Comparison of the effects of omapatrilat and irbesartan/hydrochlorothiazide on endothelial function and cardiac hypertrophy in the stroke-prone spontaneously hypertensive rat: sex differences.
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
Delyth
D
BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, UK. dg74s@clinmed.gla.ac.uk
Hamilton
Carlene
C
Beattie
Elisabeth
E
Spiers
Angela
A
Dominiczak
Anna F
AF
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure; D002217:Carbachol / Q000494:pharmacology; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000187:drug effects; D004357:Drug Synergism; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006728:Hormones / Q000097:blood; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics; D012727:Sex Characteristics; D020521:Stroke / Q000235:genetics; D013599:Systole; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology*; D014664:Vasodilation
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D006728:Hormones; D011725:Pyridines; D013777:Tetrazoles; D013841:Thiazepines; D006852:Hydrochlorothiazide; D009569:Nitric Oxide; C106266:omapatrilat; D002217:Carbachol; D000077405:Irbesartan