atrial-natriuretic-factor and candoxatrilat

Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone.. Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12+/-2%; P=0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (P=0.6) after pretreatment with both placebo (13+/-1%, P=0.006) and enalapril (17+/-6%, P=0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ETA antagonist BQ-123 (100 nmol/min), and both combined. Thiorphan caused local forearm vasoconstriction (13+/-1%, P=0.0001); BQ-123 caused local vasodilatation (33+/-3%, P=0.0001). Combined thiorphan and BQ-123 caused vasodilatation (32+/-1%, P=0.0001) similar to BQ-123 alone (P=0.98). In a fourth study, 6 hypertensive patients (blood pressure >160/100 mm Hg) received intra-arterial thiorphan (30 nmol/min). Thiorphan caused a slowly progressive forearm vasoconstriction (10+/-2%, P=0.0001).. Inhibition of local NEP causes vasoconstriction in forearm resistance vessels of both healthy volunteers and patients with hypertension. The lack of effect of ACE inhibition on the vasoconstriction produced by thiorphan and its absence during concomitant ETA receptor blockade suggest that it is mediated by endothelin-1 and not angiotensin II. These findings may help to explain the failure of systemic NEP inhibition to lower blood pressure.

Topics: Adult; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Coronary Vessels; Cross-Over Studies; Cyclohexanecarboxylic Acids; Enalapril; Endothelin-1; Humans; Hypertension; Injections, Intra-Arterial; Male; Middle Aged; Myocardium; Neprilysin; Peptides, Cyclic; Protease Inhibitors; Renin; Single-Blind Method; Thiorphan; Vasoconstriction

Atrial natriuretic factor (ANF) has natriuretic, renin-suppressing and chronic hypotensive actions that may be utilized by inhibition of ANF degradation by neutral endopeptidase, E.C.24.11 (NEP). Three groups of 8 male patients [GFR 103 +/- 8 (Normal), 64 +/- 6 (Moderate CRF), and 16 +/- 2 ml/min (Severe CRF)] received 100 mg i.v. bolus of the NEP inhibitor candoxatrilat or placebo in random order in a double-blind crossover study. GFR (51CR-EDTA), ERPF (125I-hippuran). ANF (IRMA), urinary cGMP (RIA) and albumin (RIA) and sodium excretion and flow rate were measured hourly for two hours before and for seven hours after candoxatrilat administration. After candoxatrilat plasma ANF rose two- to threefold from baseline, and remained elevated for 5(N) and 7(M,S) hours (P < 0.01(N,S), P < 0.03(M)) associated with an immediate rise in urine cGMP excretion from 23.5(N), 25.4(M) and 10.4(S) nmol/hr (base) to 51.7(N), 73.8(M) and 27.5(S)(peak) lasting 7(N,M,S) hours (P < 0.01(N,M,S)). There was a marked natriuresis in all three groups, the cumulative sodium excretion at seven hours post-candoxatrilat being 104(N), 140(M), 102(S) mmol (P < 0.05(N,M,S)). This was greatest in those with moderate CRF (moderate CRF vs. normal, P = 0.036, moderate vs. severe CRF, P = 0.01, normal vs. severe CRF, P = 0.74). Following candoxatrilat there was a near doubling of the urine flow rate (P < 0.01(N,S), P < 0.02(M)). Urine albumin excretion increased in patients with renal failure (P < 0.01), but there was no change in GFR, ERPF or systemic blood pressure. We conclude that the marked natriuretic effects of acute NEP inhibition seen in normal subjects are enhanced in the presence of moderate CRF and sustained even in severe renal impairment.

Topics: Adult; Aged; Albuminuria; Atrial Natriuretic Factor; Cross-Over Studies; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuresis; Double-Blind Method; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Natriuresis; Neprilysin; Protease Inhibitors; Renal Circulation

Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function.. Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study. Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation.. After administration of candoxatrilat, plasma atrial natriuretic factor rose from 12.8+/-1.6 (mean +/- SEM) to 44.1+/-6.8 pmol/L (P<0.001) in association with a threefold increase in urine cGMP excretion (573+/-195 pmol/min baseline to 1823+/-545 pmol/ min; P<0.001), marked natriuresis (207+/-34 micromol/min baseline to 416+/-62 micromol/min; P<0.001), fractional sodium excretion (3.3+/-0.5% baseline to 5.6+/-0.7%; P<0.01), and diuresis (3.4+/-0.5 ml/min baseline to 7.4+/-1 ml/min; P<0.001). All parameters remained elevated above baseline for the remaining 7-hr study period. In response to candoxatrilat, the glomerular filtration rate rose by 19% (P=0.01), renal plasma flow by 7% (P=0.04), renal blood flow by 13% (P=0.03) in association with an increase in filtration fraction from 24+/-2% to 28+/-2% (P=0.002) and small fall in renal vascular resistance from 0.38+/-0.04 to 0.30+/-0.04 mmHg x min x 1.73 m2 x ml(-1) (P=0.02). There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median urinary albumin excretion increased after candoxatrilat administration from 48 (3-131) to 114 (32-641) microg/min (P<0.01).. Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Cyclic GMP; Cyclohexanecarboxylic Acids; Cyclosporine; Diuresis; Double-Blind Method; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neprilysin; Protease Inhibitors; Regional Blood Flow; Renal Circulation; Sodium; Vascular Resistance

