Urinary Cyclic GMP Excretion Research Articles

An antagonist for atrial natriuretic peptide receptors ameliorates glomerular hyperfiltration in diabetic rats

SUMMARY: To evaluate the possible contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration, we examined the effect of nonpeptide competitive antagonist for biological receptors of ANP, HS-142-1, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in diabetic rats. Increased GFR and RPF in diabetic rats were significantly ameliorated by the injection of HS-142-1, while blood pressure remained unchanged. Urinary cyclic GMP excretion was significantly higher in diabetic rats than in control rats and HS-142-1 decreased urinary cGMP excretion significantly. These results indicate that atrial natriuretic peptide contributes to the development of glomerular hyperfiltration and hyperperfusion in diabetes and HS-142-1 might be useful in the treatment of them.

Exercise Increases Systemic Nitric Oxide Production in Men

Our aim was to compare the effects of exercise on systemic nitric oxide formation, assessed from the urinary excretion rates of nitrate and of cyclic GMP, in endurance-trained and untrained men. Ten endurance-trained and six untrained men underwent a submaximal exercise test for 30 min at 60% of their individual maximal work capacity. Urinary excretion rates of nitrate (measured using gas chromatography) and cyclic GMP (measured using a radioimmunoassay) were assessed at hourly intervals. Urinary nitrate excretion was comparable at rest in the two groups (104 +/- 35 and 110 +/- 19 mumol/mmol creatinine; NS), more than doubled during exercise in both groups (236 +/- 88 mumol/mmol creatinine in untrained and 252 +/- 39 mumol/mmol creatinine in trained participants; P < 0.01 for both groups) and decreased rapidly after the completion of the exercise test. Excretion of urinary cyclic GMP at rest was four times higher in the endurance-trained than in the untrained men (21 +/- 5 compared with 6 +/-1 nmol/mmol creatinine; P < 0.05). During the exercise test, GMP excretion approximately doubled in both groups (52 +/- 12 and 10 +/- 1 nmol/mmol creatinine, respectively; P < or = 0.01 for both groups) and returned to baseline at the end of the test. Urinary cyclic GMP and nitrate excretion correlated well in both groups (p < 0.05). Atrial natriuretic factor is also a stimulator of cyclic GMP formation but resting plasma levels of atrial natriuretic factor did not differ between the groups (22 +/- 3 compared with 21 +/- 4 pmol/l; NS). An acute submaximal exercise test increases the formation of nitric oxide, reflected in the increase in urinary excretion of nitrate and cyclic GMP. This increase may contribute to vasodilatation during physical exercise and at least partly explain the beneficial effects of physical training in patients with vascular diseases.

Atrial natriuretic peptide and C-type natriuretic peptide in spontaneously hypertensive rats and their vasorelaxing actions in vitro.

The present study determined circulating concentrations of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) and also investigated the vasorelaxing action of ANP and CNP on isolated contracted aorta. We also defined the vasorelaxing action of a novel and newly synthesized 27-amino acid chimera of ANP and CNP termed vasonatrin peptide (VNP), which we compared with ANP and CNP in WKY rats and SHR. Plasma and urinary cyclic GMP and sodium excretion were also investigated. Plasma ANP was increased in SHR in contrast to no change in circulating CNP. Plasma and urinary cyclic GMP and sodium excretion were no different between WKY rats and SHR. In WKY rats maximal relaxations to VNP in aortic rings without endothelium were greater than those to ANP and CNP. In SHR aortic rings the potency of VNP relaxation was preserved, the actions of ANP were enhanced, and the actions of CNP were markedly impaired. In association with these vasorelaxing actions, these data suggest that (1) circulating CNP is not different in SHR and WKY rats, but the aortic relaxing action of CNP is markedly impaired in SHR; (2) endogenous plasma ANP is significantly increased in SHR without associated increases in plasma or urinary cyclic GMP; (3) there is an increase in aortic relaxation to exogenous ANP in SHR; and (4) VNP has a potent endothelium-independent aortic relaxing action in both WKY rats and SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms underlying the augmented responses of deoxycorticosterone acetate-salt hypertensive rats to neutral endopeptidase inhibitors

