YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase

Br J Pharmacol. 1995 Oct;116(3):1973-8. doi: 10.1111/j.1476-5381.1995.tb16400.x.


1. Our previous study demonstrated that YC-1, a derivative of benzylindazole, is a novel activator of soluble guanylate cyclase (sGC) in rabbit platelets. This work investigated whether the antiplatelet effect of YC-1 was mediated by a nitric oxide (NO)/sGC/cyclic GMP pathway in human platelets. 2. In human washed platelets, YC-1 inhibited platelet aggregation and ATP released induced by U46619 (2 microM), collagen (10 micro ml(-1)) and thrombin (0.1 u ml(-1)) in a concentration-dependent manner with IC50 values of (microM) 2.1 +/- 0.03, 11.7 +/- 2.1 and 59.3 +/- 7.1, respectively. 3. In a 30,000 g supernatant fraction from human platelet homogenate, YC-1 (5-100 microM) increased sGC activity in a concentration-dependent manner. At the same concentration-range, YC-1 elevated cyclic GMP levels markedly, but only slightly elevated cyclic AMP levels in the intact platelets. 4. MY-5445, a selective inhibitor of cyclic GMP phosphodiesterase, potentiated the increases in cyclic GMP caused by YC-1, and shifted the concentration-anti-aggregation curve of YC-1 to the left. In contrast, HL-725, a selective inhibitor of cyclic AMP phosphodiesterase, did not affect either the increases in cyclic nucleotides or the anti-aggregatory effect caused by YC-1. 5. Methylene blue, an inhibitor of sGC, blocked the increases of cyclic GMP caused by YC-1, and attenuated markedly the anti-aggregatory effect of YC-1. The adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA) did not affect YC-1-induced inhibition of platelet aggregation. 6. Haemoglobin, which binds NO, prevented the activation of sGC and anti-aggregatory effect caused by sodium nitroprusside, but did not affect YC-1 response. 7. These results would suggest that YC-1 activates sGC of human platelets by a NO-dependent mechanism, and exerts its antiplatelet effects through the sGC/cyclic GMP pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Adenosine Triphosphate / pharmacology
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism*
  • Collagen / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Dideoxyadenosine / analogs & derivatives
  • Dideoxyadenosine / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Furans / pharmacology*
  • Guanylate Cyclase / metabolism*
  • Hemoglobins / physiology
  • Humans
  • Indazoles / pharmacology*
  • Nitric Oxide / metabolism*
  • Phosphodiesterase Inhibitors / pharmacology
  • Phthalazines / pharmacology
  • Platelet Aggregation Inhibitors / pharmacology*
  • Prostaglandin Endoperoxides, Synthetic / pharmacology
  • Solubility
  • Thrombin / pharmacology
  • Thromboxane A2 / analogs & derivatives
  • Thromboxane A2 / pharmacology
  • Vasoconstrictor Agents / pharmacology


  • Furans
  • Hemoglobins
  • Indazoles
  • Phosphodiesterase Inhibitors
  • Phthalazines
  • Platelet Aggregation Inhibitors
  • Prostaglandin Endoperoxides, Synthetic
  • Vasoconstrictor Agents
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • Nitric Oxide
  • Dideoxyadenosine
  • Thromboxane A2
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Adenosine Triphosphate
  • Collagen
  • 2',5'-dideoxyadenosine
  • Cyclic AMP
  • Thrombin
  • Guanylate Cyclase
  • MY 5445
  • Cyclic GMP