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.