Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca(2+)-dependent K+ channels.
During their reproductive years, women have a much lower incidence of coronary heart disease compared with men of similar age. Estrogen appears to be largely responsible for this decrease in cardiovascular mortality in women. In the present study, isolated pressurized coronary arteries from rats were used to assess the role of gender and circulating estrogen on coronary vascular function. Pressure-induced constrictions ("myogenic tone") were greater (approximately 2-fold) in isolated coronary arteries from estrogen-deficient male or ovariectomized (OVX) rats compared with similar arteries obtained from female rats or OVX rats receiving physiological levels of estrogen replacement (OVX+E group). These differences in coronary artery diameter were abolished by removal of the vascular endothelium or chemical inhibition of NO synthase. The anti-estrogen, tamoxifen, increased pressure-induced constrictions of coronary arteries from female and OVX+E rats. Dilations of pressurized coronary arteries from female and OVX animals to sodium nitroprusside, a nitrovasodilator that generates NO, were reduced by > 50% by iberiotoxin (IBTX), an inhibitor of Ca(2+)-dependent K+ (KCa) channels. Sodium nitroprusside (10 mumol/L) hyperpolarized coronary arteries by 13 +/- 2 mV, an effect that was greatly diminished (approximately 80%) by IBTX. Coronary arteries isolated from female rats produced greater constrictions in response to IBTX and KT 5823, an inhibitor of cGMP-dependent protein kinase, compared with coronary arteries from OVX rats. cGMP-dependent protein kinase increased the activity of KCa channels 16.5 +/- 5-fold in excised membrane patches from smooth muscle cells enzymatically isolated from these small coronary arteries. We propose that physiological levels of circulating 17 beta-estradiol elevate basal NO release from the endothelial cells, which increases the diameter of pressurized coronary arteries. Further, our results suggest that part of the effect of this NO is through activation of KCa channels in the smooth muscle cells of the coronary arteries.
Department of Pharmacology, University of Vermont, UVM Medical Research Facility, Colchester 05446, USA.
G C
GC
Wellman
A D
AD
Bonev
M T
MT
Nelson
J E
JE
Brayden
D000818:Animals; D002118:Calcium / Q000502:physiology*; D003331:Coronary Vessels / Q000033:anatomy & histology* / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010052:Ovariectomy; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013629:Tamoxifen / Q000494:pharmacology; D014664:Vasodilation
D004965:Estrogen Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013629:Tamoxifen; D009569:Nitric Oxide; D004958:Estradiol; D019001:Nitric Oxide Synthase; D002118:Calcium