Tyrosine kinase inhibitor-sensitive contractile action of ethanol in gastric smooth muscle: comparison with the action of epidermal growth factor.
We have evaluated the signal transduction pathways whereby, in comparison with epidermal growth factor-urogastrone, ethanol causes a rapid contractile response in guinea pig gastric longitudinal muscle. As for epidermal growth factor (EGF), the ethanol-induced contraction required extracellular calcium, was sensitive to the tyrosine kinase inhibitors genistein and tyrphostin 47 (AG213), and was blocked by both the cyclo-oxygenase inhibitor, indomethacin, and the diacylglycerol lipase inhibitor, U57908. The 50% effective concentration (EC50) for the contractile action of ethanol (approximately 140 mM) was lower than that for propanol and methanol and was not affected by the aldehyde dehydrogenase inhibitor, 4-methyl pyrazole. The actions of ethanol were distinct from those of EGF in that EGF-induced contractions were sensitive to the kinase C inhibitor GF109203X, and the EGF receptor kinase inhibitor PD153035, whereas ethanol-induced contractions were refractory to these inhibitors. Further, EGF-induced contractions were attenuated by the voltage-sensitive calcium channel antagonist, nifedipine, whereas the ethanol-induced contractile response was resistant to nifedipine but blocked by the "receptor-operated" calcium channel antagonist SKF96365. We conclude that ethanol without metabolism via alcohol dehydrogenase causes a contractile response in gastric longitudinal muscle tissue via a tyrosine kinase inhibitor-sensitive signal pathway that is parallel in many respects but yet is distinct from that activated by EGF.
Zheng
X L
XL
Department of Pharmacology and Therapeutics, University of Calgary, Faculty of Medicine, Canada.
Hollenberg
M D
MD
D000433:1-Propanol / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D003512:Cyclohexanones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D000077604:Fomepizole; D019833:Genistein; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D000432:Methanol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D020032:Tyrphostins
D002396:Catechols; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D007211:Indoles; D007529:Isoflavones; D008301:Maleimides; D009570:Nitriles; D011720:Pyrazoles; D011799:Quinazolines; D020032:Tyrphostins; C060152:tyrphostin 47; D000431:Ethanol; D004815:Epidermal Growth Factor; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D000077604:Fomepizole; D000433:1-Propanol; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C070515:bisindolylmaleimide I; D002118:Calcium; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline; D007213:Indomethacin; D000432:Methanol