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 sla ck length (=100%) produced a contraction in dog cerebral artery. The s tretch-induced contraction was potentiated by 2 - 3 times in the prese nce of hemolysate (0.2 mg oxyHb/ml) only when the endothelium was inta ct. The stretch-induced contraction was also augmented by vasoconstric tor prostaglandins (PGs) such as PGF(2 alpha) or a stable thromboxane A(2) (TXA(2)) analogue, U46619 (9, 11-dideoxy-11 alpha, 9 alpha-epoxym ethano prostaglandin F-2 alpha). ONO-3708 (7-[2 alpha, 4 alpha-(dimeth ylmethano-6 beta-(2-cyclopentyl-2 beta- hydroxyacetamido)-1 alpha-cycl ohexyl]-5(z) heptenoic acid), a specific receptor antagonist for throm boxane A(2) (TXA(2))/prostaglandin (PG) endoperoxide, inhibited the po tentiated stretch-induced contraction in the presence of hemolysate by about 50%. The compound completely inhibited the increase of stretch- induced contraction by PGF,, or U46619. A cyclooxygenase inhibitor, ac etylsalicylate, or a TXA, synthetase inhibitor, OKY-046 ((E)-3-[4-(1-i midazolyl methyl)phenyl]-2-propenate) did not affect the potentiated s tretch-induced contraction. The amount of PGF(2 alpha) released from t he cerebral artery was not increased by hemolysate. These findings sug gest that the potentiation of the stretch-induced contraction by hemol ysate/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 mechanism s other than antagonism for cyclooxygenase products.