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PubMedDate not supplied

Mechanism of renal effects of intracerebroventricular histamine in rabbits.

Histamine, when given intracerebroventricularly (i.c.v.), has been reported to produce antidiuresis in the rabbit. In this study it was attempted to elucidate the mechanism involved in the effect. Histamine (H), 100 micrograms/kg i.c.v., produced antidiuresis with decreases in renal plasma flow and glomerular filtration rate in urethane-anesthetized rabbits. With larger doses, a tendency towards increased electrolyte excretion was noted in spite of decreased filtration. In the denervated kidney, marked diuresis and natriuresis were observed following i.c.v. H, whereas the contralateral innervated kidney responded with typical antidiuresis. Reserpinized rabbits also responded with marked natriuresis to i.c.v. H. Diphenhydramine (D), 250 micrograms/kg i.c.v., increased urine flow rate, sodium and potassium excretion, along with increase in renal perfusion. With 750 micrograms/kg i.c.v., marked natriuresis was observed in spite of decreased filtration. When H was given after D (250 micrograms/kg) the antidiuresis was completely abolished, and diuresis became more prominent. Cimetidine, 250 micrograms/kg i.c.v., elicited antidiuresis with decreases in renal hemodynamics, the pretreatment with cimetidine did not influence the antidiuresis by H and no natriuresis was noted. The present study suggests that histamine, given i.c.v., influences renal function in dual ways, i.e., antidiuresis by increasing the sympathetic tone to the kidney and diuresis due to some humoral natriuretic factor, the latter becoming apparent only when the former influence has been removed, and further suggests that H1-receptors might be involved in the nerve-mediated antidiuresis, whereas H2-receptors might mediate the humorally induced natriuresis and diuresis.

Animals↗

PubMed1996

Central role of the kidney and abnormal fluid volume control in hypertension.

In human essential hypertension, and in all forms of experimental hypertension studied thus far, volume regulation and the relationship between blood pressure (BP) and sodium excretion (pressure natriuresis) are abnormal. Considerable evidence indicates that resetting of pressure natriuresis plays a key role in causing hypertension, rather than merely occurring as a consequence of increased BP. In patients with essential hypertension, resetting of pressure natriuresis is characterized either by a parallel shift to higher BPs and salt-insensitive hypertension, or by a decreased slope of pressure natriuresis and salt-sensitive hypertension. This clearly indicates that essential hypertension cannot be ascribed to a single abnormality of kidney function. Multiple physiological studies have shown that salt-sensitive hypertension can be elicited by renal abnormalities that cause either loss of functional kidney mass or an inability to modulate the renin-angiotensin-aldosterone (RAA) system appropriately; these abnormalities include loss of functional nephrons, decreased glomerular capillary filtration coefficient, patchy renal ischemia, and increased distal and collecting tubular reabsorption. Renal abnormalities that cause salt-insensitive hypertension are characterized by normal functional kidney mass, and the ability to appropriately modulate the renin-angiotensin system during changes in sodium intake; important causes of salt-insensitive hypertension include widespread increases in preglomerular resistance and increased reabsorption in the proximal tubules and loops of Henle. By comparing the characteristics of pressure natriuresis in essential hypertensive subjects with those found in experimental hypertension of known origin, we can gain considerable insight into the etiology of human hypertension.

Blood Pressure↗

PubMedDate not supplied

Effect of inhibitors of prostaglandin synthesis on induced diuresis in cirrhosis.

The effect of inhibitors of prostaglandin synthesis on diuretic action was examined in patients with ascites due to chronic liver disease and in normal subjects. In patients with ascites, natriuresis after 80 mg i.v. furosemide was reduced 82% by pretreatment with indomethacin. Creatinine clearance was reduced only 16%. These effects were likely due to inhibition of renal prostaglandin synthesis, since urinary prostaglandin E2 fell and there was also reduction in natriuresis with naproxen (52%). The effects were not specific for furosemide since spironolactone-induced natriuresis was also reduced by indomethacin (82%), naproxen (52%), and aspirin (33%). In normal subjects, indomethacin reduced furosemide natriuresis by only 14% while creatinine clearance was not affected. The mechanisms of these drug interactions are uncertain but probably involve renal hemodynamics which appear to be supported importantly by renal prostaglandins in patients with ascites due to liver disease.