To explore the mechanisms for augmented neutral endopeptidase inhibitor-induced natriuresis in deoxycorticosterone acetate (DOCA)-salt rats. We examined effects of a neutral endopeptidase-inhibitor, candoxatril, on plasma and urinary brain natriuretic peptide (BNP) levels, the influence of a specific atrial natriuretic peptide (ANP) receptor antagonist, HS-142-1, on the response to candoxatril, and the renal neutral endopeptidase activity in DOCA-salt rats. Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats. These effects were associated with a significant rise in the plasma BNP level and the plasma ANP level in DOCA-salt rats. Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril. Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion. Urinary neutral endopeptidase-like activity was greater in DOCA-salt rats than in control rats. Northern blot analysis revealed that the ratio of renal neutral endopeptidase messenger RNA (mRNA) to beta-actin mRNA was comparable between the two groups. The neutral endopeptide inhibitor exerted its hypotensive and natriuretic effects mainly via the potentiation of the endogenous natriuretic peptides, including BNP. The augmented response of DOCA-salt rats also seems to be mediated by both the downregulation of clearance receptors and an increase in renal neutral endopeptidase activity.

Role of nitric oxide synthesis in salt-sensitive hypertension in Dahl/Rapp rats.

Nitric oxide is a potent endogenous vasodilator that regulates arterial tone. A family of nitric oxide synthases uses L-arginine and L-homoarginine stereospecifically as substrates for nitric oxide production in vivo. By preventing expression of inducible but not constitutive nitric oxide synthases, glucocorticoids differentiate which enzyme in this family is the predominant source of nitric oxide generation in a given situation. We proposed that defective production of nitric oxide produces salt-sensitive hypertension in the Dahl/Rapp rat. Plasma concentrations of L-arginine, citrulline, and ornithine of salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats on 8% sodium chloride chow for 1 week did not differ. However, intravenous infusion of L-arginine and L-homoarginine, but not D-arginine, increased urinary excretion of nitrate, the degradation product of nitric oxide, and simultaneously lowered blood pressure in hypertensive SS/Jr rats. Oral L-arginine also prevented development of hypertension and increased urinary excretion of cyclic GMP and nitrate in these rats. Dexamethasone, in a dose that prevented hypotension from parenteral injection of lipopolysaccharide, completely prevented the increase in excretion of cyclic GMP and nitrate, and hypertension resulted despite concomitant treatment with L-arginine. These studies supported an important role of dexamethasone-suppressible nitric oxide synthesis in the prevention of salt-sensitive hypertension in the Dahl/Rapp rat.

Atrial natriuretic peptide in renal development

Although discovered little more than a decade ago, atrial natriuretic peptide (ANP) has been shown to play a significant role in the maintenance of sodium homeostasis. Immediately after birth, plasma ANP concentration is very high concurrent with right atrial dilatation and a high urinary excretion of cyclic GMP (cGMP), the second messenger for ANP. Following postnatal diuresis and natriuresis, atrial volume, plasma ANP concentration, and urinary cGMP excretion decrease to baseline levels. In the ensuing suckling period, the diuretic and natriuretic response to acute saline volume expansion are attenuated, an effect which is offset by the lower hematocrit at this age. Increase in hematocrit by isovolemic exchange transfusion results in a greater rise of plasma ANP concentration following volume expansion, but a reduced excretion of cGMP. Intravenous infusion of ANP results in greater plasma ANP concentration, and greater urinary excretion of cGMP and sodium, in adult than in young rats. This increased metabolic clearance of ANP during early development is due at least in part to increased activity of clearance receptors. In addition, neutral endopeptidase contributes to removal of circulating ANP in maturing as well as adult rats. Infusion of ANP in neonatal or adult rats results in accumulation of cGMP in glomerular podocytes, with a higher threshold for activation in immature animals. Despite the similar response of intracellular generation of cGMP following exposure to ANP in neonatal and adult rats, egression of ANP out of glomeruli is low in neonates, an effect that is due to immaturity of an organic acid transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of neutral endopeptidase inhibition in euvolemic and hypervolemic rats

