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.
Tanaka
Y
Y
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Nakayama
K
K
Shigenobu
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010108:Oxyhemoglobins / Q000494:pharmacology; D010120:Oxytocics / Q000494:pharmacology; D012026:Reflex, Stretch; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D008689:Methacrylates; D010108:Oxyhemoglobins; D010120:Oxytocics; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C049855:ONO 3708; D015237:Dinoprost; D013930:Thromboxane-A Synthase; C034364:ozagrel; D001241:Aspirin