Systemic Vascular Effects of Thrombin and Thrombin Receptor Activating Peptide in Rats

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• 作者：Sicker ; Thomas ; Wuchold ; Frank ; Kaiser ; Brigitte ; Glusa ; Erika
• 关键词：Thrombin ; TRAP ; Vascular effects ; Blood pressure ; l-NAME ; N^G-nitro-l-arginine-methylester ; MAP ; mean arterial blood pressure ; NO ; nitric oxide ; PAR ; protease-activated receptor ; TRAP ; thrombin receptor activating peptide
• 刊名：Thrombosis Research
• 出版年：2001
• 出版时间：March 15, 2001
• 年：2001
• 卷：101
• 期：6
• 页码：467-475
• 全文大小：219 K

文摘

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 μM) 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 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 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.