We studied six healthy male subjects in a randomized, placebo-controlled, single-blind fashion to determine the comparative effects on renal hemodynamics and natriuresis of the angiotensin-converting enzyme inhibitor enalapril (5 mg on each of 5 days preceding the study), the neutral endopeptidase inhibitor candoxatrilat (200 mg IV), and the combination of enalapril and candoxatrilat. Enalapril pretreatment alone, compared with placebo, produced slight nonsignificant increments in absolute and fractional sodium excretions and a marked increase in effective renal plasma flow but no change in glomerular filtration rate. Candoxatrilat alone produced marked augmentation of both absolute and fractional sodium excretions. The candoxatrilat-mediated increment in absolute sodium excretion was significantly correlated with increases in urinary cGMP and plasma atrial natriuretic peptide in response to this drug, but neither effective renal plasma flow nor glomerular filtration rate was altered compared with placebo. Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor. Blood pressure was reduced by enalapril alone compared with placebo, whereas candoxatrilat treatment alone led to a marginal but significant enhancement of blood pressure. The combination of enalapril and candoxatrilat abolished any significant blood pressure change compared with placebo. Thus, candoxatrilat-mediated natriuresis occurs via a renal tubular rather than glomerular mechanism and is blunted by enalapril. This attenuation by enalapril may occur by interference with angiotensin II-dependent effects on the renal tubule or on systemic blood pressure.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Cyclohexanecarboxylic Acids; Double-Blind Method; Drug Interactions; Enalapril; Glomerular Filtration Rate; Humans; Male; Natriuresis; Neprilysin; Renal Circulation; Single-Blind Method

Our primary objective was to compare the effects of three different doses of candoxatrilat with the effects of placebo on urinary volume in patients with moderately severe heart failure. The effects of candoxatrilat on urinary composition, neuroendocrine indexes and renal hemodynamic function were also studied.. Candoxatrilat, a neutral endopeptidase inhibitor, reduces degradation of atrial natriuretic peptide and provokes diuresis in patients with mild heart failure, but the renal effects have not been studied in patients with moderately severe heart failure in a placebo-controlled study.. In a double-blind crossover trial, the effects of intravenous boluses of saline vehicle (placebo) and 50, 100 and 200 mg of candoxatrilat were compared on separate days in 12 patients with heart failure. Urinary output and composition were measured for 8 h. Renal blood flow and glomerular filtration rate were determined by radionuclide techniques. Blood was withdrawn for the measurement of hormones before and 3 h after dosing.. All doses of candoxatrilat increased urinary volume (e.g., [mean +/- SEM] 263 +/- 53 to 490 +/- 82 ml for saline solution and the 200-mg dose, respectively, p < 0.01) and sodium content (14 +/- 4 to 37 +/- 11 mmol, p < 0.001) in the 1st 4 h after dosing. Plasma atrial natriuretic peptide increased (140 +/- 26 to 279 +/- 37 pg/ml, p < 0.01), whereas aldosterone decreased (178 +/- 41 to 125 +/- 35 pg/ml, p < 0.01), and renin activity was unchanged (10 +/- 2 to 12 +/- 3 ng/ml per h).. Candoxatrilat given acutely causes diuresis, even in patients with moderately severe heart failure.

Topics: Aged; Aldosterone; Atrial Natriuretic Factor; Cross-Over Studies; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuresis; Double-Blind Method; Drug Administration Schedule; Electrolytes; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Neprilysin; Renal Circulation; Sodium; Urine; Vasoactive Intestinal Peptide

Topics: Atrial Natriuretic Factor; Cyclohexanecarboxylic Acids; Double-Blind Method; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Neprilysin

+/- Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.. This was a single blind, randomised comparison of +/- candoxatrilat and placebo in patients with mild heart failure. All patients received two intravenous doses of +/- candoxatrilat and two placebo doses on four consecutive days.. A teaching hospital department of cardiology.. Six men (mean age 52 years) with mild heart failure (New York Heart Association class II) due to ischaemic heart disease (four patients) or dilated cardiomyopathy (two patients) were included. Mean ejection fraction was 37.5% and mean peak oxygen consumption was 20.4 ml/min/kg.. Plasma ANF concentrations, haemodynamic indices and left ventricular diastolic function measured by early to atrial filling rate (E:A ratio) with Doppler echocardiography were determined before and after +/- candoxatrilat and placebo.. +/- Candoxatrilat caused a threefold rise of plasma ANF compared with placebo (p < 0.005), but there was no significant change in heart rate, blood pressure, or cardiac output. Mean right atrial pressure fell from 6.7 to 4.7 mmHg (NS) and pulmonary artery wedge pressure fell from 9.2 to 6.7 mmHg (p < 0.05). Doppler echocardiographic measurements of transmitral blood flow showed a significant fall in peak early left ventricular filling velocity from 39.5 to 34.2 cm/s (p < 0.05), along with a non-significant rise in peak atrial filling velocity from 39.7-41.6 cm/s after +/- candoxatrilat. The E:A ratio, a Doppler index of left ventricular diastolic function, fell from a mean of 1.04 to 0.87 (p < 0.05).. +/- Candoxatrilat increased plasma ANF concentrations and reduced right atrial and pulmonary artery wedge pressures. No evidence of an improvement in left ventricular systolic or diastolic function was found, so the fall in preload was due to peripheral effects, either an increase in venous capacitance or a fall in circulating blood volume.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclohexanecarboxylic Acids; Heart Rate; Humans; Male; Middle Aged; Neprilysin; Pulmonary Wedge Pressure; Random Allocation; Single-Blind Method; Ventricular Function, Left

The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.

