This proposal examines the role of nitric oxide (NO) as a mediator of the cellular and molecular events which promote dilation in the cerebrovasculature. NO is formed within vessels and brain parenchyma by the enzyme NOS (nitric oxide synthase), and both are potential mediators of vasodilation. NO synthesis involves the incorporation of molecular oxygen and L-arginine [L-ARG] into NO and citrulline. Linkage between NO, dilation and rCBF increases during hypercapnia, and brain metabolism has been established by L-arginine substrate analogues that inhibit NOS. We propose to use mutant mice in which either vascular (KV) or neuronal (KN isoforms of NOS have been selectively knocked-out to determine the role of NO in normal rCBF regulation and during ischemia. To these ends, we have: established a dedicated mouse physiology unit (2 stations) in which rCBF, expiratory CO2, arterial blood pressure, core and brain temperature, EcoG can be monitored on-line from mechanically ventilated animals and developed in the mouse, the thread model of focal ischemia. The goals of these experiments are to:
(AIM I) characterize the responses of pial vessels to topical endothelium-dependent relaxing factor (EDRF) and non-EDRF generating compounds in Wild type and mutants, (Aim II) determine the role and sources of NO during hypercapnia and cortical barrel field activation.
(Aim III) examine the role of NO in focal and global cerebral ischemia. We will compare and contrast the evolution of infarction in the Wild type to KV and KN following middle cerebral artery occlusion (MCAO) (thread models) and ischemia reperfusion [bilateral CCA (common carotid artery) + hypotension] and determine whether the lack of neuronal and/or vascular NOS affects the volume of tissue injury, the production of free radicals, the extent of cellular injury as compared to Wild type, and the adaptive circulatory responses which characterize focal and global ischemia. By so doing, we hope to clarify whether vascular and/or neuronal NO mechanisms predominate in response to focal ischemia and to thereby clarify the molecular events underlying the regulation of the cerebrovasculature during health and disease.
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