Antagonistic Effects of 17β-Estradiol, Progesterone, and Testosterone on Ca ²⁺ Entry Mechanisms of Coronary Vasoconstriction

Abstract

Abstract-The clinical observation that coronary artery disease is more common in men and postmenopausal women than in premenopausal women has suggested cardioprotective effects of female sex hormones including hormone-mediated coronary vasodilation. The purpose of this study was to investigate whether the sex hormone-induced coronary relaxation is caused by inhibition of Ca 2ϩ mobilization into coronary smooth muscle. Key Words: sex hormones Ⅲ calcium Ⅲ coronary Ⅲ contraction C oronary artery disease is one of the most common and costly diseases. Coronary vasospasm and subsequent occlusion are frequently associated with increased cardiovascular risk and may lead to myocardial infraction and death. 1 Clinical data suggest that the incidence of coronary heart disease is greater in men and postmenopausal women compared with premenopausal women. This is believed to be because of putative cardioprotective effects of the female sex hormone estrogen. The cardioprotective effects of estrogen have been explained by several mechanisms, including modification of lipid and carbohydrate metabolism, 2 modification of the composition of circulating lipoproteins, 3-5 and changes in blood coagulation, 6 as well as direct cardiovascular protective effects on hemodynamics. 7 Estrogens are vasodilators. For example, it has been reported that subcutaneous administration of ␤-estradiol in female guinea pigs reversibly and significantly lowers both the resting systolic blood pressure and the peak systolic blood pressure induced by a pressor challenge of norepinephrine. 8 Also intravenous infusion of estrogen in ovariectomized nonpregnant sheep has been shown to cause a significant increase in cardiac output and a decrease in systemic vascular resistance whereas local application of estrogen to the uterine artery only causes uterine vasodilation and increased uterine blood flow. 9 The vasodilator effects of estrogen have also been observed in normal coronary arteries. 10 The vascular endothelium has been suggested to play a role in mediating the estrogen-induced vasodilation. However, indomethacin does not affect the 17␤-estradiol-induced relaxation in endothelium-intact coronary arteries, 10 indicating that the release of vasodilator prostanoids is not involved in the 17␤-estradiol-induced coronary relaxation in vitro. Furthermore, estrogen causes vasodilation in deendothelialized rabbit coronary artery precontracted by endothelin-1, prostaglandin F 2␣ (PGF 2␣ ), and high-potassium depolarizing solution 10 suggesting that the estrogen-induced inhibition of vascular tone has an endothelium-independent component that involves direct action on vascular smooth muscle. 5,11,12

The enhanced endothelin-1-induced contraction in cultured coronary arteries from mature female pigs is not antagonized by 17β-estradiol

“…We hypothesized that the ET-1-induced contraction (due to the sustained ET-1-mediated influx of calcium) and may be inhibited by 17β-estradiol, which can mediate arterial smooth muscle relaxation by inhibiting calcium influx (Crews and Khalil, 1999;Salom et al, 2002). We found that the ET-1-induced constrictive response is unaffected by short-term exposure to physiological (1 × 10 −9 M to 1 × 10 −8 M) and pharmacological (1 × 10 −7 M to 1 × 10 −4 M) concentrations of 17β-estradiol in fresh and organ cultured coronary arteries.…”

Hormonal effects on blood vessels

“…Estrogen enhances endothelium-dependent vasorelaxation via increased release of nitric oxide (NO), [20][21][22] endothelium-derived hyperpolarizing factor 23 and PGI 2 24,25 and decreased production of endothelin-1 (Table 1). 26 Several studies have demon-strated that estrogen inhibits calcium influx 27,28 and stimulates calcium efflux 29 in vascular smooth muscle cells (VSMCs), leading to endothelium-independent vasodilation. Moreover, estrogen inhibits neointima formation in response to balloon injury 30,31 and perivascular cuff placement.…”

The effects of testosterone on isolated sheep coronary artery

“…Potassium (K + ) channels activation or 2. Calcium (Ca 2+ ) channel antagonism (1,2,8,(19)(20)(21)26,37,38,42,43,(45)(46)(47).…”