Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

Abstract

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (>90%, P<.001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, / > <.01) and remained elevated, although to a lesser extent (+34%, P<.01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96±27 mmol sodium, / > <.001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis CP<.01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3±3/-3.8±l mm Hg, P<.05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7±1 beats per minute, / > <.01). Mean 24-hour values of plasma renin activity (+33%, i»<.05), aldosterone (+36%, P<.05), and norepinephrine (+40%, P<.001) were all clearly increased above placebo values with established enzyme inhibition. In summary, inhibition of endopep-tidase 24.11 in essential hypertension leads to both acute and sustained increases in plasma atrial natriuretic factor and cyclic guanosine monophosphate, with an associated acute natriuresis. The renin-angiotensin-aldosterone and sympathetic nervous systems exhibit delayed activation, and these latter compensatory responses may limit the antihypertensive effect of endopeptidase inhibition. (Hyper-tension 1993;22:119-126) KEY WORDS • membrane metalloendopeptidase • atrial natriuretic factor • renin-angiotensin system • catecholamines • natriuresis • blood pressure • hypertension, essential T he neutral metalloendopeptidase EC 3.4.24.11 (EC 24.11) initiates degradation of atrial natri-uretic factor (ANF). 1-2 This discovery has stimulated interest in specific inhibitors as potential therapeutic agents in hypertension. 3 " 6 Because prolonged infusions of physiological doses of ANF in hypertensive humans and in animal models of hypertension reduce blood pressure 79 and genetically engineered transgenic mice with an enhanced ANF productive capacity exhibit lower blood pressures than control animals, 10 chronic increments in plasma and/or tissue concentrations of ANF induced by inhibition of EC 24.11 may offer a new means of lowering blood pressure. Endopeptidase inhibition by a number of different inhibitors results in a hypotensive effect in several

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

“…However, the therapeutic usefulness of the natriuretic peptides may be limited in vivo by low bioavailability and rapid clearance from the circulation (30). Neutral endopeptidase contributes significantly to the hydrolysis of natriuretic peptides, and selective neutral endopeptidase inhibitors reduce cardiac remodelling and hypertrophy in vivo (15,16). We therefore investigated whether the neutral endopeptidase inhibitor candoxatrilat was an effective alternative to ACE inhibition in preventing acute hypertrophic responses in diabetic hearts.…”

Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

“…45 For example, in this study in heart failure, NEP inhibition did not change plasma ANP, yet in both experimental hypertension and essential hypertension, SCH42495 increased plasma ANP. 10,46 It has also been shown in human heart failure that one NEP inhibitor, candoxatril, increased exercise duration, 47 whereas another, ecadotril, had no effect on symptoms. 48 The relative degree of ACE versus NEP inhibition also varies between vasopeptidase inhibitors; in the rat, omapatrilat has similar potency to inhibit renal NEP and ACE, 11 whereas S21402 has greater efficacy to inhibit renal NEP compared with ACE.…”

Omapatrilat Versus Lisinopril

“…10,11 NEP inhibitors, when given alone, have not been effective as long-term antihypertensive agents in humans, perhaps because of compensatory reflex renin-angiotensin-aldosterone system activation. 12,13 These limitations may be overcome by VPIs through their additional ability to inhibit ACE and to potentiate the kallikrein-kinin system, resulting in additional vasodilation. 14 Patients with salt-sensitive hypertension (SSH) do not respond as well to ACE inhibitor monotherapy as hypertensive patients who are not salt sensitive.…”