Interaction between Adrenergic and Nitric Oxide-releasing Nerves in Cerebral Arteries

Of all body tissues, the brain is the least tolerant of ischemia so much that interruption of cerebral blood flow by 5 sec can cause syncope, with irreversible tissue damage if the ischemia last a few minutes. In this respect, the body has an imperative duty of ensuring constant and adequate blood supply to the brain. It does so through a series of intrinsic and extrinsic control factors of which adrenergic and nitric oxide-releasing nerves are components. My research examined the interaction between these two nerve-types with emphasis on the mechanisms involved as well as on changes in their functions as the animal adapts to stress such as chronic hypoxia. An overview of endogenous NO which is synthesized by nNOS, reveals that NO exhibits numerous and wide spread interactions in the nervous system with implications in disease conditions such as Multiple Sclerosis, Schizophrenia, Parkinson’s and Alzheimer’s diseases. On the other hand, beneficial effects of NO include a role in synaptic plasticity and modulation of sympathetic nerve activity in cerebral arteries with potential to modulate cerebral circulation. This thesis provides evidence supporting the hypothesis that adrenergic and nNOS nerves co-exist within cerebral arteries and strongly suggest an interaction between these two neuron types such that NO released from the nNOS nerves serves to facilitate NE released from the adjacent adrenergic nerves. In addition, evidence in this thesis also show that in the course of adapting to stress such as chronic high altitude hypoxia, the ability of nNOS nerves to modulate adrenergic function is lost. This lost of nNOS nerve function is due at least in part to a decline in the expression of nNOS protein. The mechanism by which NO modulates adrenergic nerve function has been proposed to involve a cascade of reactions leading to the mobilization of intracellular free calcium within adrenergic nerve terminals. Recall that the release of neurotransmitter such as NE from stored vesicles requires an increase in [Ca2+]i. This thesis provides data in support of the hypothesis that the NO/cGMP-dependent protein kinase -1 pathway controls intracellular calcium mobilization which could underlie the mechanism of NO modulation of adrenergic nerve function in cerebral arteries. However, it remains to be ascertained whether the NO/cGMP-dependent protein kinase-induced mobilization of [Ca2+]l is mediated via cADP ribose