Antiplatelet properties of a novel, non-NO-based soluble guanylate cyclase activator, BAY 41-2272.
Nitric oxide (NO) plays an important role in cardiovascular homeostasis, particularly in the regulation of vascular tone and the reactivity of platelets and circulating cells. Soluble guanylate cyclase (sGC) acts as the principal biological target for NO and catalyses the formation of the intracellular second messenger cyclic GMP (cGMP); activation of this enzyme is thought to be responsible for the majority of cardiovascular actions of NO. In the present study, we have evaluated the antiplatelet effects of a novel non-NO-based sGC activator, BAY 41-2272, in vitro and in vivo. BAY 41-2272 produced a marked inhibition of platelet aggregation in washed platelets with a potency (IC(50) approximately 100 nM) some threefold less than the NO donor S-nitrosoglutathione. BAY 41-2272 also prevented aggregation in platelet-rich plasma (PRP), albeit with a much lower potency. Both NO and prostacyclin exhibited synergistic activity with BAY 41-2272 to inhibit platelet aggregation. In vivo, at doses of BAY 41-2272 that significantly reduced blood pressure, the compound had little effect on FeCl(3)-induced thrombosis. These data confirm that intraplatelet sGC activation results in inhibition of aggregation and suggests that novel non-NO-based sGC activators, which possess both hypotensive and antiplatelet activities, may be useful as therapeutic agents.
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000517:prevention & control; D002712:Chlorides; D006152:Cyclic GMP / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology; D005290:Ferric Compounds; D006162:Guanylate Cyclase; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D000959:Antihypertensive Agents; D002712:Chlorides; D020536:Enzyme Activators; D005290:Ferric Compounds; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; C024555:ferric chloride