Adult↗

PubMed1982

Water and sodium excretion in unilaterally denervated normal and sodium depleted anesthetized rats before and after plasma volume repletion.

The possible role of a reduction in plasma volume (PV) by surgery as well as the importance of dietary Na supply in denervation natriuresis have been investigated on Inactin-anesthetized male rats subjected to acute unilateral renal sympathectomy. Four groups were studied: I. Normal Na diet (n = 14); II. Low Na diet (boiled rice for 2 weeks) -- isotonic glucose infusion (n = 10); III. Low Na diet -- isotonic saline infusion (n = 5); IV. Normal and low Na diet rats served as conscious control (n = 10). Surgery caused a 9-11% increase in hematocrit and a 15-18% decrease in PV in groups I-III. Plasma volume repletion (PVR) reverted these changes. In group I sodium excretion from both kidneys was only a fraction of that in conscious animals kept on the same diet (group IV) and marked denervation natriuresis was observed. After PVR sodium output of innervated (I) kidneys was not different from that of conscious rats but denervated (D) kidneys excreted twice that amount. In group II Na excretion was increased compared to conscious Na depleted controls, and PVR augmented further this difference. Surprisingly, the difference in urinary sodium excretion (UNaV) between I and D kidneys was absent after surgery and was minimal after PVR in this group. In group III physiological saline infusion reverted the effect of Na depletion and denervation natriuresis was present both before and after PVR. It is concluded that PV reduction does not play a major role in denervation phenomenon. In Na depleted anesthetized rats denervation natriuresis is absent or minimal.

Anesthesia↗

PubMed1986

Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous furosemide.

Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II-IV were essentially the same, but about 20% higher than those in treatment I. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I-IV, respectively. Except for treatment III, diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.

Animals↗

PubMed2001

The role of dopamine-metabolizing enzymes in the regulation of renal sodium excretion in the rat.

The intrarenal natriuretic hormone dopamine (DA) is metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). We have previously shown that inhibition of COMT by entacapone results in a potent D1-like receptor-mediated natriuretic response. The present study was performed using anaesthetized rats to compare the importance of MAO and COMT in DA-mediated natriuresis by use of the MAO inhibitor phenelzine. Urinary sodium and DA excretion remained unchanged after MAO inhibition, while excretion of the main metabolite dihydroxyphenylacetic acid (DOPAC) decreased by 55%. The response was unaltered if 5-hydroxytryptamine receptors (5-HT1A) were blocked during MAO inhibition. We also investigated the specific renal activities of MAO and COMT in rat renal cortex during DA-influenced natriuresis. Specific COMT activity in the renal cortex was reduced by 13% after isotonic sodium loading (5% of body mass) whereas renal MAO-A and MAO-B activities remained unaltered. Furthermore, preliminary data obtained from spontaneously hypertensive rats, whose basal urinary DA excretion is higher than that of normotensive Wistar-Kyoto rats, show a tendency for renal COMT activity to be lower. It is concluded that MAOinhibition by phenelzine does not alter sodium excretion. Furthermore, specific renal cortical COMT activity is reduced during partly D1-like receptor-mediated natriuresis, whereas MAO activity remains unchanged. The results suggest that MAO is less important than COMT in regulating DA-mediated natriuresis in the rat kidney.

Animals↗

PubMed2006

The significance of the furosemide test for predicting ascites control by diuretics in cirrhotics: a comparison with volume expansion and octreotide infusion.

To verify prospectively the usefulness of the furosemide-induced natriuresis test in predicting ascites control by medical treatment, 15 stable cirrhotics (9 male) with ascites were studied. Sodium excretion was measured after this test and after volume expansion with saline associated with intravenous infusion of octreotide; 6 months later, response to medical treatment was rated as good (N=9) or poor (N=6). Patients with poor ascites control had lower sodium excretion with the furosemide-induced natriuresis test (median, 88 vs 201 mmol; P < 0.01). Poor control was observed in four of four patients with sodium excretion < or =125 mmol, and good control in six of six patients with sodium excretion >175 mmol (P < 0.002). Volume expansion was followed by limited natriuresis (median, 20 mmol), in inverse relationship with plasma active renin concentration (P < 0.001). In conclusion, long-term ascites control is well predicted by the furosemide-induced natriuresis test.