Topics: Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Carbamates; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Injections, Intravenous; Kidney; Male; Middle Aged; Natriuresis; Neprilysin; Propionates; Renin; Sodium

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Carbamates; Cardiac Output, Low; Chronic Disease; Cyclohexanecarboxylic Acids; Diuresis; Dose-Response Relationship, Drug; Hemodynamics; Humans; Kidney; Male; Middle Aged; Natriuresis; Neprilysin; Propionates; Pulmonary Wedge Pressure; Renin; Sodium

UK 69 578 is a competitive inhibitor of endopeptidase 24.11 (the enzyme that degrades atrial natriuretic factor) in vitro. In vivo, UK 69 578 has renal and cardiovascular effects similar to low-dose atrial natriuretic factor infusion, and may be a useful agent in hypertension and heart failure.

Topics: Animals; Atrial Natriuretic Factor; Clinical Trials as Topic; Coronary Disease; Cyclohexanecarboxylic Acids; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Drug Evaluation, Preclinical; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged; Natriuresis; Nephrectomy; Neprilysin; Rats; Rats, Inbred Strains; Time Factors

In liver cirrhosis atrial natriuretic peptide (ANP) decreases portal vascular resistance and tributary flow. The enzyme neutral endopeptidase (NEP) degrades ANP and bradykinin and generates endothelin-1 from big-endothelin. We determined the effects of NEP inhibition by candoxatrilat on hormonal status, liver function and arterial and portal pressures in rats with CCl4-induced cirrhosis.. Two groups of seven control rats received 1 ml 5% glucose solution alone or containing 10 mg/kg candoxatrilat; three groups of 10 ascitic cirrhotic rats received placebo, 5 or 10 mg/kg candoxatrilat. NEP protein concentration and immunostaining were analyzed in normal and cirrhotic livers.. In cirrhotic rats 10 mg/kg candoxatrilat significantly increased steady-state indocyanine green clearance (a parameter reflecting liver plasma flow) (P<0.01), decreased portal pressure (P<0.01), had no effect on arterial pressure and plasma renin activity but increased ANP plasma levels (P<0.05) and urinary excretions (P<0.01) of ANP and cGMP. In the cytosol fraction of rat cirrhotic livers a 280% increase in NEP content was found (P<0.01), chiefly localized in desmin-positive myofibroblast-like cells of fibrous septa.. Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance.

Topics: Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Carbon Tetrachloride; Cyclic GMP; Cyclohexanecarboxylic Acids; Cytokines; Endothelin-1; Humans; Hypertension, Portal; Liver; Liver Cirrhosis, Experimental; Male; Neprilysin; Portal Vein; Protease Inhibitors; Rats; Rats, Wistar; Vascular Resistance

Recent reports presented contradictory results regarding the catabolism of mature atrial (ANP) and brain (BNP) natriuretic peptides in circulation. Especially the role of neutral endopeptidase (NEP) in BNP degradation was conversely discussed. Our present in vitro-studies characterize the NEP-dependent metabolism of ANP and BNP in different tissues via HPLC-analysis using NEP-deficient mice and specific NEP inhibitors. Our results show a strong tissue-dependent degradation pattern of both peptides, which are not only due to the different NEP activities in these tissues. Whereas NEP rapidly degraded ANP, it had no influence in BNP-metabolism. Additional experiments with purified NEP confirmed this result. Moreover, we describe a degradation of ANP and BNP in NEP-deficient- and NEP-inhibited membranes. Consequently, we postulate the existence of at least one further natriuretic peptide (NP) degrading enzyme, which has not been characterized yet. Thus, the commonly accepted model of the natriuretic peptide system with NEP as the central degrading peptidase has to be partly revised. Moreover, the NEP-independent BNP degradation provides an effective means for achieving a beneficial BNP increase in cardiovascular pathology by inhibiting the assumed novel NP-degrading peptidase(s).

