Systemic vascular effects of thrombin and thrombin receptor activating peptide in rats

The proteolytic enzyme thrombin activates its receptor by cleavage of a pep tide 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 throm bin 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 TRA P (1, 3, 10, 20, 40 muM) 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 T RAP 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/ k g iv, 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 tre ated (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. Hep arin and hirudin also inhibited the hypotensive response to thrombin. The T RAP-induced triphasic reaction on MAP was not affected by the serotonin ant agonists ketanserin and tropisetron, as well as the aminopeptidase inhibito r amastatin. Pretreatment with L-NAME led to an inhibition of hypotension i nduced by TRAP at 0.1 mg/kg, as well as of the initial transient fall in bl ood pressure at doses of 0.3 and 0.6 mg/kg. The studies suggest that the th rombin- and TRAP-induced vasodilation in vitro and in vivo is in part due t o the release of endothelial NO. In the blood pressure response to TRAP, ad ditional effects seem to be involved. (C) 2001 Elsevier Science Ltd. All ri ghts reserved.