Thrombin receptor-mediated vascular relaxation differentiated by a receptor antagonist and desensitization.
The vasorelaxant actions of the serine protease, alpha-thrombin, are selectively blocked by the thrombin active site inhibitors, suggesting that proteolytic cleavage is required for alpha-thrombin-induced release of nitric oxide. Whether these relaxations are caused by interaction with a thrombin receptor was evaluated using a prototype thrombin receptor antagonist, a decapeptide analogue of the tethered ligand thrombin receptor [3-mercapto-propionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-amide (c186-65)]. In rings of pig coronary arteries with endothelium contracted submaximally with U-46619, the relaxation caused by extremely low concentrations of alpha-thrombin were mimicked by the synthetic thrombin receptor-activating peptide (TRAP-7: SFLLRNP). These relaxations were inhibited by C186-65. In contrast, C186-65 had no effect on the relaxations caused by bradykinin and serotonin. Exposure of arteries to alpha-thrombin or TRAP-7 caused heterologous desensitization to subsequent stimulation by alpha-thrombin or TRAP-7 but not by bradykinin. These studies support the hypothesis that alpha-thrombin-induced endothelium-dependent relaxations occur by activation of the cloned "tethered-ligand" thrombin receptor in vascular endothelium.
Tesfamariam
B
B
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D013552:Swine; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C090291:C186 65; D009842:Oligopeptides; D010446:Peptide Fragments; D011450:Prostaglandin Endoperoxides, Synthetic; D018179:Receptors, Thrombin; D014662:Vasoconstrictor Agents; C086309:thrombin receptor peptide SFLLRNP; D012701:Serotonin; D013373:Substance P; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D001920:Bradykinin