Topics: Animals; Atrial Natriuretic Factor; Brain; Cell Membrane; Cyclohexanecarboxylic Acids; Enzyme Inhibitors; Heart; Humans; Kidney; Lung; Mice; Mice, Knockout; Natriuretic Peptide, Brain; Neprilysin

Topics: Animals; Atrial Natriuretic Factor; Cyclohexanecarboxylic Acids; Dogs; Drugs, Investigational; Endopeptidases; Heart Failure; Hemodynamics; Humans; Neurotransmitter Agents; Protease Inhibitors; Renal Agents

This study was performed to determine effects of atrial and brain natriuretic peptides (ANP, BNP) on neutrophils-induced endothelial injury which is known to play a role in the pathophysiology of ischemia/reperfusion myocardial injury and to examine whether the effects of ANP and BNP on neutrophils are modulated by neutral endopeptidase 24.11 (NEP) in neutrophils themselves. The incubation of human neutrophils with ANP and BNP inhibited the neutrophils-induced detachment of cultured human endothelial cells (HEC). The inhibitory effect of ANP and BNP was associated with the suppressions of the neutrophils adhesiveness to HEC, CD18 expression on the neutrophils and elastase release from the neutrophils. Coincubation with UK73967 or phosphoramidon, inhibitors of NEP, potentiated all of the effects of ANP and BNP on the neutrophil functions, and the NEP inhibitors protected degradation of ANP and BNP by the neutrophils. NEP enzymatic activity in the particulate fractions and immunoreactive NEP expression were found to increase in the neutrophils from patients with early phase of acute myocardial infarction (AMI) by 5.2- and by 4.2-fold of the neutrophils from patients with late phase of AMI, respectively. In an in vivo canine model of myocardial ischemia/reperfusion, the intravenous administration of UK73967 suppressed the neutrophil adherence to endothelium and the neutrophil accumulation in the ischemic/reperfused myocardium. The results indicate that ANP and BNP, which are known to increase in AMI, modulate the neutrophil functions and exert protective effects against the neutrophils-induced endothelial cytotoxity. But the effects are suppressed due to their degradation by the neutrophil own NEP. Thus, neutrophil NEP, which also increases in AMI, may play a role in the pathophysiology of neutrophils-mediated ischemia/reperfusion endothelial and myocardial injury.

Topics: Animals; Atrial Natriuretic Factor; Calcium; Cells, Cultured; Cyclic GMP; Cyclohexanecarboxylic Acids; Dogs; Endothelium, Vascular; Female; Humans; Male; Myocardial Infarction; N-Formylmethionine Leucyl-Phenylalanine; Natriuretic Peptide, Brain; Neprilysin; Nerve Tissue Proteins; Neutrophils

The selection of therapeutic agents for clinical development is principally based upon pharmacodynamic and pharmacokinetic criteria. Although many compounds are routinely tested in pharmacologic assays, direct pharmacokinetic assessment is difficult and not applicable to a large number of agents. Therefore, we have developed a rapid indirect method based on enzyme inhibition for determining the unbound concentration of NEP 24.11 inhibitors in rat plasma. In the present study, drug levels of compounds from three different classes of NEP 24.11 inhibitors: mercaptoalkyl, carboxyalkyl and aminophosphonates were compared. Studies were carried out in conscious, unrestrained rats. Arterial blood samples were obtained 10, 30, 60, 120, and 240 min after drug administration at 10 mg/kg i.v. or 30 mg/kg p.o. The blood was collected in EDTA and plasma prepared immediately. Protein bound NEP inhibitor was separated from plasma by centrifugation through an ultrafiltration membrane. Following acidification and serial dilution, the concentration of unbound inhibitor was determined in the plasma ultrafiltrate using the in vitro assay for NEP 24.11 inhibition. The results of this study indicated that the mercaptoalkyl inhibitor thiorphan was cleared rapidly from plasma, whereas, the plasma concentrations of the carboxyalkyl inhibitor CGS 23880A (UK-69,578), and the plasma concentrations of the aminophosphonate, CGS 24128, were maintained at high levels for at least 4 hours. Furthermore, the ratio of the NEP inhibitor concentration/IC50 value correlated well with the pharmacologic activity of these compounds.

Topics: Animals; Atrial Natriuretic Factor; beta-Alanine; Cyclohexanecarboxylic Acids; Enzyme Inhibitors; Kidney Cortex; Male; Methods; Neprilysin; Organophosphonates; Rats; Rats, Sprague-Dawley; Thiorphan

To further investigate the mechanisms of renal effects of neutral endopeptidase 24.11 (NEP) inhibition, we employed a specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), or nitric oxide (NO) synthase inhibitor, N-monomethyl-L-arginine (L-NMMA), in Sprague-Dawley rats, and evaluated the urinary NEP, kinins, cGMP and plasma atrial natriuretic peptide (ANP). None of the variables changed with vehicle injection. After injection of UK, NEP decreased significantly and urinary kinins, cGMP, urine volume (UV) and urinary sodium excretion (UNaV) increased significantly. Injected Hoe canceled the increase in UV and UNaV induced by UK. Plasma ANP did not show any difference between vehicle and UK groups. With a pretreatment of L-NMMA, injected UK decreased NEP and increased kinins, while urinary cGMP, UV and UNaV did not increase. In conclusion, augmented kinins may play an important role in the renal water-sodium metabolism by NEP inhibition, and NO may contribute to the kinins' action on this mechanism, while ANP may not contribute to it, at least in normotensive rats. Moreover, changes in urinary cGMP do not reflect the changes in plasma ANP, but rather, those in NO under this condition.

