Vasorelaxing effects of estetrol in rat arteries

Abstract

This study comparedex vivorelaxing responses to the naturally occurring human hormone estetrol (E4) vs 17β-estradiol (E2) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E4and E2(0.1–100 μmol/l) were constructed. In all arteries tested, E4had lower potency than E2, although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1 μmol/l) caused a significant rightward shift in the CRC to both E4and E2, indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases byNω-nitro-l-arginine methyl ester (l-NAME) blunted E2-mediated but not E4-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E4or E2in uterine arteries. Combined blockade of NO release and action withl-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E4compared with E2in uterine arteries. Endothelium denudation inhibited responses to both E4and E2, while E4and E2concentration-dependently blocked smooth muscle cell Ca2+entry in K+-depolarized and Ca2+-depleted uterine arteries. In conclusion, E4relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E4-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca2+entry, but not NO synthases or endothelium-dependent hyperpolarization.