title: Testosterone and dihydrotestosterone inhibit gallbladder motility through multiple signalling pathways.
abstract: Testosterone (T) has been shown to cause vasodilation in rabbit coronary arteries through a nongenomic pathway. Part of this T-induced relaxation was shown to be mediated by opening voltage dependent K(+) channels. T infusion also reduces peripheral resistance in human males with heart failure. The effects of T or its active metabolite 5-alpha dihydrotestosterone (DHT) are not well studied. This study investigates the effect of T and DHT on contraction in guinea pig gallbladder strips. T or DHT induced a concentration-dependent relaxation of cholecystokinin octapeptide (CCK)-induced tension. Pretreatment of the strips with PKA inhibitor 14-22 amide myristolated had no significant effect on the relaxation induced by either T or DHT. Pretreatment of strips with 2-APB, an inhibitor of IP(3) induced Ca(2+) release, produced a significant (p<0.001) reduction in the T- or DHT-induced relaxation. Bisindolymaleimide IV and chelerythrine Cl(-) when used in combination had no significant effect on the amount of CCK-induced tension, but significantly (p<0.01) decreased the amount of T- or DHT-induced relaxation. The flavone chrysin, an aromatase inhibitor, and genistein, an isoflavone, each produced a significant (p<0.01) reduction in CCK-induced tension. Chrysin significantly (p<0.05) increased T-induced relaxation; however, genistein had no effect on T-induced relaxation. It is concluded that T and DHT inhibits gallbladder motility rapidly by nongenomic actions of the hormones. Multiple pathways that include inhibition of intracellular Ca(2+) release, inhibition of extracellular Ca(2+) entry, and the actions of PKC may mediate this effect.
authors.affiliation: University of Alberta, Department of Physiology, Edmonton, Alberta T6G 2H7, Canada. lkline@ualberta.ca
authors.forename: Loren W
authors.initials: LW
authors.lastname: Kline
authors.forename: Edward
authors.initials: E
authors.lastname: Karpinski
mesh_terms: D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002766:Cholecystokinin / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D016473:Gallbladder Emptying / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D053119:Benzophenanthridines; D001896:Boron Compounds; D005419:Flavonoids; D007211:Indoles; D007295:Inositol Phosphates; D008301:Maleimides; C118500:inositol 3,4,5-trisphosphate; D013196:Dihydrotestosterone; C043561:chrysin; D013739:Testosterone; D002766:Cholecystokinin; C016299:chelerythrine; C109986:2-aminoethoxydiphenyl borate; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D002118:Calcium