Aged↗

PubMed1989

The diuretic and natriuretic action of human atrial natriuretic peptide in humans: lack of effect of exogenous insulin.

The interaction of exogenous, synthetic human atrial natriuretic peptide [(hANP) (ANF 99-126)] and of exogenous insulin was investigated in six healthy men and in seven type I diabetic patients using the euglycemic clamp technique. A primed-continuous (1.0 mU/kg x min) infusion of biosynthetic human insulin was administered to acutely raise and maintain plasma insulin concentrations at approximately 75 to 100 microU/mL during four hours while plasma glucose concentrations were maintained constant at the fasting level by a variable infusion of glucose. In healthy men a decrease in natriuresis (P less than .01) was seen during a euglycemic clamp study without exogenous hANP. No changes in diuresis and natriuresis were seen during a control experiment without exogenous insulin and glucose. Both in healthy men and in the type I diabetics sequential IV bolus doses of hANP of 100, 200, and 400 micrograms induced an increase in urine flow (P less than .01) and in natriuresis (P less than .01). In healthy men these effects were comparable to those achieved by hANP in the absence of induced hyperinsulinemia. It is concluded that the antinatriuretic action of insulin is of no major relevance in counteracting the pharmacologic action of hANP in healthy men. The effects of pharmacologic doses of hANP on diuresis and natriuresis in patients with type I diabetes mellitus is comparable to that in healthy men.

Adult↗

PubMed2007

Role of PI3K and PKB/Akt in acute natriuretic and NO-mimetic effects of leptin.

Apart from controlling energy balance, leptin, a peptide hormone secreted by white adipose tissue, is also involved in the regulation of cardiovascular function. Previous studies have documented that leptin stimulates natriuresis and nitric oxide (NO) production, but the mechanism of these effects is incompletely elucidated. We examined whether phosphoinositide 3-kinase (PI3K) and its downstream effector, protein kinase B/Akt are involved in acute natriuretic and NO-mimetic effects of leptin in anaesthetized rats. Leptin (1 mg/kg i.v.) induced a marked increase in natriuresis and this effect was abolished by pretreatment with either wortmannin (15 microg/kg) or LY294002 (0.6 mg/kg), two structurally different PI3K inhibitors. Moreover, leptin increased plasma concentration and urinary excretion of NO metabolites, nitrites+nitrates (NO(x)), and of NO second messenger, cyclic GMP. In addition, leptin increased NO(x) and cGMP in aortic tissue. The stimulatory effect of leptin on NO(x) and cGMP was prevented by PKB/Akt inhibitor, triciribine, but not by either wortmannin or LY294002. Triciribine had no effect on leptin-induced natriuresis. Leptin stimulated Akt phosphorylation at Ser(473) in aortic tissue but not in the kidney. These results suggest that leptin-induced natriuresis is mediated by PI3K but not Akt, whereas NO-mimetic effect of leptin results from PI3K-independent stimulation of Akt.

Animals↗

PubMed1998

Effects of endothelin-3 on water and sodium excretion during extracellular volume expansion.

The aim of the present study was to elucidate the role of an IV dose of endothelin-3 (ET-3) (5 ng Kg-1 min-1) on mean arterial pressure (MAP), on diuresis and natriuresis in control and in volume expanded anesthetized rats. A systemic infusion of ET-3 in normal rats (Group I) increased MAP and produced a trend of increasing diuresis, without changes in natriuresis. A 10% body weight expansion (Group II) increased diuresis and natriuresis without changes in MAP. The simultaneous infusion of ET-3 and expansion with saline (Group III) resulted in an increase in MAP, an enhanced diuretic response, and a natriuresis of similar magnitude to that observed in Group II. These results suggest that the diuresis produced by a low dose of exogenous ET-3 in control rats, is independent of sodium excretion. Furthermore, the enhanced diuresis caused by ET-3 during expansion is greater than the addition of ET-3 and expansion effects, suggesting that new mechanisms are triggered in order to maintain volume and salt homeostasis in this state.

Animals↗

PubMed1991

Natriuretic effect of calcium-channel blockers in hypertensives.

