NEUROGENIC VASODILATION--MEDIATORS AND MECHANISMS

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Arteries throughout the cerebral circulation have intrinsic tone, which is generated by mechanisms that are still not well-defined. Autoregulation of cerebral blood flow is accomplished by increasing or decreasing the level of this basal tone and it is the interplay of a variety of constrictor and dilator influences, including endothelial derived substances, tissue metabolites and perivascular nerves that determine the contractile state from moment to moment. The cerebral circulation is unique in many respects. Neurally mediated vasodilation is pronounced in this bed. Endothelium-dependent constriction and dilation of these arteries are associated with large, sustained changes in membrane potential and with changes in levels of both cyclic AMP and cyclic GMP. However, many of the mechanisms of cerebral vasomotor control have not yet been fully elucidated. The specific aims of this proposal are: 1) to determine whether endothelium-dependent hyperpolarization, which is transient in systemic arteries, is sustained in cerebral arteries due to intrinsic properties of the cerebral vascular smooth muscle cells or is a result of unique actions of the endothelium-derived hyperpolarizing factor in this vascular bed, 2) to reveal which of two probable mechanisms, increased potassium conductance or enhanced electrogenic Na/K ATPase activity, is responsible for endothelium-dependent hyperpolarization in cerebral arteries, 3) to establish the temporal relationship between alterations in cyclic nucleotide levels and vasodilation, which will be evoked by activation of periarterial nerves and by endothelium-independent and endothelium- dependent dilators and 4) to test the hypothesis that the contribution of the endothelium to pressure-induced cerebral arterial depolarization and constriction is dependent on arterial size. The following techniques will be employed: 1) continuous diameter measurements on isolated, pressurized cerebral arteries using a high resolution video dimension analyzer, 2) isometric force measurements on arterial ring- segments, 3) intracellular recordings of membrane potential and 4) measurement of cyclic nucleotide content by radioimmunoassay. Elucidation of the cellular mechanisms that determine cerebrovascular tone will contribute to a better understanding of autoregulation and will be relevant to future investigations of the etiology of vascular diseases such as hypertension, vasospasm and vascular headache.