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Research ArticleCARDIOVASCULAR

Vascular Contraction and Relaxation to Thrombin and Trypsin: Thrombomodulin Preferentially Attenuates Thrombin-Induced Contraction

Anindya Bhattacharya and Marlene L. Cohen
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 284-290;
Anindya Bhattacharya
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Marlene L. Cohen
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Abstract

Thrombin and trypsin activate protease-activated receptors (PARs) that modulate vascular tone. In addition to the PARs, thrombin also binds to thrombomodulin via exosite 1, a domain also involved in the interaction of thrombin with PAR-1 but not PAR-2. The purpose of this study was to determine whether thrombomodulin would alter thrombin-induced vasoconstriction, thought to be mediated predominantly by PAR-1, but not PAR-2, which mediates vascular relaxation. For comparison, thrombomodulin was examined for its effect on both thrombin and trypsin-induced responses. Trypsin was 2000-fold more potent as a relaxant than as a contractile peptide, whereas thrombin was only 7.8-fold more potent as a relaxant than contractile agonist, consistent with activation of PAR-1 predominantly mediating contraction and PAR-2 predominantly mediating relaxation. Although thrombomodulin (10−7 M) alone did not alter vascular tone or the rate of thrombin-induced vascular responses, thrombomodulin (10−8and 10−7 M) attenuated maximal thrombin (10−8and 10−7 M)-induced vasoconstriction preferentially compared with thrombin-induced relaxation and had no effect on equieffective trypsin-induced responses. The inhibition of thrombin-induced contraction resulted from the interaction of thrombin with thrombomodulin rather than any direct effect of thrombomodulin on tissue PARs. Thus, this study describes a novel vascular action of thrombomodulin to selectively attenuate thrombin-induced vascular contractility. This action of thrombomodulin may serve to protect vasculature from thrombin-induced vasoconstriction during conditions of endothelial injury known to increase plasma and cellular levels of thrombomodulin.

Footnotes

  • Send reprint requests to: Anindya Bhattacharya, Ph.D., Neuroscience Drug Discovery, Eli Lilly & Company, Drop Code 0522, Indianapolis, IN 46285. E-mail:bhattacharya_anindya{at}lilly.com

  • ↵1 This study was supported by Eli Lilly & Company.

  • Abbreviation:
    PAR
    protease-activated receptor
    • Received April 12, 2000.
    • Accepted June 26, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleCARDIOVASCULAR

Vascular Contraction and Relaxation to Thrombin and Trypsin: Thrombomodulin Preferentially Attenuates Thrombin-Induced Contraction

Anindya Bhattacharya and Marlene L. Cohen
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 284-290;

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Research ArticleCARDIOVASCULAR

Vascular Contraction and Relaxation to Thrombin and Trypsin: Thrombomodulin Preferentially Attenuates Thrombin-Induced Contraction

Anindya Bhattacharya and Marlene L. Cohen
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 284-290;
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