Enhanced nitric oxide and cyclic GMP formation plays a role in the anti-platelet activity of simvastatin

T. C. Chou, Y. F. Lin, W. C. Wu, K. M. Chu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background and purpose: It has been found that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert various vascular protective effects, beyond their cholesterol-lowering property, including inhibition of platelet-dependent thrombus formation. The objective of the present study was to determine whether the nitric oxide (NO)/cyclic GMP-mediated processes in platelets contribute to the anti-aggregatory activity of simvastatin. Experimental approach: After rabbit platelets were incubated with simvastatin for 5 min, aggregation was induced and the platelet aggregation, nitric oxide synthase activity, guanylyl cyclase activity, NO and cyclic GMP formation were measured appropriately. Key results: Treatment with simvastatin concentration-dependently inhibited platelet aggregation induced by collagen or arachidonic acid with an IC 50 range of 52-158 μM. We also demonstrated that simvastatin (20-80 μM) concentration-dependently further enhanced collagen-induced NO and cyclic GMP formation through increasing NOS activity (from 2.64±0.12 to 3.52±0.21-5.10±0.14 μmol min -1 mg protein -1) and guanylyl cyclase activity (from 142.9±7.2 to 163.5±17.5-283.8±19.5 pmol min -1 mg protein -1) in the platelets. On the contrary, inhibition of platelet aggregation by simvastatin was markedly attenuated (by about 50%) by addition of a nitric oxide synthase inhibitor, a NO scavenger or a NO-sensitive guanylyl cyclase inhibitor. The anti-aggregatory effects of simvastatin were significantly increased by addition of a selective inhibitor of cyclic GMP phosphodiesterase. Conclusions and implications: Our findings indicate that enhancement of a NO/cyclic GMP-mediated process plays an important role in the anti-aggregatory activity of simvastatin.

Original languageEnglish
Pages (from-to)1281-1287
Number of pages7
JournalBritish Journal of Pharmacology
Volume153
Issue number6
DOIs
Publication statusPublished - Mar 2008
Externally publishedYes

Fingerprint

Simvastatin
Cyclic GMP
Nitric Oxide
Blood Platelets
Platelet Aggregation
Guanylate Cyclase
Nitric Oxide Synthase
Collagen
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Phosphoric Diester Hydrolases
Arachidonic Acid
Blood Vessels
Oxidoreductases
Proteins
Thrombosis
Cholesterol
Rabbits

Keywords

  • Cyclic GMP
  • Nitric oxide
  • Platelet aggregation
  • Simvastatin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Enhanced nitric oxide and cyclic GMP formation plays a role in the anti-platelet activity of simvastatin. / Chou, T. C.; Lin, Y. F.; Wu, W. C.; Chu, K. M.

In: British Journal of Pharmacology, Vol. 153, No. 6, 03.2008, p. 1281-1287.

Research output: Contribution to journalArticle

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abstract = "Background and purpose: It has been found that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert various vascular protective effects, beyond their cholesterol-lowering property, including inhibition of platelet-dependent thrombus formation. The objective of the present study was to determine whether the nitric oxide (NO)/cyclic GMP-mediated processes in platelets contribute to the anti-aggregatory activity of simvastatin. Experimental approach: After rabbit platelets were incubated with simvastatin for 5 min, aggregation was induced and the platelet aggregation, nitric oxide synthase activity, guanylyl cyclase activity, NO and cyclic GMP formation were measured appropriately. Key results: Treatment with simvastatin concentration-dependently inhibited platelet aggregation induced by collagen or arachidonic acid with an IC 50 range of 52-158 μM. We also demonstrated that simvastatin (20-80 μM) concentration-dependently further enhanced collagen-induced NO and cyclic GMP formation through increasing NOS activity (from 2.64±0.12 to 3.52±0.21-5.10±0.14 μmol min -1 mg protein -1) and guanylyl cyclase activity (from 142.9±7.2 to 163.5±17.5-283.8±19.5 pmol min -1 mg protein -1) in the platelets. On the contrary, inhibition of platelet aggregation by simvastatin was markedly attenuated (by about 50{\%}) by addition of a nitric oxide synthase inhibitor, a NO scavenger or a NO-sensitive guanylyl cyclase inhibitor. The anti-aggregatory effects of simvastatin were significantly increased by addition of a selective inhibitor of cyclic GMP phosphodiesterase. Conclusions and implications: Our findings indicate that enhancement of a NO/cyclic GMP-mediated process plays an important role in the anti-aggregatory activity of simvastatin.",
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