Cerebral blood vessels from several species receive both vasoconstrictor and dilator nerves. Norepinephrine (NE) released from sympathetic nerves and acetylcholine (ACh) from parasympathetic cholinergic nerves were first suggested to be the respective transmitters for vasoconstriction and dilation. Electrical stimulation or denervation of the sympathetic nerves however has a weak or no effect on resting cerebral blood flow, and cerebral vascular smooth muscle is relatively insensitive to NE. In addition, the direct effect of ACh on cerebral vascular smooth muscle is constriction, not dilation. The exact transmitter role of NE and ACh in regulating cerebral vascular tone therefore remains unclarified. There is compelling evidence to indicate that nitric oxide (NO) plays a predominant role in cerebral neurogenic vasodilation. ChAT (Choline acetyltransferase) and NOS (nitric oxide synthase) are colocalized in the same cerebral perivascular nerves, and that ACh acts presynaptically to inhibit release of co-transmitter NO resulting in a decrease in neurogenic vasodilation. Close apposition of adrenergic and nonadrenergic/NOergic nerve terminals has been frequently observed in large cerebral arteries from different species. We have recently demonstrated that nicotine-induced NO-mediated cerebral neurogenic vasodilation is sensitive to propranolol and is dependent exclusively on intact sympathetic innervation. It is our hypothesis that NE released from the sympathetic nerves acts on presynaptic beta- adrenoceptors located on the neighboring NOergic nerves to cause release of NO resulting in vasodilation. NE and ACh therefore act more like presynaptic transmitters in positive and negative modulation of NO release, respectively. The proposed study will focus on characterization of the transmitter mechanisms of NE and its role in modulating NO-mediated cerebral neurogenic vasodilation in the pig and cat. The in vitro tissue bath techniques, and techniques of biochemical and chemical analysis, and morphology (light and ultrastructural immunocytochemistry) will be utilized to provide a comprehensive and multi-faceted approach to the problem. We plan to examine in cerebral arteries: 1) the close apposition of adrenergic and NOergic nerve terminals; 2) co-localization of ChAT and nitric oxide synthase (NOS) in cerebral perivascular nerves; 3) the obligatory role of sympathetic nerves in nicotine-induced neurogenic vasodilation; and 4) the significance of beta-adrenoceptors in mediating nicotine-induced NO-mediated neurogenic vasodilation; whether presynaptic beta2-adrenoceptors mediate nicotine-induced relaxation; whether release of NE and NO in cerebral arteries induced by nicotine is quantitatively correlated; and whether beta2-adrenoceptors are present on NOergic nerve terminals. Results of these studies will provide fundamental information for establishing a functional role of sympathetic innervation in modulating NOergic neurogenic vasodilation and a new insight in understanding the nature of neurogenic control of cerebral circulation. This research is a step toward our long-term goal to define the transmitter mechanisms in cerebral vasodilation and constriction, and their alterations in cerebral vascular diseases.
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