Ovariectomy promotes the enhancement of endothelium-derived hyperpolarizing factor-mediated relaxation in mesenteric arteries of rats with chronic nitric oxide synthase inhibition

Abstract

BACKGROUND AND OBJECTIVES: 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 reduced bioavailability of nitric oxide. Therefore, the effects of ovariectomy with and without 17β-estradiol supplement on endothelial function were examined in rats following chronic inhibition of nitric oxide synthases with L-NAME. METHODS: Female Sprague Dawley rats were ovariectomized or shamoperated at 12 weeks old. Half of ovariectomized rats were supplemented with 17β-estradiol (25 μgkg-1day-1, intramuscularly) or its vehicle (olive oil) until they were sacrificed. At 18 weeks old, all rats were administered daily with L-NAME (60 mgkg-1, by gavage) or its vehicle (drinking water) for 6 weeks. Rats were then anaesthetized for blood pressure measurement and for isolation of mesenteric arteries for isometric tension measurement in organ baths. RESULTS: Chronic L-NAME treatment did not increase blood pressure in all rats, but impaired endothelium-dependent relaxation in ovariectomized rats without 17β-estradiol supplement. This impairment was reversed in the presence of indomethacin (a cyclooxygenase inhibitor). Chronic L-NAME treatment improved endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation only in mesenteric arteries of ovariectomized rats without 17β-estradiol supplement, although ovariectomy alone reduced EDHFmediated relaxation. CONCLUSIONS: Inhibition of cyclooxygenase alone, but not 17β-estradiol supplement, improved endothelial function in ovariectomized rats with chronic nitric oxide synthase inhibition. This greater relaxation appears to be mediated by EDHF, the function of which is enhanced when there is the occurrence of cyclooxygenase-dependent contraction. This study was supported by a General Research Fund of the Research Grant Council of HKSAR, and a Committee on Research and Conference Grant, The University of Hong Kong.