Secondary factors, such as hypoxia, hypotension and ischemia, can adversely affect the outcome of head injuries. In addition to these well-recognized secondary factors, subarachnoid hemorrhage (SAH), alcohol (EtOH), and hyperglycemia may also contribute to adverse outcome. In the present proposal, we will test the hypothesis that the secondary factors of SAH, EtOH and hyperglycemia exert their deleterious effects by altering the physiology of the cerebral microcirculation. Specifically, we will determine if these factors alter signal transduction caused by adenosine and other vasodilators (acetylcholine, prostacyclin and sodium nitroprusside). We will first emphasize adenosine-related vasodilation since its effects on the microcirculation of the brain in physiologic and pathophysiologic (e.g., reperfusion injury) states are well defined. Next we will investigate acetylcholine (ACh), prostacyclin (PGI2) and sodium nitroprusside; vasodilators which elicit their effects by different mechanisms. We will utilize a multifaceted approach to study the effects of these secondary factors on the biology of the vessel wall: (1) in vivo analysis of the response of the cerebral arterioles; (2) in vitro studies of isolated microvessels; and (3) by using electrophysiologic techniques (patch clamp, whole cell and single-channel recordings) on cell cultures of cerebrovascular endothelial and vascular smooth muscle (VSM), we will study the subcellular mechanisms by which these secondary factors alter signal transduction in vessel wall. Thus we propose to study the effect of SAH, EtOH and hyperglycemia, three factors that exacerbate recovery from head injury, from the level of physiologic function to the level of cellular biochemical mechanism.
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