Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

Abstract

Abstract-This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (PϽ0.001 versus placebo; PϽ0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (PϽ0.01). These hormonal effects were associated with a significant fall in blood pressure (PϽ0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (PϽ0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (PϽ0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (PϽ0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (PϭNS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy. Key Words: hemodynamics, renal Ⅲ sodium Ⅲ angiotensin-converting enzyme Ⅲ neutral endopeptidase Ⅲ omapatrilat Ⅲ vasopeptidase Ⅲ human A ngiotensin II is an important physiological modulator of renal function through its hemodynamic, glomerular, and tubular effects. 1 Hence, under most circumstances, interruption of the renin-angiotensin cascade with ACE inhibitors or angiotensin II type 1 receptor antagonists in humans promotes sodium excretion and increases renal blood flow without affecting glomerular filtration rate (GFR). As a result, filtration fraction decreases. 2 Atrial natriuretic peptide (ANP), the brain natriuretic peptide, and the C-type natriuretic peptide represent another family of peptides that have an important impact on renal function. 3,4 Indeed, in addition to a peripheral vasodilation, these peptides elicit diuresis and natriuresis, an attenuation of the release of renin and aldosterone and of the sympathetic nervous activity. 3 High plasma ANP and brain natriuretic peptide levels have been measured under several clinical conditions in which sodium and water retention occur, such as congestive heart failure or chronic renal failure. 3,4 In humans, the administration of exogenous ANP and the inhibition of natriuretic peptide...

Neutral Endopeptidase Inhibition Augments Vascular Actions of Bradykinin in Patients Treated With Angiotensin-Converting Enzyme Inhibition

“…Augmentation of bradykinin-mediated vasodilatation within the kidney may also contribute to the greater increase in renal blood flow observed with combined ACE and NEP inhibition than ACE inhibition alone. 38 As a result, it has been suggested that combined ACE and NEP inhibition may afford greater renal protection than ACE inhibition alone. 38 However, it should be noted that potentiating the vascular actions of kinins may have detrimental effects.…”

“…38 As a result, it has been suggested that combined ACE and NEP inhibition may afford greater renal protection than ACE inhibition alone. 38 However, it should be noted that potentiating the vascular actions of kinins may have detrimental effects. Bradykinin has been implicated in the pathogenesis of ACE inhibitor-mediated angioedema.…”

Vasopeptidase Inhibition

“…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. Omapatrilat, but not the fosinopril/hydrochlorothiazide combination, produced a marked increase in renal plasma flow, indicative of renal vasodilatation, without change in GFR.…”

“…Omapatrilat, but not the fosinopril/hydrochlorothiazide combination, produced a marked increase in renal plasma flow, indicative of renal vasodilatation, without change in GFR. 69 …”

Recent clinical trials with omapatrilat: New developments

“…Interestingly, preliminary studies conducted with omapatrilat failed to demonstrate significant changes in urinary sodium excretion, suggesting that the drug is not functioning primarily as an ACE inhibitor-diuretic combination. More recent studies, however, have demonstrated that omapatrilat indeed increases renal sodium excretion [16,17]. Over 1 week, the natriuretic properties of omapatrilat were comparable to the natriuretic effects of an ACE-hydrochlorothiazide fixed combination [16].…”