Abstract

The clinical observation that coronary heart disease is more common in men and postmenopausal women than in premenopausal women has suggested cardiovascular protective effects of female sex hormones including hormone-mediated coronary vasodilation. We investigated whether the sex hormones induced coronary relaxation is due to a decrease in [Ca²⁺]_i as measured in single coronary smooth muscle cells isolated from gonadectomized male and female pigs. In the presence of external Ca²⁺, prostaglandin F_2α (PGF_2α; 10⁻⁵ M) and membrane depolarization by 51 mM KCl caused significant cell contraction and maintained increase in [Ca²⁺]_i to 297 ± 4 and 341 ± 20 nM, respectively. At 10⁻⁹ to 6 × 10⁻⁷M, 17β-estradiol, progesterone, and testosterone caused inhibition of PGF_2α- and KCl-induced contraction and [Ca²⁺]_i with 17β-estradiol being most effective. 17α-Estradiol did not affect PGF_2α-induced contraction, and the inhibition of PGF_2α contraction by 17β-estradiol, progesterone, or testosterone was abolished by tamoxifen and ICI 182,780, RU-486, or flutamide, respectively. 17β-Estradiol caused similar inhibition of PGF_2α- and KCl-induced contraction and [Ca²⁺]_i. Progesterone and testosterone caused greater inhibition of PGF_2α-induced cell contraction and [Ca²⁺]_i compared with the KCl responses. In Ca²⁺-free (2 mM EGTA) solution, caffeine (10 mM) and carbachol (10⁻⁵ M), which activate Ca²⁺release from intracellular stores, caused small cell contraction and transiently increased [Ca²⁺]_i to 256 ± 53 and 262 ± 32 nM, respectively. Sex hormones did not significantly affect caffeine- or carbachol-induced contraction or [Ca²⁺]_i. Thus, 17β-estradiol, progesterone, and testosterone cause relaxation of coronary smooth muscle cells and decrease [Ca²⁺]_i mainly by inhibiting Ca²⁺ entry from extracellular space but not Ca²⁺ release from intracellular stores. The differences in potency of sex hormones in reducing cell contraction and [Ca²⁺]_i suggest differences in the sensitivity of the PGF_2α- and depolarization-activated Ca²⁺ entry pathways to inhibition by sex hormones.