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 antihypertensive therapy, namely vasopeptidase inhibition. Omapatrilat (BMS-186716) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hypotensive peptides in addition to interruption of the renin-angiotensin system. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function were 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 resistance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with omapatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure of 230+/-2 mm Hg that was significantly reduced (P<0.05) by omapatrilat (145+/-3 mm Hg). Omapatrilat treatment improved endothelium-dependent relaxation of resistance arteries as elicited by acetylcholine (10(-5) mol/L) but had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). This suggested that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood pressure-lowering effect of omapatrilat. Media width and media/lumen ratio were significantly decreased (P<0.05) by omapatrilat, and a trend (P=0.07) to increase lumen diameter was observed. Vascular stiffness (slope of the elastic modulus versus stress curve) was unaltered by omapatrilat. In conclusion, omapatrilat, acting as a potent antihypertensive agent, may improve structure and endothelial function of resistance arteries in SHRSP, a severe form of genetic hypertension.
Intengan
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HD
MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Schiffrin
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EL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics; D020521:Stroke / Q000235:genetics; D013841:Thiazepines / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D015260:Neprilysin