Effects of antihypertensive therapy on factors mediating endothelium-dependent relaxation in rats treated chronically with L-NAME

Objectives To evaluate the relative participation of endothelium-derived fa ctors mediating relaxation in response to acetylcholine in isolated mesente ric vascular beds from rats treated chronically with NG-nitro-L-arginine me thylester (L-NAME); and to compare the consequences of prolonged treatment with either an angiotensin converting enzyme inhibitor or a calcium channel blocker on the components of acetylcholine-induced relaxation in this vasc ular preparation. Materials and methods Male Sprague-Dawley rats were treated for 8 weeks wit h L-NAME (40 mg/kg per day), quinapril (10 mg/kg per day), diltiazem (100 m g/kg per day), L-NAME + quinapril and L-NAME + diltiazem. Systolic blood pr essure was estimated by a tail-cuff plethysmograph. Relaxing responses to a cetylcholine (10(-12) to 10(-8) mol) in mesenteric vascular beds precontrac ted with phenylephrine (10(-5) mol/l) were studied in the presence and abse nce of L-NAME (10(-5) mol/l), L-NAME + indomethacin (10(-5) mol/l) or L-NAM E + indomethacin + potassium chloride (6 x 10(-5) mol/l). The area under th e dose-response curve was used to calculate the approximate participation o f nitric oxide, prostaglandins or endothelium-derived hyperpolarizing facto r in the acetylcholine-induced relaxation. Results Chronic administration of L-NAME increased blood pressure levels an d vascular responsiveness to phenylephrine. Treatments with either quinapri l or diltiazem reduced blood pressure levels and attenuated the increased r esponse to phenylephrine. Relaxing responses to acetylcholine were similar in all groups, independently of the treatment received. The calculated part icipation of endothelium-derived hyperpolarizing factor in the acetylcholin e-induced relaxation was higher than that of nitric oxide and prostaglandin s in all groups, but was higher in L-NAME-treated than in untreated rats. I n contrast, the participation of both nitric oxide and prostaglandins was h igher in control than in L-NAME-treated rats. Quinapril increased the parti cipation of prostaglandins in L-NAME-treated rats. Diltiazem increased the participation of nitric oxide in L-NAME-treated rats. Conclusions The administration of L-NAME in Sprague-Dawley rats increased t he production of endothelium-derived hyperpolarizing factor as a compensato ry mechanism to maintain acetylcholine-induced relaxation. Antihypertensive therapy with either quinapril or diltiazem produced a selective redistribu tion of the endothelial factors mediating acetylcholine-induced relaxation. (C) Lippincott Williams & Wilkins.