Topics: Adrenergic beta-Antagonists; Animals; Arginine; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cyclohexanecarboxylic Acids; Kidney; Kinins; Male; Neprilysin; Nitric Oxide; omega-N-Methylarginine; Protease Inhibitors; Rats; Rats, Sprague-Dawley

To further elucidate the renal effects of NEP inhibition, we employed NEP inhibitor UK 73967 (UK), with or without a kinin receptor antagonist Hoe 140 (Hoe), in Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats. In Sprague-Dawley rats: 1) injected UK significantly decreased NEP, and increased kinins, urine volume (UV) and urinary sodium excretion (UNaV), while none of the variables changed with vehicle treatment; 2) no difference was found in plasma ANP between the vehicle and UK groups; and 3) Hoe canceled the increases of UV and UNaV caused by UK. In DOCA-salt rats: 1) infused UK significantly decreased NEP, and increased UV and UNaV, while UV and UNaV were slightly decreased, and NEP did not change with vehicle treatment; 2) plasma ANP was significantly higher in UK group than in the vehicle group; and 3) Hoe could not abolish the increase of UV and UNaV induced by UK. These data indicate that the contributions of renal kinins and plasma ANP to the diuretic and natriuretic mechanisms of NEP inhibition may differ between Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats.

Topics: Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Bradykinin; Cyclohexanecarboxylic Acids; Desoxycorticosterone; Hypertension; Kidney; Kinins; Male; Neprilysin; Protease Inhibitors; Rats; Rats, Sprague-Dawley

The activity of the renal kallikrein-kinin system is controlled by the concentration of intrarenal kinins. Neutral endopeptidase 24.11 (NEP) cleaves kinins as effectively as kininase I and kininase II. It is also well known that NEP metabolizes atrial natriuretic peptide (ANP). The present study evaluated the effects of NEP inhibitor on renal action by kinins, ANP and nitric oxide in Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats. In normotensive rats, we demonstrated that 1) inhibition of NEP potentiates the contribution of kinins to the renal water-sodium metabolism and overcomes the contribution of ANP to that metabolism, 2) nitric oxide participates in the action of kinins, and 3) changes in urinary cGMP excretion do not reflect the changes in plasma ANP, but the changes in nitric oxide, under these conditions. On the other hand, it was also suggested that augmented ANP may contribute mainly to renal water-sodium handling by NEP inhibitor in DOCA-salt rats. Therefore, the contributions of the two systems to the diuretic and natriuretic mechanisms of NEP inhibition may differ between Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuresis; Kallikrein-Kinin System; Kidney; Kinins; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley; Sodium

To further elucidate the natriuretic mechanisms of neutral endopeptidase 24.11 (NEP) inhibition, we employed a new specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), in Sprague-Dawley rats, and evaluated the renal NEP, kinins and plasma ANP simultaneously. There were no significant changes in urinary NEP, kinins, urine volume (UV) or urinary sodium excretion (UNaV) with vehicle treatment in anesthetized normotensive rats. Infused UK (10 mg/kg) significantly decreased NEP, and increased kinins, UV and UNaV. There was not a significant difference in plasma ANP between the vehicle and UK groups. Simultaneous administration of Hoe (20 nmol/kg) canceled the increases of UV and UNaV caused by UK. From these results, we conclude that inhibition of NEP may exaggerate the contribution of renal kinins to the renal water-sodium metabolism and overcome the contribution of ANP on that metabolism at least in normotensive rats.

Topics: Animals; Atrial Natriuretic Factor; Bradykinin; Cyclohexanecarboxylic Acids; Diuresis; Kidney; Kinins; Male; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley

The aim was to investigate whether infusion of either atrial natriuretic factor (ANF, 800 ng.h-1.rat-1) or a specific inhibitory of neutral endopeptidase 24.11 (NEI, UK 73,967, 5.4 mg.kg-1.d-1) can influence the reversal of the pulmonary vascular remodelling produced by exposure to hypoxia.. Male Wistar rats were kept in a normobaric hypoxic chamber (FiO2 = 10%) for 7 d. Chronically hypoxic rats were then treated with intravenous infusion of vehicle, ANF, or NEI by osmotic minipumps. Measurements of pulmonary artery pressure, systemic blood pressure, heart rate, right ventricular hypertrophy, micro-haematocrit, and pulmonary vascular remodelling (percentage of thick walled peripheral vessels) were made in all the rats at different time points.. The changes in packed cell volume, right ventricular hypertrophy, and pulmonary hypertension induced by a 7 d hypoxic exposure diminished gradually and returned to normal at different time points during the 24 d recovery period. In contrast, vascular hypertrophy in peripheral pulmonary arteries was present after 24 d. There were no significant differences in pulmonary arterial pressure, packed cell volume, right ventricular hypertrophy and vascular remodelling between ANF, NEI, and vehicle treatment groups at either day 8 or day 15.. ANF and NEI treatment had no effect on the reversal of pulmonary hypertension, right ventricular hypertrophy, and vascular remodelling, in contrast to the beneficial actions of ANF and NEI during the development of pulmonary vascular remodelling.

