Mechanisms of relaxation of rat aorta in response to progesterone and synthetic progestins

Abstract

Objective: To compare the acute effects of progesterone, chlormadinone acetate (CMA), norethisterone acetate (NETA) and dienogest (DNG) with those of 17 β-estradiol (17 β-E 2) on the vascular reactivity of male rat thoracic aorta. Methods: Aortic rings with or without endothelium were placed in an organ bath for isometric tension recording. The integrity of the endothelium was assessed by the relaxant response of precontracted rings to acetylcholine (1 and 10 μM), which was diminished after mechanical removal of the endothelium. The concentrations of the steroid hormones were 0.01–10 μM. Results: In vessels precontracted with phenylephrine (1 μM), CaCl 2 (3 mM) or KCl (30 mM), progesterone, CMA and NETA (10 μM each) an endothelium-independent relaxation of 20–35% resulted, with a maximum response after 20–30 min, while DNG had a negligible effect in all experiments. The same concentration of 17 β-E 2 was twice as potent as the progestins. Indomethacin, the cyclooxygenase inhibitor and glibenclamide, an inhibitor of the ATP-sensitive potassium channels, did not affect the relaxant responses. The antagonists of progesterone receptors J 867 (1 μM) as well as of estrogen receptors ICI 182780 (1 μM) did not counteract the relaxation induced by progesterone and 17 β-E 2, respectively. Progesterone (10 μM) did not interfere with endothelium-dependent acetylcholine-induced relaxation of precontracted aortic rings. Pretreatment of the vessels with the hormones attenuated the maximal contractile response to phenylephrine. In the presence of verapamil (1 μM) or progesterone (10 μM) or 17 β-E 2 (1 and 10 μM) the concentration-response curves for calcium-induced contractions in K +-depolarized vessels were shifted to the right, with suppression of the maximum response. Conclusions: These studies suggest that in addition to 17 β-E 2 the progestins, progesterone, CMA and NETA caused a reduction of vascular tone, probably due to blockade of voltage-dependent and/or receptor-operated calcium channels.