Candoxatrilat is a potent and selective inhibitor of neutral endopeptidase (EC 3.4.24.11), the enzyme responsible for the degradation of atrial natriuretic factor (ANF). In these studies, the renal effects of candoxatrilat were in euvolemic and hypervolemic anaesthetised rats. In euvolemic rats, candoxatrilat (675 μg/kg per h) had no effect on urine output, sodium and potassium excretion or urinary cyclic GMP excretion. However, in hypervolemic rats, the natriuretic responses to volume expansion were markedly potentiated by the candoxatrilat infusion, with a concomitant increase in urinary cyclic GMP. Acute volume expansion was characterised by natriuresis, diuresis and increased levels of plasma ANF and cyclic GMP (1.5-fold and 2-fold increases respectively, when compared to euvolemic rats). The results presented suggest that plasma ANF levels and volume status modulate responses to neutral endopeptidase inhibition. The development of the neutral endopeptidase inhibitor, candoxatrilat, provides the opportunity to exploit endogenous ANF effectively in disease state with elevated ANF.

Antagonist for Atrial Natriuretic Peptide Receptors Ameliorates Glomerular Hyperfiltration in Diabetic Rats

To evaluate the possible contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration, we examined the effect of non-peptide competitive antagonist for biological receptors of ANP, HS-142-1, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in diabetic rats. Increased GFR and RPF in diabetic rats were significantly ameliorated by the injection of HS-142-1, while blood pressure remained unchanged. Urinary cyclic GMP excretion was significantly higher in diabetic rats than in control rats and HS-142-1 decreased urinary cGMP excretion significantly. These results indicate that atrial natriuretic peptide contributes to the development of glomerular hyperfiltration and hyperperfusion in diabetes and HS-142-1 might be useful in the treatment of them.

Renal lymphatic obstruction in diabetic rats induces systemic hypotension.

We obstructed renal lymph drainage from a single kidney in diabetic rats who had received 65 mg/kg streptozotocin 6 months prior to the study. Lymphatic obstruction led to a progressive fall in systematic blood pressure from a mean arterial pressure of 101 +/- 5 (SEM) mm Hg (n = 7) to 62 +/- 4 mm Hg (n = 5) (p < .02) after 1.5 h. No change was seen in a sham-operated animal. Despite the decline in systemic blood pressure there was no significant change in the GFR of either kidney. Sodium excretion increased significantly in the experimental kidney. There was no change in the urinary excretion of cyclic GMP from either kidney, and plasma levels of atrial natriuretic peptide (ANP) did not change (55 +/- 21 pg/mL pre- to 64 +/- 18 postobstruction). The results are consistent with a systemic vasodilatation after lymphatic obstruction. The mechanism of this response is still under investigation, but apparently it does not involve ANP.

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)

Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome.

Experimental nephrotic syndrome results in sodium retention, reflecting, at least in part, an intrinsic defect in renal sodium handling in the distal nephron. We studied the relationships among plasma atrial natriuretic peptide (ANP) concentration, sodium excretion (UNaV), and urinary cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP in vitro, in rats with adriamycin nephrosis (6-7 mg/kg body weight, intravenously). 3-5 wk after injection, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline, 2% body weight given over 5 min. 30 min after onset of the infusion, plasma ANP concentrations were elevated in normals and were even higher in nephrotics. Despite this, nephrotic animals had a reduced rate of UcGMPV after the saline infusion, and accumulation of cGMP by isolated glomeruli and IMCD cells from nephrotic rats after incubation with ANP was significantly reduced compared to normals. This difference was not related to differences in binding of 125I-ANP to IMCD cells, but was abolished when cGMP accumulation was measured in the presence of 10(-3) M isobutylmethylxanthine or zaprinast (M&B 22,948), two different inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Infusion of zaprinast (10 micrograms/min) into one renal artery of nephrotic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. These results show that, in adriamycin nephrosis, blunted volume expansion natriuresis is associated with renal resistance to ANP, demonstrated both in vivo and in target tissues in vitro. The resistance does not appear related to a defect in binding of the peptide, but is blocked by PDE inhibitors, suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.

