A new vasodilator 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (KC-404) has a dual mechanism of action on platelet aggregation.
3-Isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (KC-404) at a concentration of greater than or equal to 4.34 X 10(-5) M inhibited adenosine diphosphate-, arachidonic acid- and collagen-induced aggregation of rabbit platelets. In rabbit, KC-404 (0.5 and 2 mg/kg, i.v.) caused a decrease in weight of collagen strip extracorporeally superfused with arterial blood, because of a disaggregation of deposited platelet aggregates. This disaggregatory effect of KC-404 was markedly diminished by the pretreatment of animals with aspirin. KC-404 (greater than or equal to 4.34 X 10(-6) M) and its major metabolite diOH-KD-404 (greater than or equal to 3.78 X 10(-7) M) significantly potentiated the anti-aggregatory action of prostacyclin on rabbit platelets. KC-404 (greater than or equal to (4.34 X 10(-8) M) exerted a similar effect in rat platelets. KC-404 had no significant effect on 6-keto-PGF1 alpha and thromboxane A2 formation by rat aortic segment and rabbit platelets, respectively. KC-404 inhibited cyclic AMP phosphodiesterase (Ki = 91 microM). The present results indicate that KC-404 exhibits its anti-platelet effect via the inhibition of cyclic AMP phosphodiesterase activity in platelets and via the potentiation of anti-aggregatory activity of prostacyclin on platelets.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000097:blood; D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis / Q000097:blood; D000818:Animals; D011464:Epoprostenol / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013928:Thromboxane A2 / Q000096:biosynthesis; D014665:Vasodilator Agents / Q000494:pharmacology*; D007212:Indolizines; D011720:Pyrazoles
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D011725:Pyridines; D013928:Thromboxane A2; D014665:Vasodilator Agents; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles