Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease

Kubota, Eiji; Dean, Rachael; Balding, Leanne C.; Johnston, Colin I.; Burrell, Louise M.

doi:10.1007/s11906-001-0105-8

Cited by 6 publications

(9 citation statements)

References 19 publications

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“…17,18 Several experimental studies have demonstrated their efficiency in lowering high blood pressure. 19,20 However, few studies have evaluated their effects on end-stage renal disease during the course of hypertension. Here, we compared the effects of the selective ACE inhibitor captopril and of the vasopeptidase inhibitor omapatrilat on renal injury induced by NO deficiency in rats fed a normal-or a high-sodium diet.…”

Section: Discussionmentioning

confidence: 99%

“…24 In fact, in previous studies performed in renin-dependent hypertensive models, dual inhibition of NEP and ACE was as efficient as selective ACE inhibition on blood pressure 1,2,17 and end-organ protection. 19,[25][26][27] Moreover, in recent studies, Ferrario et al 28,29 observed that omapatrilat did not decrease but increased the renal levels of Ang-(1-7) by blocking its catabolism. Confirming these data, our study shows that SBP, as well as plasma creatinine, proteinuria, and glomerulosclerosis index, were equally reduced with both drugs.…”

Section: Figurementioning

confidence: 99%

“…19,41,42 These studies concluded that vasopeptidase inhibitors conferred greater renal protection than did ACE inhibitors. The major quantitative effect of omapatrilat overwhelming that of enalapril affected proteinuria, as reported by Taal et al 21 in a protocol characterized by delayed treatment with both drugs until 4 weeks after the onset of hypertension.…”

Section: Figurementioning

confidence: 99%

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Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide–Deficient Rats

et al. 2003

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Abstract-Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received N G -nitro-L-arginine methyl ester (L-NAME, 20 mg · kg Ϫ1 · d Ϫ1 ) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg · kg) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was Ϸ90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet. Key Words: hypertension, renal Ⅲ kidney failure Ⅲ angiotensin-converting enzyme Ⅲ peptides Ⅲ nitric oxide Ⅲ sodium, dietary V asopeptidase inhibitors are novel molecules that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). 1 The emergence of this new class of drugs followed the demonstration that ACE and NEP are 2 key enzymes that play a major role in regulating cardiovascular and renal functions. The simultaneous inhibition of these 2 enzymes can reduce the vasopressive, hypertrophic, and antinatriuretic activities of the renin-angiotensin system and potentiate the vasodilatory, natriuretic, and antiproliferative effects of bradykinin and natriuretic peptides. 2 As a component of the circulating and local renin-angiotensin system, ACE catalyzes the conversion of angiotensin I (Ang I) to Ang II, a vasoconstrictor agent playing a central role in the pathogenesis of hypertension. In addition to its direct actions, Ang II increases the production of endothelin-1 (ET-1), and plasminogen activator inhibitor-1, both of which promote vasoconstriction, thrombosis, and fibrosis. 3,4 ACE inhibition is a well-established and effective treatment for hypertension. Nevertheless, it has been recently proposed that, in addition to ACE inhibition, inhibition of NEP, which augments the effects of natriuretic peptides, including atrial, B-type, and C-type natriuretic p...

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide–Deficient Rats

et al. 2003

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“…Vasopeptidase inhibitors represent a novel therapeutic strategy for the treatment of cardiovascular disease (1). By simultaneously inhibiting both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), vasopeptidase inhibitors are associated with a reduction in the vasoconstrictor and trophic agent angiotensin II, and accumulation of the vasodilators atrial natriuretic peptide (ANP), adrenomedullin and bradykinin (2).…”

Section: Introductionmentioning

confidence: 99%

Cardiorenal Protective Effects of Vasopeptidase Inhibition with Omapatrilat in Hypertensive Transgenic (mREN‐2)27 Rats

Mifsud

Burrell

Kubota

et al. 2004

Clinical and Experimental Hypertension

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Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 +/- 3 mmHg; fosinopril 10 mg/kg/day, 130 +/- 4 mmHg; omapatrilat 10 mg/kg/day, 110 +/- 3 mmHg; omapatrilat 40 mg/kg/day, 91 +/- 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.

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“…However, neprilysin activity was also significantly higher in the female Lewis strain, and angiotensin content and blood pressure were similar between the male and female Lewis rats. Moreover, neprilysin inhibitors are generally thought to lower blood pressure, although these agents are more effective when combined with an ACE blocker (14,34,37). To our knowledge, experimental studies with neprilysin inhibitors have predominantly, if not exclusively, used male hypertensive strains.…”

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confidence: 99%

Sex differences in circulating and renal angiotensins of hypertensive mRen().Lewis but not normotensive Lewis rats

Pendergrass

Pirro²,

Westwood³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

109

148

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Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease

Cited by 6 publications

References 19 publications

Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide–Deficient Rats

Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide–Deficient Rats

Cardiorenal Protective Effects of Vasopeptidase Inhibition with Omapatrilat in Hypertensive Transgenic (mREN‐2)27 Rats

Sex differences in circulating and renal angiotensins of hypertensive mRen().Lewis but not normotensive Lewis rats

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