Topics: Animals; Atrial Natriuretic Factor; Cyclohexanecarboxylic Acids; Hematocrit; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Muscle, Smooth, Vascular; Neprilysin; Rats; Rats, Wistar; Time Factors

1. The present studies examined the effect of (a) a specific endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) and (b) a ligand for the atrial natriuretic peptide (ANP) clearance receptor (SC 46542) on the renal and blood pressure response to brain natriuretic peptide (BNP) in conscious rats. 2. Infusion of BNP 200 ng kg-1 min-1 for 60 min produced a small rise in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion with a non-significant fall in mean arterial blood pressure. 3. Candoxatrilat (3 mg kg-1) alone had no significant effect on sodium excretion or blood pressure but markedly potentiated the natriuretic response to BNP. 4. Similarly SC 46542 (68 micrograms kg-1; 6.8 micrograms kg-1 min-1) which produced no significant effect on its own, potentiated the natriuresis-induced by BNP, although the effect was of shorter duration compared to that of candoxatrilat. 5. The data indicate two approaches to the potentiation of the renal activity of BNP and suggest that BNP may mediate some of the activity of E-24.11 inhibitors reported in cardiac failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuretics; Glomerular Filtration Rate; Infusions, Intravenous; Kidney; Ligands; Male; Natriuretic Peptide, Brain; Neprilysin; Nerve Tissue Proteins; Peptide Fragments; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Sodium

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 investigated in euvolemic and hypervolemic anaesthetised rats. In euvolemic rats, candoxatrilat (675 micrograms/kg per h) had no effect on urine output, sodium and potassium excretion or urinary cyclic GMP excretion. However, in hypervolemic rats, the natriuretic and diuretic 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 states with elevated ANF.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclohexanecarboxylic Acids; Hemodynamics; Male; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley; Renin

1. The present studies compared the renal and hypotensive response to (a) exogenous atrial natriuretic peptide (ANP) (99-126), (b) an endopeptidase-24.11 inhibitor (candoxatrilat) and (c) an antagonist of ANP clearance receptors (SC 46542) in conscious rats. 2. Infusion of low-dose-ANP (100 ng kg-1 min-1) produced a gradual increase in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion without significant change in glomerular filtration rate (GFR) or fractional lithium clearance (FeLi). There was a significant fall in blood pressure. 3. Infusion of high-dose ANP (300 ng kg-1 min-1) produced a brisk, 3 fold increase in urinary sodium and cyclic GMP excretion along with a rise in GFR, but had no significant effect on FeLi compared to the control group. The renal response was accompanied by a pronounced fall in blood pressure. 4. Candoxatrilat or SC 46542, alone, had no significant effect on sodium excretion compared to control animals. Both compounds enhanced the natriuretic and cyclic GMP responses to a low-dose ANP infusion (100 ng kg-1 min-1) to levels similar to, or greater than, those observed with the high-dose ANP (300 ng kg-1 min-1). However, unlike high-dose ANP, these renal effects were not accompanied by a significant change in GFR and neither compound potentiated the hypotensive effect of the low-dose ANP infusion. Only candoxatrilat when given with ANP produced a marked rise in FeLi.5. Similarly, combined administration of candoxatrilat and SC 46542 (without exogenous ANP) induced an increase in sodium and cyclic GMP excretion comparable to high-dose ANP but did so without a significant increase in GFR and with a significantly smaller fall in blood pressure. Interestingly, there was no increase in FeLi with the combination of the two compounds, suggesting that the major contribution to sodium excretion came from SC 46542.6. Both candoxatrilat and SC 46542 increased sodium and cyclic GMP excretion in the rat A-V fistula model of heart failure, a model hyporesponsive to infusions of ANP, without significant change in blood pressure.7. These data show that candoxatrilat and SC 46542 do not simply reproduce the effects of an ANP infusion but preferentially enhance the natriuretic response to ANP. Inhibition of E-24.11 may potentiate a tubule action of ANP while the renal mechanism of action of the C-ANP receptor ligand needs further study. Both manipulations are of potential value in the management of heart failure.

Topics: Animals; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuretics; Glomerular Filtration Rate; Lithium; Male; Natriuresis; Neprilysin; Peptide Fragments; Rats; Rats, Wistar

