Effects of ONO-3708, an antagonist of the thromboxane A2/prostaglandin endoperoxide receptor, on blood vessels.
The pharmacological properties of a novel thromboxane A2/prostaglandin endoperoxide receptor antagonist, ONO-3708, on blood vessels were examined in vitro and in vivo. ONO-3708, 10 microM, inhibited the rabbit aorta contractions induced by thromboxane A2, prostaglandin H2, 11,9-epoxymethano-prostaglandin H2 (U-46619) or prostaglandin F2 alpha without affecting the contractions induced by angiotensin II, serotonin or norepinephrine. ONO-3708, at a concentration of 1 to 100 nM, appeared to be a competitive inhibitor of the contractile responses of the canine basilar artery to 9,11-epithio-11,12-methano-thromboxane A2 (STA2), U-46619 and PGF2 alpha, and a non-competitive inhibitor of the contractile responses to 15-hydroperoxy-eicosatetraenoic acid (15-HPETE). In in vivo studies, ONO-3708 (10 and 100 micrograms/kg per min i.v.) ameliorated the decrease in diameter of the basilar artery induced by the i.v. infusion of STA2 (0.1 microgram/kg per min) in cats. Furthermore, infusion of ONO-3708 (10 and 30 micrograms/kg per min i.v.) prevented the cerebral vasospasm in an experimental subarachnoid hemorrhage model in dogs. These results indicate that ONO-3708 is a potent antagonist of the thromboxane A2/prostaglandin endoperoxide receptor in vitro and in vivo and may be of therapeutic use in preventing cerebral vasospasm.
Kondo
K
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Seo
R
R
Omawari
N
N
Imawaka
H
H
Wakitani
K
K
Kira
H
H
Okegawa
T
T
Kawasaki
A
A
D000818:Animals; D001011:Aorta / Q000502:physiology; D001488:Basilar Artery / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects* / Q000648:ultrastructure; D002415:Cats; D004285:Dogs; D005260:Female; D002546:Ischemic Attack, Transient / Q000517:prevention & control; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000187:drug effects; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D011982:Receptors, Prostaglandin; C055662:prostaglandin endoperoxide receptor; D013928:Thromboxane A2; C037866:STA 2; C049855:ONO 3708