Vasodilator proteins: role in delayed cerebral vasospasm.

Abstract

Blood proteins could play a critical role in the pathogenesis of cerebral vasospasm in subarachnoid hemorrhage (SAH) as agonists and as antagonists of vasoconstriction. The present study was designed primarily to quantify the inhibition produced by antithrombin III of the phasic responses elicited by cumulative doses of KCl, serotonin (5-HT), uridine triphosphate (UTP), and thrombin in isolated canine basilar arteries, and to ascertain whether other proteins might act similarly. Antithrombin III (1 unit/ml and 3 units/ml) given 2 min beforehand inhibited all agonists. The inhibition was not dependent on a functional endothelium nor due to stimulation of the electrogenic sodium pump. Alpha2-macroglobulin (0.1 mg/ml and 0.4 mg/ml) inhibited the contractile responses to high K+, 5-HT and thrombin. Kallikrein (1 and 4 units/ml) did not inhibit UTP but inhibited high K+ and 5-HT through an effect on the endothelium. Kallikrein (1 unit/ml) irreversibly blocked the responses to thrombin. Globulins (3 mg/ml) and fibrinogen (0.3 mg/ml) were not inhibitory. The results demonstrate that anticoagulant proteins are very effective nonspecific inhibitors of the vasoconstriction, whereas the serine protease kallikrein selectively blocks thrombin. The remarkable potency of antithrombin III suggests that it may protect cerebral arteries from exhibiting vasospasm in SAH.

Thrombin Reduces Cerebral Arterial Contractions Caused by Cerebrospinal Fluid From Patients With Subarachnoid Hemorrhage

“…[33][34][35][36] By extension, a protective role for thrombin antagonists against the development of vasospasm has been proposed. 7 Part of the discrepancy between that hypothesis and the findings in the present study may be the vasoactivity of fibrinopeptides, which are the products of the cleavage of thrombin to fibrinogen. Fibrinopeptides are known to cause vasoconstriction in various peripheral arteries.…”

“…6 The inability of hemoglobin to determine SAH CSF contractility and the disparity in contraction caused by SAH CSF and erythrocyte hemolysate may be due to the presence of vasoactive plasma proteins that would be present in the CSF after SAH. 7,8 One such protein is the serine protease thrombin. Thrombin has an established role in vasospasm at sites of blood coagulation in coronary arteries.…”