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 μmol/l versus omapatrilat, 0.05 ± 0.01 μmol/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.
