Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats

The antihypertensive agent omapatrilat represents a novel approach to antih ypertensive therapy, namely vasopeptidase inhibition, Omapatrilat (BMS-1867 16) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hy potensive peptides in addition to interruption of the renin-angiotensin sys tem. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function wer e unknown. We tested omapatrilat in stroke-prone spontaneously hypertensive rats (SHRSP), a malignant model of hypertension, with the hypothesis that it would improve the structure and endothelial function of mesenteric resis tance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with om apatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 mu m) were st udied on a pressurized myograph. After 10 weeks, untreated SHRSP had a syst olic blood pressure of 230+/-2 mm Hg that was significantly reduced (P<0.05 ) by omapatrilat (145+/-3 mm Hg). Omapatrilat treatment improved endotheliu m-dependent relaxation of resistance arteries as elicited by acetylcholine (10(-5) mol/L) but had no significant effect on endothelium-independent rel axation produced by a nitric oxide donor (sodium nitroprusside). This sugge sted that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood p ressure-lowering effect of omapatrilat. Media width and media/lumen ratio w ere significantly decreased (P<0.05) by omapatrilat, and a trend (P=0.07) t o increase lumen diameter was observed. Vascular stiffness (slope of the el astic modulus versus stress curve) was unaltered by omapatrilat, In conclus ion, omapatrilat, acting as a potent antihypertensive agent, may improve st ructure and endothelial function of resistance arteries in SHRSP, a severe form of generic hypertension.