Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery

Dmitry N. Derkach, Eikichi Ihara, Katsuya Hirano, Junji Nishimura, Shosuke Takahashi, Hideo Kanaide

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Abstract

1 Using a method employing front-surface fura-2 fluorometry to measure the cytosolic Ca2+ concentration, [Ca2+]i, the mechanism of endothelium-dependent regulation of vascular tone by thrombin was studied in porcine renal interlobar arterial strips. 2 At concentrations lower than 3 u ml-1, thrombin evoked only early transient relaxation, while at 3 u ml-1 and higher concentrations, thrombin caused an early relaxation and a subsequent transient contraction. Both thrombin-induced relaxation and contraction were abolished by removing the endothelium. Similar biphasic responses were observed with a protease-activated receptor-1-activating peptide. 3 Early relaxation was associated with a decrease in [Ca2+]i, while the transient contraction was not associated with a change in [Ca2+]i of smooth muscle cells. 4 A thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist (10-5 M ONO-3708) completely inhibited the thrombin-induced contraction, whereas a thromboxane A2 synthase inhibitor (10-5 M OKY-046) only partly inhibited it. 5 When the thrombin-induced contraction was inhibited by ONO-3708, either pretreatment with Nω-nitro-L-arginine methylester (L-NAME) or an increase in the amount of external K+ to 40 mM did not abolish thrombin-induced relaxation during phenylephrine-induced sustained contraction. However, the combination of pretreatment with L-NAME and an elevation of external K+ to 40 mM completely abolished the relaxation. 6 There was no significant difference in the concentration-dependent effects of thrombin on the initial early relaxation between conditions in which the contractile components either were or were not inhibited. 7 Thrombin is thus considered to mainly activate protease-activated receptor-1 and cause a biphasic response, early relaxation and a transient contraction, in the porcine renal interlobar artery in an endothelium-dependent manner. The thrombin-induced endothelium-dependent relaxation was mediated by nitric oxide and hyperpolarizing factors, while the contraction was mediated by TXA2 and PGH2.

Original languageEnglish
Pages (from-to)1635-1642
Number of pages8
JournalBritish Journal of Pharmacology
Volume131
Issue number8
DOIs
Publication statusPublished - Jan 1 2000

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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