Background: Omapatrilat has potent enzymatic inhibitory effects on the angiotensin-converting enzyme and neutral endopeptidase. The prolonged effects of this inhibition on systemic and regional hemodynamics, cardiovascular mass, and hydroxyproline concentration in spontaneously hypertensive rats were studied. The contribution of endogenous bradykinin on the cardiovascular actions of omapatrilat in this genetic model of hypertension was also investigated.
Methods and results: Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic masses, and hydroxyproline concentration were determined in 35-week-old spontaneously hypertensive rats after 12 weeks of treatment with omapatrilat (40 mg/kg/day), with and without the bradykinin receptor antagonist icatibant (500 microg/kg/day). Omapatrilat decreased mean arterial pressure, reducing total peripheral resistance as well as decreased left ventricular and aortic mass indices. It also induced a profound renovasodilation associated with a decrease renal vascular resistance that markedly increased renal blood flow. Coronary hemodynamics and left ventricular hydroxyproline concentration remained unaltered. Concomitant blockade of bradykinin receptors partially attenuated the hypotensive effect of omapatrilat and its effect on aortic mass; and icatibant did not influence the renovasodilation.
Conclusion: Omapatrilat produced profoundly beneficial effects on systemic and renal hemodynamics, as well as on left ventricular and aortic masses, without any effect on coronary hemodynamics. These effects of omapatrilat on arterial pressure and aortic mass, but not on renal hemodynamics and left ventricular mass, may have been at least partially mediated through the action of bradykinin.