The role of the central nervous system in the initiation and maintenance of elevated blood pressure associated with hypertensive disease has been emphasized with the development of antihypertensive drugs typified by the alpha-adrenergic agonist, clonidine, which decrease blood pressure through an action on the central nervous system. Recent studies in this laboratory have indicated that many of these agents produced a striking reduction in the function of central cholinergic neurons. The doses of these agents require to elicit an antihypertensive response were found to be consistent with those which produce a similar degree of central cholinergic inhibition. Furthermore, neurochemical estimates of cholinergic neuronal activity have indicated that such activity is greatly enhanced in hypertensive compared with normotensive control rats. This brain cholinergic activity intensifies with age and correlates significantly with the level of resting blood pressure. Therefore, it is the working hypothesis of this study that central cholinergic neurons participate in the development and/or the maintenance of experimental hypertension and that clonidine's antihypertensive action is related to its ability to inhibit this activity. The purpose of this study is to provide further evidence in support of this possibility. This will be accomplished by employing new neurochemical techniques of analysis and pharmacological tools to alter brain cholinergic function. Accordingly, quantitative receptor autoradiographic techniques will be employed to identify pre- and postsynaptic markers for cholinergic and adrenergic neurons in whole sections of brain and spinal cord from hypertensive and normotensive rats. This whole brain 'mapping' technique should allow the localization and quantitation of potential defects of adrenergic-cholinergic interactions in hypertensive animals. also, studies of spinal cord adrenergic, cholinergic and peptidergic pathways in cardiovascular regulation will be undertaken. Our preliminary findings indicate that the spinal cord may provide a more simplified model system for the study of cental cardiovascular regulation as well as provide new insight into the role of the spinal cord in cardiovascular disease. Finally, several clonidene-like antihypertensive agents will be examined for central inhibition of cholinergic function in this spinal model system, and a new class of cholinergic presynaptic antagonists, the cholinergic false transmitters, will be examined for antihypertensive properties.
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