Omapatrilat significantly reduced left ventricular hypertrophy (P<0.0001) and improved endothelial function in male stroke-prone spontaneously hypertensive rats compared to controls.
Does omapatrilat improve endothelial function and reduce cardiac hypertrophy compared to irbesartan/hydrochlorothiazide in stroke-prone spontaneously hypertensive rats?
In a rat model of hypertension, omapatrilat provided similar blood pressure and hypertrophy reduction as irbesartan/hydrochlorothiazide but offered additional benefits in endothelial function via NO-dependent mechanisms.
p-value: p=<0.0001
OBJECTIVE: The novel antihypertensive agent, omapatrilat, is both an inhibitor of neutral endopeptidase and angiotensin-converting enzyme. This study investigated the effects of omapatrilat in comparison with an angiotensin I-receptor antagonist/diuretic combination on blood pressure, endothelial function and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: Male and female SHRSP were treated orally with omapatrilat or irbesartan plus hydrochlorothiazide (I + H) or vehicle for 8 weeks. Systolic blood pressure was measured weekly by tail-cuff. Cardiac hypertrophy was monitored by echocardiography at 8, 12 and 16 weeks of age. Endothelial function basal nitric oxide (NO) bioavailability and stimulated NO release was examined in carotid arteries using organ bath pharmacology and in mesenteric resistance arteries using wire myography. RESULTS: Compared with untreated controls, omapatrilat and I + H significantly attenuated hypertension male control, 198.3 +/- 6.9 mmHg versus omapatrilat, 149.6 +/- 3.8 mmHg (F = 8.63 P < 0.0001), versus I + H, 145.6 +/- 5.1 mmHg (F = 7.38 P < 0.0001); female control, 170.3 +/-8.3 mmHg versus omapatrilat, 120.0 +/- 4.6 mmHg (F = 8.36, P < 0.0001), versus I + H, 112.2 +/- 2.9 mmHg (F = 9.08, P < 0.0001) and left ventricular hypertrophy male + female controls, 3.02 +/- 0.38 mg/g versus omapatrilat, 2.47 +/- 0.26 mg/g (P < 0.0001; 95% confidence interval, 0.27, 0.83), versus I + H, 2.49 +/- 0.21 mg/g (P < 0.0001; 95% confidence interval, 0.25, 0.83). Both treatments also significantly increased male carotid artery basal NO bioavailability relative to control control, 0.62 +/- 0.17 g/g versus omapatrilat, 1.95 +/- 0.17 g/g (P < 0.0001; 95% confidence interval, -1.83, -0.36), versus I + H, 1.57 +/- 0.21 g/g (P < 0.026; 95% confidence interval, -1.31, -0.12). However, stimulated NO (EC50) was only improved in omapatrilat-treated males controls, 0.19 +/- 0.06 micromol/l versus omapatrilat, 0.05 +/- 0.01 micromol/l (P = 0.05; 95% confidence interval, -1.16, -0.03). CONCLUSIONS: Omapatrilat treatment significantly reduced left ventricular hypertrophy and improved endothelial function in carotid arteries from male SHRSP by NO-dependent mechanisms. Despite equivalent antihypertensive and antihypertrophic actions, a similar improvement in endothelial function, specifically stimulated NO release, was not observed after treatment with I + H.
Graham et al. (Thu,) conducted a other in Hypertension and cardiac hypertrophy. Omapatrilat vs. Irbesartan plus hydrochlorothiazide (I + H) or vehicle was evaluated on Systolic blood pressure, endothelial function and cardiac hypertrophy (95% CI 0.27, 0.83, p=<0.0001). Omapatrilat significantly reduced left ventricular hypertrophy (P<0.0001) and improved endothelial function in male stroke-prone spontaneously hypertensive rats compared to controls.
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