Pertubations in CBF, mediated in part by constriction and dilation of cerebral vessels, contribute significantly to the morbidity and mortality which accompany brain injury and stroke. New findings reflect on the importance of neurogenic mechanisms of vasodilation in brain and are the subject of this renewal application: 1. Chronic unilateral parasympathetic nerve sections raise the lower limits of autoregulation in preliminary studies, and significantly increase infarct volume after MCA occlusion. 2. Trigeminovascular fibers contribute significantly to the development of cortical hyperemia via axon reflexes.
Specific aims will pursue mechanisms of action and activation based on knowledge of pathway anatomy, chemistry and pharmacology. I. Expts will address the importance of parasympathetic axons to vasodilation in the normal circulation, to hyperemia (seizures) in brain, and to collateral blood flow. We will test the hypothesis that parasympathetic fibers are essential for compensatory vasodilation. Expts will take advantage of recent information about rat neuroanatomy which facilitates selective denervation of Willis' circle. CBF changes will be compared in the MCA territory of the two hemispheres at rest and during increases and decreases in paCO2 and paO2, and MABP. We will measure rCBF during MCA occlusion, in order to test the hypothesis that neurogenic mechanisms promote increases in blood flow within ischemic tissue. We postulate that the absence of parasympathetic fibers during MCA occlusion shifts the autoregulatory curve so that flow is lower than predicted in an area of reduced perfusion pressure. Iodoantipyrene, cranial window, and laser Doppler flowmetry (LDF) are the proposed methods of study. II. The trigeminovascular system represents a new and potentially important mechanism for mediating hyperemia. Marked flow attenuations (30-80%) occur after chronic trigeminal sectioning or following topical capsaicin during postocclusive hyperemia in cats. Studies are proposed to examine the effects of nerve sectioning on tissue outcome in the global model by serial MRI, SEPs, and albumin transport and gravitometric measurements. Expts on the trigeminal nerve will investigate the transmitter mediators of the axon reflex in brain (preliminary data suggest the importance of CGRP). We will test the hypothesis that some agents which promote vasodilation such as ADP and the nitrates, relax vessels by release of sensory neuropeptides from perivascular fibers. The proposed studies are intended to increase our knowledge about the physiology of the brain's circulation and adaptive circulatory mechanisms during cerebral ischemia. Findings may prove relevant to the cerebrovascular dynamics of patients with autonomic neuropathy (diabetics) who are at risk for stroke. Long term goals are to use this new knowledge to develop strategies to prevent and treat injured brain.
