Effect of endothelin on sex-dependent regulation of tone in coronary resistance vessels

There is now strong epidemiological evidence that estrogen replacement therapy has a protective effect in postmenopausal women. The cardiovascular protective action of estrogen is reported to be mediated indirectly by an effect on lipoprotein metabolism and by a direct effect on the vessel wall itself. Estrogen is active both in vascular smooth muscle and endothelium. Functionally competent estrogen receptors have been identified in vascular smooth muscle cells, and specific binding sites have been demonstrated in endothelium. Estrogen administration promotes vasodilation both in human and experimental animals, in part by stimulating] prostacyclin and nitric oxide synthesis. Both the prostaglandin synthase and the constitutive nitric oxide synthase were recently reported to be induced by estrogen treatment. In vitro, estrogen exerts a direct inhibitory effect on the smooth muscle by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, estradiol-17 beta prevents neointimal thickening after balloon injury and in rabbit cardiac transplant allografts. These data are consistent with in vitro studies wherein estrogen inhibits [3H]thymidine uptake by arterial segments from porcine coronary artery as well as proliferation of rabbit aortic vascular smooth muscle cells induced by hyperlipedemic serum. Recent studies have also reported an effect of estrogen on directed vascular smooth muscle cell migration. Furthermore, like other steroids, the effect of estrogen on the vessel wall has a rapid nongenomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression. The nature of these estrogen response genes in the vessel wall and their relation to vasodilation and antiproliferation remain to be determined. Show more

This study was designed to examine whether endothelin is released from the intima of intact arteries, and whether endothelium-derived nitric oxide regulates its production. Endothelin was detected in the incubating medium of unstimulated pig aortae with, but not in those without endothelium. In preparations with endothelium, thrombin (2-6 U/ml) and the calcium ionophore A23187 (10(-6) M) stimulated the release of the peptide. The basal and thrombin-stimulated production of endothelin were prevented by the protein synthetase inhibitor cycloheximide (10(-6) M). The production of endothelin upon stimulation with thrombin (4 U/ml) was potentiated by L-NG-monomethyl arginine and methylene blue and reduced by superoxide dismutase and 8-bromo cyclic guanosine 5'-monophosphate (GMP), while the basal release of the peptide was unaffected. Thus, (a) endothelin is released from the intimal layer of intact blood vessels, both under basal conditions and after stimulation with thrombin and the calcium ionophore A23187, and (b) endothelium-derived nitric oxide released during stimulation with thrombin inhibits the production of the peptide via a cyclic GMP-dependent pathway. Show more

Background Women with type 2 diabetes (T2D) are less likely to reach the goals for hemoglobin A1c compared with men, and have higher all-cause mortality. The risk of cardiovascular disease is elevated among both men and women with T2D, however, the risk has declined among men over recent years while it remains stationary in women. Reasons for these sex differences remain unclear, and guidelines for diabetes treatment do not differentiate between sexes. Possible causes for varying outcome include differences in physiology, treatment response, and psychological factors. This review briefly outlines sex differences in hormonal pathophysiology, and thereafter summarizes the literature to date on sex differences in disease course and outcome. Methods Systematic searches were performed on PubMed using “sex”, “gender”, and various glucose-lowering therapies as keywords. Earlier reviews are summarized and results from individual studies are reported. Reference lists from studies were used to augment the search. Results There is an increased risk of missing the diagnosis of T2D when screening women with only fasting plasma glucose instead of with an oral glucose tolerance test. The impact of various risk factors for complications may differ by sex. Efficacy and side effects of some glucose-lowering drugs differ between men and women. Men with T2D appear to suffer more microvascular complications, while women have higher morbidity and mortality in cardiovascular disease and also fare worse psychologically. Conclusion Few studies to date have focused on sex differences in T2D. Several questions demand further study, such as whether risk factors and treatment guidelines should be sex-specific. There is a need for clinical trials designed specifically to evaluate sex differences in efficacy and outcome of the available treatments. Show more