Vasorelaxing effects of estetrol in rat arteries

This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E(4)) vs 17β-estradiol (E(2)) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E(4) and E(2) (0·1-100  μmol/l) were constructed. In all arteries tested, E(4) had lower potency than E(2), 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 E(4) and E(2), indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases by N(ω)-nitro-L-arginine methyl ester (L-NAME) blunted E(2)-mediated but not E(4)-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E(4) or E(2) in uterine arteries. Combined blockade of NO release and action with L-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E(4) compared with E(2) in uterine arteries. Endothelium denudation inhibited responses to both E(4) and E(2), while E(4) and E(2) concentration-dependently blocked smooth muscle cell Ca(2)(+) entry in K(+)-depolarized and Ca(2)(+)-depleted uterine arteries. In conclusion, E(4) relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E(4)-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca(2)(+) entry, but not NO synthases or endothelium-dependent hyperpolarization.