Effect of neutral endopeptidase inhibitor in rats with congestive heart failure.

1. The acute hormonal, renal and haemodynamic effects of SCH 39370, a new neutral endopeptidase (NEP) inhibitor, were evaluated in rats with congestive heart failure (CHF) produced by coronary ligation. 2. Left ventricular systolic pressure and left ventricular end diastolic pressure were significantly decreased by SCH 39370 treatment. 3. SCH 39370 improved cardiac function by increasing cardiac index and decreasing total peripheral resistance. 4. SCH 39370 induced a transient but significant diuresis and natriuresis. 5. These effects were associated with significant increases in urinary atrial natriuretic peptide (ANP) and cyclic GMP excretion, but not with an increase in plasma ANP levels. 6. The results suggest that NEP inhibition may be a new therapeutic method for treating CHF possibly by potentiating the biological activities of endogenous ANP.

Effects of saline loading during head down tilt on ANP and cyclic GMP levels and on urinary fluid excretion

In the present study the renal and humoral effects of acute saline infusions were investigated in six healthy male volunteers before, during and after a ten day period of −6° head-down-tilt (HDT). During the whole 23-day study period the subjects received a standardized diet including 40 ml water and 125 mg NaCl per kg body weight per day. After the infusion of 0.9% saline (22 ml/kg within 20 minutes) plasma atrial natriuretic peptide (ANP) levels were only slightly increased (not significant) at the end of the infusion, while plasma cyclic GMP levels were significantly increased by about 40% (p<0.05) one hour later. No difference was observed in the plasma ANP and cyclic GMP changes between the pre-HDT, the HDT and the post-HDT infusion experiment. Urine flow, sodium excretion and urinary cyclic GMP excretion were significantly increased (p<0.05 and below) by 100 to 300% during the second and third hour after each saline infusion. However, during these short-term periods only 20% of the infused water and less than 20% of the infused sodium were excreted. Furthermore, a significantly increased volume, sodium and cyclic GMP excretion was observed for over 48 hours after each fluid load experiment.These data suggest that HDT does not induce major alterations in the regulation of an acute saline infusion and plasma ANP does not play a major role in the diuretic/natriuretic effects of volume loading.

Glomerular Filtration Rate in Streptozocin-Induced Diabetic Rats: Role of Exchangeable Sodium, Vasoactive Hormones, and Insulin Therapy

The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide – cyclic GMP coupling and urinary sodium excretion during acute volume expansion in man

The present study examines hormonal and renal responses to acute volume expansion in normal man, with particular emphasis on the atrial natriuretic peptide (ANP)--cyclic GMP coupling. Two liters of isotonic saline were infused into eight normotensive male subjects over a 1-h period. Plasma and urinary measurements were made before, during, and up to 300 min after the start of the saline infusion. With the initial increase in urinary sodium excretion there were increases in plasma ANP and plasma cyclic GMP, which reached maximum levels at 15 min after the end of the saline infusion. Urinary cyclic GMP increased gradually during saline infusion up to approximately 60 min after the end of the infusion. Plasma ANP and plasma and urinary cyclic GMP excretion gradually declined thereafter. By contrast, urinary sodium excretion remained elevated up to the end of the observation period. The saline infusion was associated with marked reductions in plasma renin activity and aldosterone, which persisted up to the end of the study. These results suggest a coupling between the increases in plasma ANP, the production of cyclic GMP, and urinary sodium excretion, in particular during the initial renal response to acute volume expansion. However, other mechanisms including the suppression of the renin--angiotensin--aldosterone system may become increasingly important in the later natriuretic response to acute volume expansion.

