title: Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: a shift in the relative importance of EDRFs.
abstract: Several studies suggest that diabetes affects male and female vascular beds differently. However, the mechanisms underlying the interaction of sex and diabetes remain to be investigated. This study investigates whether there are 1) sex differences in the development of abnormal vascular responses and 2) changes in the relative contributions of endothelium-derived relaxing factors in modulating vascular reactivity of mesenteric arteries taken from streptozotocin (STZ)-induced diabetic rats at early and intermediate stages of the disease (1 and 8 wk, respectively). We also investigated the mesenteric expression of the mRNAs for endothelial nitric oxide (NO) synthase (eNOS) and NADPH oxidase (Nox) in STZ-induced diabetes in both sexes. Vascular responses to acetylcholine (ACh) in mesenteric arterial rings precontracted with phenylephrine were measured before and after pretreatment with indomethacin (cyclooxygenase inhibitor), N(ω)-nitro-L-arginine methyl ester (NOS inhibitor), or barium chloride (K(ir) blocker) plus ouabain (Na(+)-K(+)-ATPase inhibitor). We demonstrated that ACh-induced relaxations were significantly impaired in mesenteric arteries from both male and female diabetic rats at 1 and 8 wk. However, at 8 wk the extent of impairment was significantly greater in diabetic females than diabetic males. Our data also showed that in females, the levels of eNOS, Nox2, and Nox4 mRNA expression and the relative importance of NO to the regulation of vascular reactivity were substantially enhanced, whereas the importance of endothelium-derived hyperpolarizing factor (EDHF) was significantly reduced at both 1 and 8 wk after the induction of diabetes. This study reveals the predisposition of female rat mesenteric arteries to vascular injury after the induction of diabetes may be due to a shift away from a putative EDHF, initially the major vasodilatory factor, toward a greater reliance on NO.
authors.affiliation: Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Der
authors.initials: D
authors.lastname: Thor
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Han
authors.forename: Leigh
authors.initials: L
authors.lastname: Anderson
authors.forename: Roshanak
authors.initials: R
authors.lastname: Rahimian
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D012737:Sex Factors; D015398:Signal Transduction; D013311:Streptozocin; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014665:Vasodilator Agents; D009569:Nitric Oxide; D013311:Streptozocin; D011464:Epoprostenol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat