MECHANISM AND THERAPY OF CEREBROVASCULAR SPASM

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Cerebrovascular spasm (CVS) is a life-threatening sequela for those who suffer subarachnoid hemorrhage (SAH). CVS occurs as a delayed phenomenon and consists of severe narrowing of cerebral arteries, resulting in high risk of cerebral ischemia or infarction. Despite intensive research effort, the cause of CVS remains unknown, and no effective treatment has been established. The objectives of this study are to test the following hypotheses: IA. CVS is induced by vasoconstrictive action of hemoglobin (Hb) and of additional hemolysates released from red blood cells; IB. these agents or other substances in blood also produce a second stage of CVS, characterized by marked pathological changes, including hyperplasia, of the arterial wall; IIA. CVS, during its initial stage of profound vasoconstriction, can be reversed using calibrated-leak, flow-directed balloon catheters to deliver pharmacological agents directly into the lumen of involved vessels; and IIB. CVS, during the later stage of vasculopathy, can be relieved through the use of intra-arterial, angioplasty catheters. We will investigate Hypothesis IA by comparing the effect of Hb with that of hemolysate upon the diameter of the intact basilar artery in cats and rhesus monkeys. The amounts of Hb which develop in clots in the prepontine cistern will also be measured. With regard to Hypothesis IB, we will determine the effects of various blood components upon vessels maintained in perfusion chambers for periods up to 9 days. We will quantitate the compliance of these vessels throughout the perfusion period; we will then assess both morphological changes by electron microscopy and functional changes by contraction chamber measurements. Our utilization of balloon-tipped catheters is stimulated by the need for delivering potent therapeutic agents into restricted vascular territories and by the need for developing methods to expand vessels which have become resistant to vasodilating substances. Using rhesus monkeys, catheters will be inserted into a femoral artery and their tips placed within the distal vertebral or proximal basilar arteries. In the first set of experiments, vascular narrowing will be induced by intra-cisternal injection of serotonin; the effects of intraluminal administration of vasodilating substances will be determined by angiography. In the second set of experiments, CVS will be induced by subarachnoid injection of blood; these animals will be continuously observed for signs of CVS, at which time the effects of vasodilating agents and of angioplasty will be studied.