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 compari son with epidermal growth factor-urogastrone, ethanol causes a rapid c ontractile response in guinea pig gastric longitudinal muscle. As for epidermal growth factor (EGF), the ethanol-induced contraction require d extracellular calcium, was sensitive to the tyrosine kinase inhibito rs genistein and tyrphostin 47 (AG213), and was blocked by both the cy cle-oxygenase inhibitor, indomethacin, and the diacylglycerol lipase i nhibitor, U57908. The 50% effective concentration (EC(50)) for the con tractile action of ethanol (approximately 140 mM) was lower than that for propanol and methanol and was not affected by the aldehyde dehydro genase inhibitor, 4-methyl pyrazole. The actions of ethanol were disti nct from those of EGF in that EGF-induced contractions were sensitive to the kinase C inhibitor GF109203X, and the EGF receptor kinase inhib itor PD153035, whereas ethanol-induced contractions were refractory to these inhibitors. Further, EGF-induced contractions were attenuated b y the voltage-sensitive calcium channel antagonist, nifedipine, wherea s the ethanol-induced contractile response was resistant to nifedipine but blocked by the ''receptor-operated'' calcium channel antagonist S KF96365. We conclude that ethanol without metabolism via alcohol dehyd rogenase causes a contractile response in gastric longitudinal muscle tissue via a tyrosine kinase inhibitor-sensitive signal pathway that i s parallel in many respects but yet is distinct from that activated by EGF.