The applicant's long-term goal is to develop a program of laboratory research that parallels the clinical problems of patients with cerebrovascular disorders. One of the most important of these is the lack of treatment options for patients who have suffered a severe subarachnoid hemorrhage (SAH). Although progress has been made in our treatment of the delayed consequences of SAH, acute SAH-induced brain injury is the primary cause of morbidity and mortality from SAH, and no effective treatment exists. In this proposal we utilize a multidisciplinary approach to examine the pathophysiology and pharmacological treatment of acute brain injury after experimental SAH. The investigators hypothesize that: 1)acute brian injury after SAH (as opposed to delayed ischemic damage) is caused by constriction of cortical microvessels, 2) acute vasoconstriction in this setting is due to a multifaceted central adrenergic pathways, and 3) SAH-induced alteration of these pathways is pharmacologically treatable within a clinically relevant time frame. The problem will be approached using a novel rat model of SAH developed in this laboratory. The physiological predictors of early mortality after SAH (cortical blood flow and cerebral perfusion pressure) will be compared with the factors known to influence (or be influenced by) vasodilatory and vasoconstrictive tone. These will include: a) the activity of nitric oxide synthase (NOS) measured by a modified citrulline assay, b) the extracellular concentrations of catecholamines and glutamate measured by cerebral microdialysis and high performance liquid chromatography, and c) histological evidence of acute vasoconstriction and ischemic brain damage. We will determine if acute cerebral ischemia, early mortality rate, and ischemic histological damage can be reduced by enhancing vasodilatory tone and inhibiting vasoconstrictive tone with the NO donor sodium nitroprusside or the cGMP-specific phosphodiesterase inhibitor Zaprinast, the nonspecific c-AMP phosphodiesterase (PDE) inhibitor papaverine hydrochloride or the type III cAMP-specific PDE inhibitor Milrinone, and for alpha adrenergic blockade the selective alpha 1 antagonist Benextramine. In addition, we will administer the NOS inhibitor NG-monomehtyl-L-arginine (L-NMMA) which, if our hypotheses are correct, should increase vasoconstriction and worsen outcome.
