D. Hock, R. Pipkorn, and W.-G. Forssmann. Isolation and structural analy-

sis of “urodilatin”, a new peptide of the cardiodilatin-(ANP)family, extracted from human urine. Klin. Wochenschr. 66: 752P., U. Honrath,

W.-G.

Forssmann,

and

H.

Endogenous natriuretic peptides: effect on collecting duct function in rat kidney. Am. J. Physiol. 259 (Renal Fluid

new natriuretic

Phur-

G. Muller-Esch.

K. Effect of diuretic and antidiuretic agents on lithium clearance as a marker for proximal delivery. Kidney Int. 37, Suppl.

Electrolyte Physiol. 28): F415-F418, 1990. 17. Sudoh, T., K. Kangawa, N. Minamino,

W.-G.

13): F455-F460,

1990. 10. Kirchner,

1121,1955, 3. Feller, S. M.,

and

J. E. Hall.

Hemodynamic, renal and endocrine effects of urodilatin ANF) in healthy volunteers (Abstract). Am. J. Hypertens.

759,1988. 16. Schulz-Knappe, Sonnenberg.

Gagelmann,

and

163: 37-

Acute and chronic servo-control of renal perfusion pressure. Am.

Effects of atria1 natriuretic factor on renal function and cyclic GMP production. Federation Proc. 45: 2122-2127, 1986. 2. Dunnett, C. W. A multiple comparison procedure for comparing several treatments with a control. J. Am. Stat. Assoc. 50: 1096M.

Res. Commun.

1988. 18. Thibault, Schiller,

peptide in porcine brain. Nature

and

H. Matsuo. A Land. 332: 78-81,

G., R. Garcia, J. Gutkowska,

E. L. Schiffrin, A. de Lean, P. W. J. Genest, and M. Cantin. Structureactivity relationships of atria1 natriuretic peptides. In: Atriul Hormones and Other Natriuretic Factors, edited by P. J. Mulrow and R. Schrier. Baltimore, MD: Williams & Wilkins, 1987, p. 77-82.

(Clin. Physiol. Ser.) K. Lithium clearance as a measure of sodium and water delivery from the proximal tubules. Kidney Int. 37, Suppl. 28:

19. Thomsen,

S-10-S-16,1990. 20. Tremblay, J., and

natriuretic 1129,1989. 21. Vollmar,

P. Hamet. Biochemical mechanisms of atria1 factor action, Can. J. Physiol. PhurmucoZ. 67: 1124-

A. M. Atria1 natriuretic peptide in peripheral other than the heart. Klin. Wochenschr. 68: 699-708,199O.

organs

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