Distinct signal transduction pathways for angiotensin-II in guinea pig gastric smooth muscle: differential blockade by indomethacin and tyrosine kinase inhibitors.

In guinea pig gastric longitudinal (LM) and circular (CM) muscle strips, angiotensin-II (Ang-II) caused a concentration-dependent contraction that required extracellular calcium and that could not be attributed to the secondary release of agonists from neural elements. Contractions in both the LM and CM were blocked by the Ang-II AT1 receptor antagonist, Losartan (DuP 753, pA2 9.1) but not by the AT2 antagonist, PD 123319. However, in the LM preparation, indomethacin (3 microM) blocked Ang-II-mediated contraction, whereas in the CM contraction was resistant to indomethacin. Contractions caused by Ang-II in the CM preparations were also unaffected by inhibitors of leukotriene biosynthesis, but were partially (58%) inhibited by the cytochrome P450 monooxygenase inhibitor, ketoconazole. The diacylglycerol lipase inhibitor, U57,908, at a concentration (20 microM) that completely blocked the contractile action of epidermal growth factor in the LM, caused a substantial inhibition of Ang-II-mediated contraction in both the LM (55% inhibition) and CM (75% inhibition). The phospholipase A2 inhibitor, mepacrine caused a modest inhibition (24%) of contraction in both preparations. In the presence of U57,908, mepacrine further inhibited contraction caused by Ang-II in the LM preparation. The tyrosine kinase (YK) inhibitors, genistein and tyrphostin (RG 50864) selectively and completely blocked Ang-II-mediated contraction in the LM, without affecting contractions caused by carbachol and bradykinin. In the CM preparation, the two YK inhibitors were selective, but only partially (40-60%) blocked Ang-II-mediated contraction, without affecting contractions caused by bradykinin and carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)