The basis for progesterone impairment of gallbladder contractility in male guinea pigs in vitro.
Progesterone suppresses gallbladder smooth muscle function but its exact mechanism is unknown. We sought to determine the cellular site where progesterone impairs gallbladder smooth muscle. Sixty-four adult male guinea pigs were injected with either progesterone (2 mg/kg/day sc) or normal saline (controls) for 7 days. Dose-response curves of gallbladder strips to cholecystokinin (CCK), bethanechol, and potassium (K+) were constructed in vitro. To better define the basis for the progesterone effect, gallbladder contractile response was determined to specific agonists: aluminum fluoride and mastoparan (direct G-protein activators), cyclopiazonic acid (CPA), and a calcium ionophore (A-23187). Gallbladder from animals on progesterone exhibited a marked decrease in contractile response to CCK and bethanechol compared with controls (P < 0.05). Further, gallbladder contraction remained depressed (P < 0.05) in progesterone-treated animals, when the G protein was directly activated with aluminum fluoride and mastoparan. In contrast, the responses to K+ (acting independent of receptor G-protein) and to A-23187 and CPA (agonists that bypassed the membrane) were comparable in both groups (NS). It is concluded that progesterone directly inhibits gallbladder smooth muscle contractility in vitro to a standard hormone, CCK, and a cholinergic agent. Such depressed contraction is not due to an altered contractile machinery, since it is normal with agonists that act independently of G-protein activation. Progesterone thus interferes with signaling through the G-protein, either by directly becoming closely associated with the cell membrane or by indirectly perturbing its receptor products.
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Department of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
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Shaffer
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D000818:Animals; D018723:Bethanechol / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000819:agonists; D005704:Gallbladder / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007211:Indoles; D007476:Ionophores; D018723:Bethanechol; D000001:Calcimycin; D011374:Progesterone; D002766:Cholecystokinin; D019204:GTP-Binding Proteins; C000543:cyclopiazonic acid