This is a proposal to study (a) factors which regulate tone in pial arteries of animals and man and (b) the changes which occur in pial arteries following a permanent occlusion of the middle cerebral artery at its origin in animal models. The structural and functional changes in these arteries may limit the ability of anastomotic flow to adequately perfuse ischemic brain tissue. Conventional in vitro methods involving the use of the resistance artery myograph and a pressurized perfusion video imaging system will be used to study vascular segments. These will be obtained from arteries not smaller than those with unstretched lumen diameters of 50 m obtained from the rabbit and cat. These are vessels that contribute in a very significant way to cerebrovascular resistance. These techniques will be supplemented by studies involving other types of techniques - including light, fluorescence, scanning and transmission electron microscopy, biochemical estimations of norepinephrine and choline acetyltransferase and also vascular biochemical estimations of norepinephrine and choline acetyltransferase and also vascular smooth muscle electrophysiology and ion flux measurements. Specific objectives are to (1) analyze the basis of flow-induced increase and decrease in cerebrovascular tone, (2) characterize the neuroeffector features of some pial arteries that seem to have diverse properties by virtue of their size, location and function, (3) investigate low affinity sites for norepinephrine (extraceptors) found in cerebrovascular smooth muscle taking advantage of pial arteries that have such sites but lack alpha- adrenoceptors, (4) characterize the time-dependent, functional changes that occur in the perivascular nerves, vascular smooth muscle and endothelial cells of pial arteries distal to permanent occlusion of the middle cerebral artery and (5) characterize the neuroeffector mechanisms of human cerebral arteries, by examining segments taken during surgery and those obtained 2- 4 hours after death. The cerebral circulation is a complex vascular bed whose function reflects the interactions of many factors on blood vessels with a diversity of properties. Since vascular changes occur not only in stroke, migraine, transient ischemic attacks, subarachnoid hemorrhage, but also in the dementias, it is important to understand normal mechanisms of tone regulation and ways in which these mechanisms can change in disease.
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