title: Systemic vascular effects of thrombin and thrombin receptor activating peptide in rats.
abstract: The proteolytic enzyme thrombin activates its receptor by cleavage of a peptide from the extracellular N-terminus. The newly generated N-terminus acts as a tethered ligand to activate the receptor. Receptor-mediated cellular effects of thrombin can be mimicked by synthetic peptides, which correspond to the amino acid sequence of the newly formed N-terminus. The aim of the present study was to investigate vascular effects of thrombin and the thrombin receptor activating peptide (TRAP: SFLLRN) in vitro and in vivo in rats. In precontracted rat aortic rings, both thrombin (0.3, 1, 3 U/ml) and TRAP (1, 3, 10, 20, 40 microM) induced endothelium-dependent relaxant responses. In anaesthetized rats, the mean arterial blood pressure (MAP) was measured continuously in the carotid artery by a pressure transducer. Thrombin and TRAP were administered as intravenous bolus injection via the femoral vein. Thrombin at doses of 3-100 U/kg, as well as TRAP at doses of 0.1-0.6 mg/kg i.v., caused a reversible decrease in MAP. Administration of TRAP at doses of 0.3 and 0.6 mg/kg led to a triphasic response in most of the animals treated (50% and 75%, respectively), i.e. a short drop of MAP was followed by an increase and finally a longer lasting decrease in MAP. Pretreatment with the nitric oxide (NO)-synthase inhibitor N(G)-nitro-L-arginine-methylester (L-NAME) suppressed the dose-dependent vasodilator effects of thrombin. Heparin and hirudin also inhibited the hypotensive response to thrombin. The TRAP-induced triphasic reaction on MAP was not affected by the serotonin antagonists ketanserin and tropisetron, as well as the aminopeptidase inhibitor amastatin. Pretreatment with L-NAME led to an inhibition of hypotension induced by TRAP at 0.1 mg/kg, as well as of the initial transient fall in blood pressure at doses of 0.3 and 0.6 mg/kg. The studies suggest that the thrombin- and TRAP-induced vasodilation in vitro and in vivo is in part due to the release of endothelial NO. In the blood pressure response to TRAP, additional effects seem to be involved.
authors.affiliation: Unit of Experimental Angiology, Center for Vascular Biology and Medicine, Faculty of Medicine, Friedrich Schiller University Jena, Nordhäuser Str. 78, D-99089, Erfurt, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Sicker
authors.forename: F
authors.initials: F
authors.lastname: Wuchold
authors.forename: B
authors.initials: B
authors.lastname: Kaiser
authors.forename: E
authors.initials: E
authors.lastname: Glusa
mesh_terms: D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D010446:Peptide Fragments; C082835:thrombin receptor peptide (42-47); D019001:Nitric Oxide Synthase; D013917:Thrombin; D019331:NG-Nitroarginine Methyl Ester