This double-blind, randomized, crossover trial characterizes the acute natriuretic response to calcium-channel blockers (CCB) and investigates the role of hemodynamic and hormonal factors in mediating the natriuresis. Thirteen male subjects with essential hypertension received a single oral 20-mg dose of nifedipine or 120 mg of diltiazem. Renal functional and hemodynamic measurements were performed prior to and hourly for 4 hours following medication. Subjects then received these medications for 4 weeks at which time the above studies were repeated. Urinary sodium excretion increased within 60 minutes of CCB administration and the natriuresis was sustained for 4 hours. Cumulative sodium loss during the 4 hours of study was greater with nifedipine (43 +/- 12 mmol) than with diltiazem (18 +/- 6 mmol) (P less than 0.05). Despite natriuresis, urinary potassium excretion was decreased by both agents. Even though both drugs decreased the mean arterial pressure, inulin and paraaminohippurate (PAH) clearances were not altered. Plasma aldosterone concentrations decreased, plasma catecholamine concentrations increased, whereas plasma-renin activity was unchanged with both drugs. Body weight, glomerular filtration rate (GFR), renal plasma flow, plasma-renin activity, plasma aldosterone, and catecholamine concentrations were unchanged following 4 weeks of therapy. The acute natriuretic response after 4 weeks of therapy was similar to the response noted after the first dose. This study concludes that CCB are acutely natriuretic. Despite systemic hypotension, renal hemodynamics are unaltered during CCB therapy. Suppression of aldosterone as well as direct tubular effects of these drugs may mediate the natriuresis. Chronic therapy with CCB does not modify the acute natriuretic response to these agents.

Adult↗

PubMed1983

The effects of rapid saline infusion on sodium excretion, renal function, and blood pressure at different sodium intakes in man.

To examine the effects of increasing dietary sodium intake on natriuresis, filtration rate, and renal blood flow following rapid volume expansion, we infused 2-liter normal saline over 2 hr into normal men in balance at 10, 300, 600, and 800 mEq/day sodium intake. Natriuresis and kaliuresis were related to prior sodium intake. Fractional excretion of sodium (6%-7%) was maximal at the 600 mEq/day sodium intake and increased no further at the 800 mEq/day sodium intake. Although blood pressure increased with rapid saline infusion, natriuresis and blood pressure were not associated. Creatinine clearance decreased or remained constant, while PAH clearance decreased during saline infusion at each level. The data suggest that although natriuresis following rapid saline infusion is dependent upon prior sodium intake, under given circumstances it may be independent of glomerular filtration rate, renal blood flow, or blood pressure.

Adolescent↗

PubMed1998

Blunted pressure natriuretic response in the old rat: participation of the renal nerves.

With advancing age, there is a generalized reduction in the ability of the kidney to generate a natriuretic response and, in addition, the incidence of salt-sensitive hypertension increases. One event that could link these changes is a defect that develops in the pressure natriuresis response of the old kidney. To test this possibility, we conducted studies on the anesthetized, male Sprague-Dawley rat to determine the effect of abrupt alterations of renal perfusion pressure (RPP) on urinary sodium excretion (U(Na)V). Young (3- to 5-month-old), middle-aged (11- to 13-month-old), and old (18 to 20-month-old) rats were studied, and RPP was varied by clamping the aorta during the infusion of a cocktail of vasoactive hormones that suppressed the activity of endogenous factors. The gain of the pressure natriuresis relationship was severely attenuated in the old rat compared with the young and middle-aged rats. This blunting of the pressure natriuresis relationship in the old rat was partially attenuated by acute renal denervation. This effect was not associated with marked alterations in the filtered load of sodium, implying that aging is associated with a loss of the tubular epithelial response to an acute change in RPP. These observations suggest that the blunted pressure natriuresis may have a role in the increased incidence of salt-sensitive hypertension and that increased renal nerve activity may have a contributory role.

Aging↗

PubMed1988

A renorenal suppression in response to atrial natriuretic peptide in the unilateral ischaemic rat.

1. The present study was carried out to investigate the haemodynamic and natriuretic effects of atrial natriuretic peptide (ANP) in normal rats and in rats with unilateral ischaemia. 2. Twenty-four hour unilateral ureter occlusion gave rise to a marked vasoconstriction in the ipsilateral kidney after its release. Intravenous infusion of ANP doubled p-aminohippurate clearance and inulin clearance and elicited massive natriuresis in the hydronephrotic kidney, while in the contralateral kidney these clearance values were decreased and there was a lack of natriuresis. The responses in the latter kidney were also different from those in the normal rat, in which significant natriuresis was elicited by ANP even though a decrease in p-aminohippurate clearance occurred. 3. After the control kidney in the unilateral hydronephrotic rat was denervated either mechanically or by pretreatment with prazosin, ANP induced a natriuresis in both kidneys. Furthermore, the renal denervation prevented the decrease in inulin clearance in the control kidney after ANP administration. 4. These findings suggest that the renal response to ANP may depend on the vascular tone before administration, and that renal nerve activity may modify the effects of ANP on renal haemodynamics and sodium excretion.

