sch-32615 and Heart-Failure

Our studies with the prototypical NEP inhibitor SCH 34826 indicate the potential role of this class of compounds in cardiovascular modulation. The data assembled to date indicate that NEP inhibition elicits significant ANF-like effects in animals and man. The early data generated to date on SCH 34826, when considered with those data generated on other NEP inhibitors, indicate that NEP inhibition may have therapeutic utility in some forms of hypertension and congestive heart failure.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Dioxolanes; Dipeptides; Drug Synergism; Heart Failure; Humans; Hypertension; Neprilysin; Prodrugs; Rats

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.

Topics: Adrenomedullin; Angiotensin II; Animals; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Dipeptides; Drug Synergism; Female; Heart Failure; Hemodynamics; Kidney; Natriuretic Peptide, Brain; Neprilysin; Peptides; Protease Inhibitors; Renin; Sheep; Vasodilator Agents

The effects of separate and combined endopeptidase inhibition (by SCH-32615) and natriuretic peptide receptor C blockade [by C-ANP-(4-23)] on the clearance and bioactivity of atrial (ANP) and brain (BNP) natriuretic peptides was investigated in eight sheep with heart failure. SCH-32615 and C-ANP-(4-23) administered separately induced significant and proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Associated with these changes were reductions in arterial pressure, left atrial pressure, and peripheral resistance and increases in cardiac output, urine volume, sodium excretion, and creatinine clearance. SCH-32615 induced greater diuresis and natriuresis than C-ANP-(4-23). Combined administration of SCH-32615 and C-ANP-(4-23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In conclusion, we find that the enzymatic and receptor clearance pathways contribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent separately.

Topics: Aldosterone; Animals; Atrial Function, Left; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dipeptides; Diuresis; Endopeptidases; Female; Guanylate Cyclase; Heart Failure; Hemodynamics; Natriuresis; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protease Inhibitors; Receptors, Atrial Natriuretic Factor; Sheep; Time Factors; Vascular Resistance

1. Atrial and brain natriuretic peptide are both circulating hormones subject to degradation by neutral endopeptidase 24.11. Whereas endogenous levels of atrial natriuretic peptide are increased by neutral endopeptidase inhibition in most pathophysiological states, the effect on brain natriuretic peptide and the influence of cardiac status is less clear. To further evaluate the role of neutral endopeptidase 24.11, we directly compared the responses of atrial and brain natriuretic peptide, together with the effects on other vasoactive hormones, haemodynamics and renal indices, to a neutral endopeptidase inhibitor, SCH32615, and a vehicle control in eight conscious sheep before and during pacing-induced heart failure. 2. In normal animals, SCH32615 significantly increased concentrations of plasma atrial natriuretic peptide (22 +/- 5 pmol/l compared with 14 +/- 2 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (6.5 +/- 1.2 pmol/l compared with 4.1 +/- 0.7 pmol/l in control, 1.6-fold increase), whereas in heart failure, plasma levels of atrial natriuretic peptide (306 +/- 38 pmol/l compared with 187 +/- 25 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (93 +/- 11 pmol/l compared with 55 +/- 9 pmol/l in control, 1.7-fold increase) were elevated to a significantly greater absolute, but proportionately similar, extent. In both normal and heart-failed animals, SCH32615 induced reductions in mean arterial pressure and left atrial pressure and increases in haematocrit, plasma cGMP and endogenous creatinine clearance. However, only in heart failure did neutral endopeptidase inhibition induce a significant and marked natriuresis (> 10-fold increase) and diuresis (4-fold increase), together with suppression of renin activity and haemodynamic effects including decreased peripheral resistance and raised cardiac output. 3. In conclusion, neutral endopeptidase inhibition increases plasma concentrations of atrial and brain natriuretic peptide to a proportionately similar extent in both normal and heart-failed sheep. The striking natriuresis and diuresis and additional haemodynamic effects demonstrated in sheep with heart failure, where natriuretic peptide levels are elevated compared with normal sheep, supports the concept that neutral endopeptidase inhibition augments endogenous atrial and brain natriuretic peptide.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Dipeptides; Diuresis; Female; Heart Failure; Natriuresis; Natriuretic Peptide, Brain; Neprilysin; Nerve Tissue Proteins; Protease Inhibitors; Renin; Sheep; Vascular Resistance