The purpose of this study was to investigate the therapeutic potential of prolonged inhibition of atrial natriuretic factor (ANF) degradation in patients with severe chronic heart failure.. The effects of repeated doses of the endopeptidase inhibitor candoxatrilat (150 mg i.v.) were examined over a 24-hour period in patients with severe chronic heart failure (New York Heart Association class III-IV). Plasma alpha-hANF(99-126) was elevated at baseline (235 +/- 59 pg/ml), increased 2.5-fold at 2 hours after the first dose, and remained significantly elevated throughout the 24-hour protocol. In contrast, pro-hANF(31-67) decreased from 3,151 +/- 616 to 2,072 +/- 362 pg/ml (p less than 0.05). Cardiac index (CI) increased only transiently after the first dose of candoxatrilat (CI, 2.11 +/- 0.2 to 2.67 +/- 0.28 l/min/m2, p less than 0.05). Sodium excretion increased sixfold (p less than 0.05) 2 hours after the first dose of candoxatrilat and remained significantly elevated throughout the protocol. Degree of natriuresis and diuresis in response to candoxatrilat was closely related to baseline cardiac output. Glomerular filtration rate and volume excretion did not change significantly. Pulmonary capillary wedge pressure fell from 23 +/- 3 to 18 +/- 3 mm Hg (p less than 0.05) and remained below baseline throughout the 24 hours. Arterial pressure, heart rate, and total peripheral resistance did not change significantly during the 24-hour period. Urinary cGMP excretion increased fivefold (p less than 0.05), whereas urinary ANF immunoreactivity and plasma cGMP levels remained unchanged. Excretion of prostacyclin metabolite 6-keto-PGF-1 alpha increased 3.3-fold (p less than 0.05). Plasma norepinephrine and epinephrine levels decreased significantly after candoxatrilat and remained suppressed over the 24-hour period. There was also a transient reduction in plasma vasopressin, aldosterone levels, and plasma renin activity. Hematocrit, total protein content, and plasma albumin concentrations did not change, indicating that no fluid shift into the extravascular space had occurred.. 1) The inhibition of ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of bradykinin breakdown (which in turn stimulates renal prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line diuretic agent early in the course of disease rather than in patients with advanced chronic heart failure.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Output; Chronic Disease; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Hormones; Humans; Kidney; Male; Middle Aged; Neprilysin; Time Factors

The effects of candoxatrilat (cis-4-([2-carboxy-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarbonyla mino)- 1-cyclohexane carboxylic acid) and the ring-deleted atrial natriuretic factor (ANF) analogue C-ANF4-23 (des[Gln18, Ser19, Gly20, Leu21, Gly22]ANF4-23-NH2) on the clearance of (3-[125I]iodotyrosyl28)ANF (125I-ANF) were studied in both intact and nephrectomized anaesthetized rats. HPLC analysis was used to verify that the 125I-labelled material isolated by solid phase extraction of rat plasma was intact ANF. In intact animals, clearance of 125I-ANF was biphasic with a T1/2 alpha of 17 sec and T1/2 beta of 95 sec. Volume of distribution (Vd) was 564 mL/kg and plasma clearance (Clp) 248 mL/min/kg. Candoxatrilat, over the dose range 0.01-10 mg/kg i.v., increased T1/2 beta (by a maximum of 56%) and decreased Clp (by up to 52%) with no effect on T1/2 alpha or Vd. C-ANF4-23 (10 micrograms/kg+1 microgram/kg/min i.v.) reduced Vd (by 57%) and Clp (by 54%) with no effect on T1/2 beta, whilst abolishing the T1/2 alpha phase in over 50% of animals. Increasing the dose of C-ANF4-23 did not increase the effect on any of these parameters, apart from a small increase in T1/2 beta. Combining the two agents resulted in a substantial decrease in Clp (76%) whilst the reduction in Vd and increase in T1/2 beta were comparable to those seen with C-ANF4-23 and candoxatrilat alone, respectively. In nephrectomized rats, the pharmacokinetics of 125I-ANF and the changes induced by candoxatrilat were similar to those observed in intact animals, whilst the effects of C-ANF4-23 alone were greater than in intact animals. The combination of C-ANF4-23 and candoxatrilat again produced a substantial increase in T1/2 beta (153%) and decreases in Vd (55%) and Clp (78%) in nephrectomized animals, although these changes could not be distinguished from those seen in intact animals treated with the same combination. Our studies indicate that neutral endopeptidase and ANF-C receptors are both major, and approximately equal, clearance mechanisms for 125I-ANF, together accounting for at least 75% of the total clearance of this peptide in the rat.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Chromatography, High Pressure Liquid; Cyclohexanecarboxylic Acids; Half-Life; Iodine Radioisotopes; Male; Metabolic Clearance Rate; Molecular Sequence Data; Nephrectomy; Neprilysin; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

We have studied the acute effect of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) on pulmonary vascular tone in normoxia and acute hypoxia in the absence and presence of a specific inhibitor of neutral endopeptidase 24.11 (NEI, UK 73, 967, candoxatrilat; Pfizer) in the isolated and blood-perfused rat lung preparation. Baseline pulmonary artery pressure (Ppa) was 16.4 +/- 0.3 mm Hg in lungs from normoxic control rats and 22.5 +/- 0.3 mm Hg in lungs from rats kept in hypoxia (FIO2 = 10%) for 7 days. Acute hypoxic pulmonary vasoconstriction (HPV delta Ppa) was similar in normoxic control rats (9.5 +/- 0.6 mm Hg) and chronically hypoxic rats (9.8 +/- 0.9 mm Hg). NEI at 0.07 and 0.2 mg had no effect on baseline Ppa or HPV delta Ppa. Synthetic BNP at 10 nM had no effect on baseline Ppa but produced a 2.8 +/- 0.2 mm Hg reduction in HPV delta Ppa alone and 2.7 +/- 0.2 mm Hg reduction in the presence of 0.07 mg NEI in normoxic control rats. In contrast, ANP at 10 nM produced a significantly greater decrease in HPV delta Ppa in the presence of 0.07 mg NEI (4.8 +/- 0.3 mm Hg, p < 0.05) compared with ANP alone (2.9 +/- 0.4 mm Hg), and similar results were also observed in chronically hypoxic rats. Thus, BNP has a vasodilator effect similar to that of ANP in the pulmonary circulation. Inhibition of neutral endopeptidase 24.11 augments the effects of ANP on HPV but does not influence the pulmonary vascular responses to BNP.