Stereoselective protection of exogenous and endogenous atrial natriuretic factor by enkephalinase inhibitors in mice and humans

We compared the relative potencies of sinorphan and retorphan, the S- and R-enantiomers of acetorphan a potent inhibitor of enkephalinase (EC 3.4.34.11), to inhibit membrane metalloendopeptidase in vivo and to protect exogenous and endogenous ANF after oral administration. In mice, sinorphan was 2–3 fold as potent as retorphan in inhibiting the specific in vivo binding of [ 3H]acetorphan to kidney enkephalinase. The same potency ration was found for the enhancement of trichloroacetic acid-precipitated radioactivity in kidneys of mice that had received 125I-ANF, which is used as a test for the protection of the hormone against inactivation in vivo. In nine healthy human volunteers who had received a low oral dosage of sinorphan or retorphan in a double-blind, placebo-controlled, randomized trial, sinorphan was also 2–3 fold more potent than retorphan in inhibiting plasma enkephalinase activity. These effects were accompanied by a related rise in plasma ANF immunoreactivity, which also reflected the difference in the effectiveness of the two compounds. Sinorphan was also more potent than retorphan in enhancing urinary cyclic GMP excretion and sodium excretion in five of these subjects. These data indicate that, in humans as in rodents, enkephalinase plays a crucial role in the inactivation of ANF, its partial inhibition in vivo being accompanied by a significant protection of the exogenous or endogenous hormone as well as by typical ANF-like responses. Thus orally administered sinorphan appears to be a promising compound for therapeutic use in cardiovascular and renal diseases in which ANF has been postulated to exert beneficial effects.

Electrolyte and Humoral Responses of Renal Transplant Patients to Head-Out Water Immersion

Eighteen renal transplant recipients and sixteen volunteers were subjected to the physiological manoeuvre of head-out water immersion, in order to compare changes in electrolyte and humoral responses known to occur in healthy individuals with those arising as a result of renal denervation in the transplant recipients. Although the tubular sodium response to water immersion was normal, tubular potassium excretion was markedly different in the transplant patients. Plasma values of atrial natriuretic factor increased in both groups and showed a close temporal relationship to urinary excretion of cyclic GMP. The attenuation in transplant recipients of the well-documented suppression of plasma renin activity during water immersion was probably due to a combination of factors, namely lack of renal innervation and an increase in circulating ANF. The small but significant increase in the excretion of enzymically active urinary kallikrein observed only in the transplant recipients during immersion still requires explanation.

The Significance of cGMP and Dopamine Receptor on the Natriuretic and Hypotensive Activities of Synthetic Atrial Natriuretic Polypeptide in Essential Hypertension

This study was undertaken to clarify the role of dopamine receptor (DA2) on the effects of atrial natriuretic polypeptide(ANP) on blood pressure, plasma and urinary cyclic GMP, and urinary sodium excretion, alpha-human ANP (alpha-hANP) was intravenously administrated to 7 normal subjects and 14 patients with essential hypertension as follows: first a dose of 0.01 micrograms/kg/min for 30 minutes, and then 0.03 micrograms/kg/min with or without metoclopramide(MC) for 30 minutes. After the infusion of the 0.03 micrograms/kg/min dose of alpha-hANP, systolic blood pressure fell from 115 +/- 17 mmHg to 109 +/- 15 mmHg in normal subjects, and fell significantly from 163 +/- 33 mmHg to 145 +/- 26 mmHg in patients with essential hypertension. Diastolic blood pressure fell from 101 +/- 14 mmHg to 92 +/- 7 mmHg in patients with essential hypertension but did not change in normal subjects. A dose of 0.03 micrograms/kg/min of alpha-hANP led to a threefold rise in urine volume and twofold rise in urinary sodium excretion in normal subjects, and a fivefold rise in urine volume and fourfold rise in urinary sodium excretion in patients with essential hypertension. However, there was no relationship between the hypotensive and natriuretic effects of alpha-hANP in either normal subjects or patients with essential hypertensions. The infusion of a 0.03 micrograms/kg/min dose of alpha-hANP increased plasma cyclic GMP concentration from 4.1 +/- 2.1 pmol/ml to 34.3 +/- 25.Opmol/ml in normal subjects and from 4.5 +/- 2.6 pmol/ml to 20.3 +/- 7.4 pmol/ml in patients with essential hypertension. The rise in plasma cyclic GMP by alpha-hANP was suppressed by MC both in normal subjects and patients with essential hypertension. Urinary cyclic GMP excretion also increased during the infusion of alpha-hANP, but this effect was not suppressed by MC. Furthermore, plasma aldosterone concentration (PAC), which was depressed by alpha-hANP in normal subjects and patients with essential hypertension, was increased by MC. These results suggest that the hypotensive effect of alpha-hANP may depend not only on the natriuretic effect, but also on vasodilatation, the inhibition of aldosterone production or the suppression of the sympathoadrenomedullary system. Cyclic GMP may be produced through the DA2 receptor in vascular tissue but not in the kidney.

