YC-1, a novel activator of platelet guanylate cyclase.
YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC-1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of guanylate cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate guanylate cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble guanylate cyclase activator in rabbit platelets. It may also possess antithrombotic potential in vivo.
Ko
F N
FN
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Wu
C C
CC
Kuo
S C
SC
Lee
F Y
FY
Teng
C M
CM
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000097:blood; D005576:Colforsin / Q000494:pharmacology; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000097:blood*; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008706:Methemoglobin / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009599:Nitroprusside / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis
D007093:Imidazoles; D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009599:Nitroprusside; D005576:Colforsin; D013928:Thromboxane A2; C029899:imidazole; D000255:Adenosine Triphosphate; D003094:Collagen; D008706:Methemoglobin; D000242:Cyclic AMP; D013482:Superoxide Dismutase; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D000527:Alprostadil; D006152:Cyclic GMP; D015230:Prostaglandin D2; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D007213:Indomethacin