Effect of endothelin-1 on guinea pig gallbladder smooth muscle in vitro.
The purpose of this study was to investigate the pharmacological activity of endothelin-1 (ET-1) on guinea pig gallbladder smooth muscle. Guinea pig gallbladder muscle strips were mounted in 10-ml siliconized organ baths containing Krebs' solution. After 1 hr of equilibration, ET-1 was added cumulatively. ET-1 induced slow-developing and long-duration contractile responses. The EC50 was approximately 10 nM. ET-1 was 5 times less potent than cholecystokinin (EC50, 2 nM), but 20 and 40 times more potent than carbachol (EC50, 200 nM) and histamine (EC50, 400 nM), respectively. The concentration-response curve to ET-1 was not affected by tetrodotoxin (0.1 microM) or by the muscarinic antagonist, atropine (10 microM). The neuronal N-type calcium channel blocker, omega-conotoxin (0.1 microM), had no significant effect on the ET-1 concentration-response curve. In contrast, the contractile effect to ET-1 was reduced markedly by removal of extracellular calcium or by the voltage-dependent calcium channel blockers nicardipine and diltiazem. Substitution of strontium (an inhibitor of intracellular calcium release) for Ca++ significantly reduced the response to ET-1. The cyclooxygenase inhibitor indomethacin had no significant effect on the contractile activity of ET-1. These finding suggest that ET-1 is a potent contractile stimulant of guinea pig gallbladder and that it acts directly on the smooth muscle. The activity depends on extracellular Ca++, suggesting involvement of Ca++ influx via the voltage-dependent Ca++ channel and on intracellular calcium.
Moummi
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C
Division of Gastrointestinal Diseases, Searle Research and Development, Skokie, Illinois.
Gullikson
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GW
Gaginella
T S
TS
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent; D004110:Diltiazem / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005704:Gallbladder / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D009529:Nicardipine / Q000494:pharmacology; D013324:Strontium / Q000378:metabolism
D002413:Cations, Divalent; D016232:Endothelins; D009498:Neurotoxins; D016718:Arachidonic Acid; D001285:Atropine; D009529:Nicardipine; D004110:Diltiazem; D002118:Calcium; D007213:Indomethacin; D013324:Strontium