Topics: Animals; Atrial Natriuretic Factor; Cyclohexanecarboxylic Acids; Drug Evaluation, Preclinical; Drug Interactions; Hypoxia; Male; Natriuretic Peptide, Brain; Neprilysin; Nerve Tissue Proteins; Pulmonary Artery; Pulmonary Circulation; Pulmonary Wedge Pressure; Rats; Rats, Wistar; Vasoconstriction; Vasodilation

Inhibition of the metabolism of endogenous atrial natriuretic peptide (ANP), by continuous infusion of a specific inhibitor of neutral endopeptidase (membrane metalloendopeptidase E.C. 3.4.24.11), UK 73,967 (candoxatrilat), was undertaken in rats, in which chronic hypoxia was used as a stimulus to induce pulmonary hypertension and right ventricular hypertrophy. Inhibition of neutral endopeptidase 24.11 with low-dose and high-dose UK 73,967 (NEI) increased endogenous plasma ANP by greater than 155% during the development of pulmonary hypertension. NEI treatment reduced mean pulmonary arterial pressure in hypoxia as follows: vehicle 26.6 +/- 4.0 mm Hg; low-dose NEI 22.7 +/- 1.9 mm Hg, and high-dose NEI 22.6 +/- 2.5 mm Hg (both p less than 0.01 compared with hypoxic vehicle); however, it was without effect on pulmonary arterial pressure in normoxia (17.6 +/- 2.2 mm Hg) or on systemic blood pressure. The development of right ventricular hypertrophy was also reduced in both groups treated with NEI (right ventricular weight/left ventricular weight: 0.43 +/- 0.03 vehicle; 0.40 +/- 0.02 low-dose NEI and 0.40 +/- 0.02 high-dose NEI, both p less than 0.05 compared with vehicle). Remodelling of the pulmonary vasculature, characterized by extension of the muscle within the small pulmonary arteries toward the periphery of the lung, was reduced by NEI treatment (percentage of thick-walled peripheral vessels; 19.2 +/- 3.1% vehicle; 10.4 +/- 2.3% low-dose NEI and 8.1 +/- 1.8% high-dose NEI, both p less than 0.001 compared with vehicle). In the isolated blood perfused rat lung pulsed doses of NEI had no effect on pulmonary vascular tone in the absence of ANP. Specific inhibition of the enzyme neutral endopeptidase reduces vascular remodelling, the development of pulmonary hypertension, and right ventricular hypertrophy. Endogenous ANP modulates vascular remodelling in vivo. Retarding the metabolism of endogenous ANP through inhibition of neutral endopeptidase 24.11 represents a potential approach toward therapy. g

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cyclohexanecarboxylic Acids; Hypertension, Pulmonary; Hypoxia; Male; Neprilysin; Pulmonary Artery; Rats; Rats, Inbred Strains

We have demonstrated that in anaesthetized rats. (+/-) candoxatrilat reduces the clearance of both 125IANF and ANF 5-28, and prolongs the elimination half-life. These effects occur independent of glomerular filtration, since they are not attenuated by nephrectomy. Moreover, they cannot be attributed to blockade of ANF-C receptors. Our findings suggest that (+/-)candoxatrilat exerts its activity in vivo by specific inhibition of atriopeptidase at both renal and extra-renal locations.

Topics: Animals; Atrial Natriuretic Factor; Carbamates; Cyclohexanecarboxylic Acids; Enzyme Inhibitors; Half-Life; Kidney; Kidney Glomerulus; Male; Nephrectomy; Peptide Fragments; Propionates; Rats; Rats, Inbred Strains; Receptors, Cell Surface

1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 3.4.24.11) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor. 2. (+/-)-Candoxatrilat, a selective neutral endopeptidase inhibitor, potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (+/-)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum. 3. (+/-)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum. 4. These data demonstrate that the neutral endopeptidase inhibitor (+/-)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents, and that these effects are mediated via endogenous atrial natriuretic factor.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclohexanecarboxylic Acids; Desoxycorticosterone; Diuresis; Hypertension; Immune Sera; Natriuresis; Neprilysin; Rats; Rats, Inbred Strains

Topics: Atrial Natriuretic Factor; Carbamates; Cyclohexanecarboxylic Acids; Depression, Chemical; Propionates; Substrate Specificity; Thiorphan

A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1' residue and in the replacement of the aza-link between P1 and P1' residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.

Topics: Animals; Atrial Natriuretic Factor; Chemical Phenomena; Chemistry; Cyclohexanecarboxylic Acids; Diuretics; Humans; Male; Mice; Microvilli; Natriuresis; Neprilysin; Rats