Animals↗

PubMed1991

Aldosterone, atrial natriuretic factor and sodium intake as determinants of the natriuretic response to head-out water immersion in healthy subjects.

1. The effect of sodium intake on the natriuresis and hormonal changes induced by head-out water immersion was studied in seven normal subjects during head-out water immersion and on a control day while successively on 20 mmol of sodium/day and 100 mmol of sodium/day diets. The effects of head-out water immersion were compared with those seen on the control day for both diets. 2. The natriuresis on the 100 mmol of sodium/day diet was significantly greater than on the 20 mmol of sodium/day diet (natriuretic peak: 10.3 +/- 2.2 versus 3.9 +/- 1 mmol of sodium/h; P less than 0.01). The total sodium excretion during the 3 h of head-out water immersion was 26.2 +/- 2.0 mmol on the 100 mmol of sodium/day diet and 9.9 +/- 0.9 mmol on the 20 mmol of sodium/day diet (P less than 0.01). In contrast, the increase in the plasma atrial natriuretic factor level was similar on both diets (peak plasma atrial natriuretic factor level 23.1 +/- 1.9 versus 26.2 +/- 1 pg/ml; not significant). As expected, the baseline serum aldosterone level was higher on the 20 mmol of sodium/day diet and, despite a significant suppression, remained significantly higher at the end of the third hour of head-out water immersion (peak serum aldosterone level: 495 +/- 130 versus 197 +/- 26 pmol/l, P less than 0.06). Furthermore, there was an inverse relationship between the serum aldosterone level and the urinary sodium excretion at the time of peak natriuresis (r = -0.59, P less than 0.01). 3. We conclude that the effect of sodium intake on the natriuresis induced by head-out water immersion is more dependent upon anti-natriuretic agents, such as aldosterone, than on natriuretic factors, such as atrial natriuretic factor.

Adult↗

PubMed1997

L-arginine reverses the antinatriuretic effect of cyclosporin in renal transplant patients.

BACKGROUND: Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine. DESIGN: Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h. RESULTS: The first day, after cyclosporin administration a significant fall (P < 0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P < 0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2. CONCLUSION: These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.

Adult↗

PubMed1988

Acute hypertensive and natriuretic responses following preoptic hypothalamic lesions.

The tissue surrounding the anteroventral portion of the third ventricle (the AV3V region) is critical for control of sodium balance and cardiovascular regulation. Ablation of this brain area results in an acute natriuresis and an increase in blood pressure. The purposes of these experiments were to determine the mechanism of the natriuretic response and assess whether the natriuresis contributes to the decreased blood volume following AV3V ablation. Rats were instrumented with metal lesioning electrodes in the AV3V region and with catheters in the femoral artery and jugular vein. Following electrolytic lesioning or control procedures, blood pressure, heart rate, urine flow rate and urinary sodium excretion were monitored. In separate groups of animals, plasma and blood volume were measured by calculating dilution of 125I-labelled serum albumin and hematocrit. Results from these studies showed that ablation of the AV3V region resulted in a significant elevation in blood pressure (18 +/- 3 mm Hg), increase in sodium excretion (212 +/- 36 mu Eq/hour), and decrease in plasma volume (10.3 +/- 0.4 mL) compared with control-treated animals (2 +/- 4 mm Hg; 89 +/- 34 mu Eq/h, 12.0 +/- 0.5 mL). This natriuretic response was accompanied by an increased plasma aldosterone concentration. Further, prevention of the hypertensive response abolished the natriuresis. These data suggest that AV3V ablation produces an acute pressure-mediated natriuresis, resulting in decreases in plasma and blood volume.

Aldosterone↗

PubMed1992

Effects of the selective neutral endopeptidase inhibitor, retrothiorphan, on renal function and blood pressure in conscious normotensive Wistar and hypertensive DOCA-salt rats.

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