BENEXTRAMINE ACTS AS AN IRREVERSIBLE NONCOMPETITIVE ANTAGONIST OF U46619-MEDIATED CONTRACTION OF THE RAT SMALL MESENTERIC-ARTERY

We have studied the effects of benextramine on the U46619 (11 alpha,9 pha-epoxymethano-15S-hydroxy-prosta-5Z,13E-dienoic acid)-mediated cont raction of the rat isolated small mesenteric artery. U46619 (10 nM-10 mu M) produced a concentration-dependent contraction of the small mese nteric artery. The selective prostanoid TP receptor antagonist, SQ 30, 741 ([1S[1 alpha,2 alpha(5Z),3 alpha,4 meththyl]7-oxabicyclo[2.2.1]hep t-2-yl]-5-heptenoic acid; 1 mu M), produced a parallel, rightward shif t of the U46619 curve with an associated pA(2) value of 7.43 +/- 0.09. Treatment of tissues with 100 mu M benextramine depressed the maximum response to U46619 in a time-dependent manner. However, neither SQ 30 ,741 (10 mu M) nor U46619 (10 mu M) incubation significantly protected against this effect. Thus, benextramine acts as an irreversible nonco mpetitive antagonist of U46619. The mechanism of this action is not ye t clear.