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
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|