Vascular actions of thrombin receptor peptide

Abstract

We have examined the action of the thrombin receptor-derived polypeptide, S42FLLRNPNDKYEPF55 (TRP 42-55), in rat and guinea pig aortic rings and helical arterial strips, and we have compared the actions of the peptide with those of thrombin. In rat preparations, both TRP 42-55 and thrombin caused a concentration-dependent endothelium-dependent relaxation that was blocked by N omega-nitro-L-arginine methyl ester; the relaxation response of the intact rat aortic strip preparation to concentrations of the peptide in the range 30-60 micrograms/mL (17-34 microM) was equivalent to the response to 0.03-0.1 U/mL of thrombin (about 0.3-0.9 nM), yielding a potency ratio (TRP 42-55:thrombin) of about 38,000:1. In contrast with the complete desensitization of thrombin-treated rat aortic preparations to a second administration of the enzyme, the rat aortic tissue was not desensitized by repeated exposures to TRP 42-55 and remained responsive to the peptide even after treatment of the tissue by thrombin. In contrast with the rat aortic tissue, in either intact or endothelium-free guinea pig aortic preparations both TRP 42-55 and thrombin caused a concentration-dependent endothelium-independent contraction. The contractile action of 60 micrograms/mL of receptor peptide (34 microM) in guinea pig aortic strip preparations was equivalent to the contractile action of 0.1-0.3 U/mL thrombin (0.9-3 nM), yielding a potency ratio of about 17,000:1. In guinea pig aortic preparations with an intact endothelium that were precontracted with noradrenaline, neither thrombin nor TRP42-55 caused relaxation, whereas substance P did so.(ABSTRACT TRUNCATED AT 250 WORDS)

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

“…56 In normal guinea-pig aortas, rabbit aortas and canine coronary arteries, thrombin has been reported to directly contract smooth muscle. 50,54,55,58 However, it has also been shown to have no direct contractile effect in normal rabbit mesenteric arteries, rabbit femoral arteries, or rat aortas, while causing slight contractions in normal rabbit basilar arteries, at high concentrations (unpublished observations). As a result, the endothelial cells are considered to be the primary cells mediating the vascular (Figure).…”

Proteinase-activated Receptors, Targets for Kallikrein Signaling

“…Aorta Ring Relaxation Assays Using Rat and Murine Vascular Tissue-Activation of either PAR 1 or PAR 2 (46,52) but not PAR 4 (49) induces an endothelium-dependent, nitric oxidemediated relaxation of rat or mouse aorta. To determine whether hKs could activate PARs in intact tissues, which unlike the cells may contain extracellular proteinase inhibitors in vivo, we examined the actions of the hKs in rat and murine aorta preparations.…”

Role of Protease-activated Receptors in the Vascular System

“…Thrombin was reported to induce endothelium-dependent relaxation (79,80,(98)(99)(100)(101), endothelium-dependent contraction (82) and endothelium-independent direct contraction in smooth muscle (79,80), depending on the species and type of blood vessel. The PAR-2-mediated regulation of vascular tone also varies with species and type of blood vessel, as observed with PAR-1.…”

“…Prostaglandin H2 and thromboxane A2 were shown to contribute to the endothelium-dependent contraction (82). On the other hand, thrombin induces endothelium-independent contraction in guinea-pig aorta, rabbit aorta and canine coronary artery (79,80,98,108). In isolated human coronary rings, PAR-1-mediated endothelium-dependent relaxation dominated when the degree of intimal proliferation was minimal (79).…”