Acute relaxation of mouse duodenun by estrogens: Evidence for an estrogen receptor-independent modulation of muscle excitability

Abstract 17-β-Estradiol, the stereoisomer 17-α-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid ( 2 and KCl. The steroidal antiestrogen 7α-[9-[(4,4,5,5,5,-pentafluoropenty)sulphinyl]nonyl]-estra-1,3,5(19)-triene-3,17β-diol (ICI182,780) failed to either mimic or prevent the effect of 17-β-estradiol. The effect of estrogens was unrelated to activation of nitric oxide (NO), mitogen-activated protein kinase (MAPK), protein kinase A (PKA), protein kinase G (PKG) or protein kinase C (PKC). Estrogen-induced relaxation was partially reversed by 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K8644), depolarization, or by application of tetraethylammonium or 4-aminopyridine, but not by glibenclamide, apamin, charybdotoxin, paxilline or verruculogen. The effects of BAY-K8644 and K + channel blockers were synergistic, and allowed relaxed tissues to recover spontaneous activity and basal tone. We hypothesize that the rapid non-genomic spasmolytic effect of estrogens on mouse duodenal muscle might be triggered by an estrogen-receptor-independent mechanism likely involving activation of tetraethylamonium- and 4-aminopyridine-sensitive K + channels and inhibition of L-type Ca2 + channels on the smooth muscle cells.