Mode of cerebral vasodilating action of KC-404 in isolated canine basilar artery.
3-Isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (KC-404) caused a potent and concentration-dependent relaxation in isolated canine basilar artery precontracted with prostaglandin (PG) F2 alpha attended by EC50 of 7.6 X 10(-8) g/ml. The relaxing action of KC-404 was little affected by the removal of vascular endothelium, whereas it was significantly diminished by pretreatment with indomethacin (10(-5) M) or acetylsalicylic acid (ASA) (10(-3) M). In PGF2 alpha-contracted canine basilar artery, KC-404-induced relaxation was markedly reversed to contraction by the subsequent addition of indomethacin (10(-5) M), ASA (10(-3) M) and phenidone (10(-4) M) by about 80%, 75% and 111%, respectively, whereas it was little affected by nordihydroguaiaretic acid (NDGA) (10(-5) M). Similar results were obtained when dipyridamole was used as a relaxant but, in contrast, papaverine-induced relaxation was little affected by indomethacin. KC-404 as well as PGI2 showed less potent or no relaxation in both PGF2 alpha-contracted rabbit aorta and KCl-contracted canine basilar artery as compared with PGF2 alpha-contracted canine basilar artery. In PGF2 alpha-contracted canine basilar artery, PGI2-induced relaxation was significantly augmented by pretreatment with KC-404 (10(-8) and 10(-7) g/ml). These results suggest that KC-404 might elicit cerebral vasorelaxation not dependent on vascular endothelium but remarkably dependent on a vasodilating cyclooxygenase metabolite, possibly PGI2.
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001488:Basilar Artery / Q000187:drug effects; D015237:Dinoprost; D004285:Dogs; D004727:Endothelium / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011460:Prostaglandins F / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*; D007212:Indolizines; D011720:Pyrazoles
D016718:Arachidonic Acid; D001095:Arachidonic Acids; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D011460:Prostaglandins F; D011725:Pyridines; D014665:Vasodilator Agents; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles