A NEW VASODILATOR 3-ISOBUTYRYL-2-ISOPROPYLPYRAZOLO[1,5-A]PYRIDINE (KC-404) HAS A DUAL MECHANISM OF ACTION ON PLATELET-AGGREGATION

  • 1 October 1986
    • journal article
    • research article
    • Vol. 283  (2) , 321-334
Abstract
3-Isobutyryl-2-isopropylpyrazolo [1,5-a] pyridine (KC-404) at a concentration of .gtoreq. 4.34 .times. 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 plated aggregates. This disaggregatory effect of KC-404 was markedly diminished by the pretreatment of animals with aspirin. KC-404 (.gtoreq. 4.34 .times. 10-6 M) and its major metabolite diOH-KC-404 (.gtoreq. 3.78 .times. 10-7 M) significantly potentiated the anti-aggregatory action of prostacyclin on rabbit platelets, KC-404 (.gtoreq. 4.34 .times. 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 .mu.M). 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.