Enkephalinase inhibition increases plasma atrial natriuretic peptide levels, glomerular filtration rate, and urinary sodium excretion in rats with reduced renal mass.

To investigate the in vivo effects of inhibition of endopeptidase 24.11, an enkephalinase enzyme shown to be involved in atrial natriuretic peptide (ANP) breakdown in vitro, we infused phosphoramidon, a specific inhibitor of endopeptidase 24.11, into rats with reduced renal mass (and chronic extracellular volume expansion) and into normal rats. Relative to baseline values in rats with remnant kidneys, phosphoramidon led to elevations of plasma ANP levels and concomitant increases in urinary sodium excretion, fractional excretion of sodium, glomerular filtration rate, filtration fraction, and urinary cyclic GMP excretion. Similar changes in renal function and urinary cyclic GMP excretion were obtained with thiorphan, another endopeptidase 24.11 inhibitor. These enhanced ANP levels and renal actions were not observed with phosphoramidon in normal rats. These results show that plasma ANP levels can be modulated in rats with reduced renal mass by inhibition of endopeptidase 24.11.

Renal and Adrenal Resistance against Atrial Natriuretic Peptide in Congestive Heart Failure: Effect of Angiotensin I-Converting-Enzyme Inhibition

We compared the natriuretic and diuretic effect of an intravenous infusion of 1-28 human atrial natriuretic peptide (hANP) (0.1 micrograms/kg/min over 30 min) in 10 patients with congestive heart failure (CHF) and in 10 control subjects of similar age and sex. In the controls, urine volume rose from 36.8 +/- 8.55 to 115.6 +/- 34.2 ml/30 min and urinary sodium excretion from 4.55 +/- 0.8 to 11.2 +/- 2.24 mEq/30 min before and during the infusion of ANP, respectively. In patients, baseline urine volume and sodium output were similar, however, rise in urine volume and urinary sodium was greatly reduced during the infusion of hANP. In patients with CHF, baseline plasma ANP levels (604.1 +/- 135.3 vs. 39.4 +/- 5.85 pg/ml; p less than 0.005) and urinary excretion of cyclic GMP (cGMP) (41.8 +/- 5.22 vs. 15.2 +/- 4.19 nmol/30 min; p less than 0.05) were significantly elevated compared to controls. The absolute and relative rise in cGMP excretion, however, was blunted in patients with CHF. In the controls, angiotensin I-converting-enzyme (ACE) inhibition by enalapril significantly reduced the urinary output of sodium and water after ANP infusion. Plasma ANP levels and urinary cGMP remained unaltered by ACE inhibition. Furthermore, treatment with enalapril resulted in a rise in renin and a drop in aldosterone levels. The reduction of plasma renin and serum aldosterone by ANP was maintained after ACE inhibition. In the patient group, administration of enalapril (3 X 2.5 mg every 6 h) reduced ACE activity in the serum from 84.7 +/- 16.9 to 2.13 +/- 0.88 U/l. Arterial blood pressure was lowered from 114.7 +/- 6.69 to 106.1 +/- 7.25 mm Hg systolic and from 76.9 +/- 3 to 69.2 +/- 3.7 mm Hg diastolic. However, natriuresis and diuresis and creatinine clearance following infusion of ANP remained unaltered.