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

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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 Ca2+ mobilization into coronary smooth muscle. The effects of 17β-estradiol, progesterone, and testosterone on vascular reactivity and 45Ca2+ influx were tested in deendothelialized coronary artery strips isolated from castrated male pigs. Prostaglandin F2α (PGF2α) (10−5 mol/L) caused significant, maintained contraction of coronary artery strips. Caffeine (25 mmol/L), an activator of Ca2+ release from intracellular stores, caused transient contraction in Ca2+-free solution whereas membrane depolarization by 96 mmol/L KCl, an activator of Ca2+ entry, caused maintained contraction in the presence of external Ca2+. The 3 sex hormones caused significant and concentration-dependent relaxation of PGF2α- and 96 mmol/L KCl-induced contractions with 17β-estradiol being the most effective. The sex hormones did not significantly affect the transient caffeine contraction in Ca2+-free solution. In contrast, the sex hormones significantly inhibited the PGF2α- and KCl-induced 45Ca2+ influx. 17β-Estradiol caused similar inhibition of PGF2α- and KCl-induced contractions, suggesting inhibition of the same Ca2+ entry mechanism. However, progesterone and testosterone caused greater relaxation of PGF2α-induced contraction than of KCl-induced contraction. We conclude that in coronary arteries of castrated male pigs, sex hormones inhibit Ca2+ entry from extracellular space but not Ca2+ release from intracellular stores. 17β-Estradiol mainly inhibits Ca2+ entry, whereas progesterone and testosterone cause coronary relaxation by inhibiting other mechanisms in addition to Ca2+ entry.