Characterization of the thrombin-induced contraction of vascular smooth muscle.
Purified human alpha-thrombin induced a sustained contraction of isolated rabbit aorta and dog coronary arteries. These vascular tissues also exhibited a refractoriness towards a second thrombin exposure. The extent of tachyphylaxis exhibited by the aorta correlated with the initial concentration of thrombin and the length of time the tissue was exposed to thrombin. The thrombin-induced contraction in the aorta was not blocked by phospholipase or cyclooxygenase inhibitors, but it was inhibited in the presence of hirudin, heparin, nitroglycerin, and nitroprusside. Nitroglycerin, nitroprusside, and hirudin also inhibited the contraction in the dog coronary artery. Ca++ channel blockers did not inhibit the thrombin-induced contraction in the coronary artery, although a small inhibition was observed in Ca++-free media. In both tissues, equivalent contractile responses were obtained using equimolar quantities of beta-, tetranitromethane-, and alpha-thrombin, even though the latter's coagulant activity was 30-40 times that of the modified thrombins. However, if the catalytic activity of thrombin was inhibited by modification with Tos-Lys-CH2Cl, hirudin, or heparin/antithrombin III, the vasoconstrictor activity was also lost. These studies suggest that alterations of the fibrinogen-binding site do not affect the contractile activity of thrombin. The contraction may be the result of a proteolytic interaction of the active site of the enzyme with vascular smooth muscle.
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011817:Rabbits; D013917:Thrombin / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D006629:Hirudins; D011448:Prostaglandin Antagonists; D014665:Vasodilator Agents; D006493:Heparin; D013917:Thrombin; D005996:Nitroglycerin