Inhibition of cyclooxygenase activity improves endothelium-dependent relaxation in mesenteric arteries of ovariectomized rats following chronic inhibition of nitric oxide synthase

Abstract

Gender differences exist in the incidence and manifestation of vascular diseases, of which endothelial dysfunction is the underlying cause. Endothelial dysfunction is associated with a reducd bioavaliability of nitric oxide. In the present study, the effect of estrogen on endothelial function were examined in rats follwoing chronic inhibition of nitric oxide synthases. Female Sprague Dawley rats were ovariectomized at 12 weeks old, and they were supplemented with 17b-estradiol (25 lg/kg, intramuscularly) or its vehicle (olive oil). At 18 weeks old, they were administered daily with L-NAME (a nitric oxide synthase inhibitor, 60 mg/kg, by gavage) or its vehicle (drinking water) for 6 weeks. 17b-estradiol supplementation increased the plasma level of high density lipoprotein without affecting the low density lipoprotein level in ovariectomized rats. Chronic L-NAME treatment did not cause a signficant increase in blood pressure in all these rats [unlike in male rats of same ages; unpublished data]. In mesenteric artery contracted with phenylephrine, chronic L-NAME treatment impaired endothelium-dependent relaxation to A23187 (a calcium ionophore) in ovariectomized rats with or without 17b-estradiol supplement. This impairment was reversed in the presence of indomethacin (a cyclooxygenase inhibitor), which did not affect A23187-induced relaxation in mesenteric arteries of rats without L-NAME treatment. Therefore, the present finding suggests that ovariectomy enhances the impairment of endothelium-dependent relaxation in L-NAME-treated rats through activation of a cyclooxygenase-dependent signaling pathway, and that 17bestradiol may not be responsible for this detrimental effect of ovariectomy.