Physiologic Consequences of Vasopeptidase Inhibition in Humans

Abstract

Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

New drug therapies interfering with the renin–angiotensin–aldosterone system for resistant hypertension

“…4,5 For example, dual neprilysin-angiotensin converting enzyme inhibition was a logical combination from a pharmacological point of view, working by mutually reinforcing the effects of vasodilatory and natriuretic peptides (ANP and bradykinin) and decreasing the effects of vasoconstrictor and anti-natriuretic peptide (angiotensin II). 7,8 Indeed, the first representative of this class, omapatrilat, had a BP-lowering effect that would have been effective to treat patients with resistant hypertension. 8 However, the benefit/risk balance of this class of drugs was unfavourable.…”

The Effect of Acute Angiotensin-Converting Enzyme and Neutral Endopeptidase 24.11 Inhibition on Plasma Extravasation in the Rat

“…Inhibition of NEP should confer additional cardiovascular benefit by virtue of enhancing the hemodynamically favorable actions of the atrial natriuretic peptides, which are substrates for NEP (Robl et al, 1997;Burnett, 1999;Weber, 2001). Data from animal studies have indicated that the VPI omapatrilat does indeed confer greater cardiovascular benefit than ACE inhibitors alone (Trippodo et al, 1998;Bä cklund et al, 2001;Pu et al, 2002), and there is some data to suggest that this can also be seen in patients (Campese et al, 2001;Azizi et al, 2002;Ferrario et al, 2002). The development of omapatrilat, however, has been hampered by a 3-fold higher incidence of angioedema than observed with an ACEI (Coates, 2002;Campbell, 2003).…”

Vasopeptidase Inhibition

“…68 These higher doses of omapatrilat produced greater suppression of plasma ACE activity and greater stimulation of plasma renin levels than did fosinopril. At 24 hours after drug dosing, in comparison with fosinopril, these 2 doses of omapatrilat produced similar decreases in blood pressure in sodium-depleted subjects and greater decreases in blood pressure in sodium-supplemented subjects.…”

“…Omapatrilat, but not fosinopril, also produced increases in plasma levels of big endothelin, but no change in endothelin level. 68 Omapatrilat (40 mg and 80 mg) was also compared with fosinopril/hydrochlorothiazide combination (20 mg and 12.5 mg) in normotensive subjects. 69 Although the acute natriuretic effects of the fosinopril/hydrochlorothiazide combination were higher, the cumulative sodium excretion was similar for omapatrilat and the fosinopril/hydrochlorothiazide combination over 7 days.…”

“…75 However, a more reasonable explanation for the failure of omapatrilat to produce a sustained hypotensive effect is the short duration of NEP inhibition produced by this compound. 68,76 Although it may be argued that a higher dosage or BD dosage may increase the benefits obtained with omapatrilat in heart failure, it could also be argued that a higher dosage of enalapril may similarly increase the benefits from ACE inhibition alone.…”