Gender-specific inhibition of Ca2+ entry mechanisms of arterial vasoconstriction by sex hormones

Abstract

1. The clinical observation that hypertension is more common in males and postmenopausal women than in premenopausal women suggests vascular protective effects of female sex hormones, including hormone-mediated inhibition of vascular tone. The purpose of the present study was to investigate whether the Ca2+ mobilization mechanisms of vascular smooth muscle contraction are modified by gender and sex hormones. 2. Active stress and [45Ca2+] influx were measured in de-endothelialized aortic strips isolated from intact and gonadectomized male and female Sprague-Dawley rats. In normal Krebs' (2.5 mmol/L Ca2+), both phenylephrine (Phe; 10(-5) mol/L) and membrane depolarization by 96 mmol/L KCl increased active stress to 15.5 +/- 1.3 x 10(3) and 14.8 +/- 1.2 x 10(3) N/m2, respectively, and Ca2+ influx to 28.4 +/- 1.4 and 32.3 +/- 1.5 mumol/kg per min, respectively, in intact males. The Phe- and KCl-induced stress and Ca2+ influx were significantly reduced in intact females. Gonadectomy was associated with no significant changes in the Phe- and KCl-induced stress and Ca2+ influx in males, but was associated with significant enhancement in females. In Ca(2+)-free (2 mmol/L EGTA) Krebs', stimulation of intracellular Ca2+ release by Phe or caffeine (25 mmol/L) caused a transient contraction that was not significantly different in all groups of rats. 3. Exogenous application of 17 beta-oestradiol, progesterone or testosterone to aortic strips caused concentration-dependent inhibition of Phe- and KCl-stimulated contractions and Ca2+ influx. 17 beta-Oestradiol was the most effective hormone and its relative potency was intact males, castrated males and ovariectomized females > intact females. 4. Thus, vascular reactivity and Ca2+ entry in aortic smooth muscle are reduced in the presence and enhanced in the absence of female gonads. Both male and female sex hormones cause vascular relaxation, mainly by inhibiting Ca2+ entry, with oestrogen being the most effective, particularly in the absence of female gonads. The results suggest that a cellular mechanism of oestrogen-induced vascular relaxation involving inhibition of Ca2+ entry into vascular smooth muscle is gender dependent.