Inhibitory actions of ONO-3708 on the stretch-induced contraction potentiated by hemolysate/oxyhemoglobin studied in dog cerebral artery.

Quick stretch at a rate of 10 cm/sec with the amount of 30% of the slack length ( = 100%) produced a contraction in dog cerebral artery. The stretch-induced contraction was potentiated by 2-3 times in the presence of hemolysate (0.2 mg oxyHb/ml) only when the endothelium was intact. The stretch-induced contraction was also augmented by vasoconstrictor prostaglandins (PGs) such as PGF2 alpha or a stable thromboxane A2 (TXA2) analogue, U46619 (9, 11-dideoxy-11 alpha, 9 alpha-epoxymethano prostaglandin F2 alpha). ONO-3708 (7-[2 alpha, 4 alpha-(dimethylmethano-6 beta-(2-cyclopentyl-2 beta-hydroxyacetamido)-1 alpha-cyclohexyl]-5(z) heptenoic acid), a specific receptor antagonist for thromboxane A2 (TXA2)/prostaglandin (PG) endoperoxide, inhibited the potentiated stretch-induced contraction in the presence of hemolysate by about 50%. The compound completely inhibited the increase of stretch-induced contraction by PGF2 alpha or U46619. A cyclooxygenase inhibitor, acetylsalicylate, or a TXA2 synthetase inhibitor, OKY-046 ((E)-3-[4-(1-imidazolyl methyl)phenyl]-2-propenate) did not affect the potentiated stretch-induced contraction. The amount of PGF2 alpha released from the cerebral artery was not increased by hemolysate. These findings suggest that the potentiation of the stretch-induced contraction by hemolysate/oxyhemoglobin is not attributable to cyclooxygenase metabolites such as vasoconstrictor PGs. ONO-3708 seems to inhibit the potentiated stretch-induced contraction by hemolysate/oxyhemoglobin via mechanisms other than antagonism for cyclooxygenase products.