Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery.
Using a method employing front-surface fura-2 fluorometry to measure the cytosolic Ca(2+) concentration, [Ca(2+)](i), the mechanism of endothelium-dependent regulation of vascular tone by thrombin was studied in porcine renal interlobar arterial strips. 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. Early relaxation was associated with a decrease in [Ca(2+)](i), while the transient contraction was not associated with a change in [Ca(2+)](i) of smooth muscle cells. A thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist (10(-5) M ONO-3708) completely inhibited the thrombin-induced contraction, whereas a thromboxane A(2) synthase inhibitor (10(-5) M OKY-046) only partly inhibited it. When the thrombin-induced contraction was inhibited by ONO-3708, either pretreatment with N(omega)-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. 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. 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 TXA(2) and PGH(2).
Derkach
D N
DN
Department of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan.
Ihara
E
E
Hirano
K
K
Nishimura
J
J
Takahashi
S
S
Kanaide
H
H
D000818:Animals; D001685:Biological Factors / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008689:Methacrylates / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D013552:Swine; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D001685:Biological Factors; D004791:Enzyme Inhibitors; D008689:Methacrylates; D010446:Peptide Fragments; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; C067410:endothelium-dependent hyperpolarization factor; C086309:thrombin receptor peptide SFLLRNP; D010656:Phenylephrine; D009569:Nitric Oxide; D013928:Thromboxane A2; C049855:ONO 3708; D019001:Nitric Oxide Synthase; D013917:Thrombin; D013930:Thromboxane-A Synthase; C034364:ozagrel; D011188:Potassium; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester