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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030046-07
Application #
3341080
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Buccafusco, J J; Yang, X (1993) Mechanism of the hypertensive response to central injection of nicotine in conscious rats. Brain Res Bull 32:35-41
Buccafusco, J J; Lapp, C A; Aronstam, R S et al. (1993) Role of prostanoids in the regulation of central cholinergic receptor sensitivity. J Pharmacol Exp Ther 266:314-22
Takahashi, H; Buccafusco, J J (1992) Excitatory modulation by a spinal cholinergic system of a descending sympathoexcitatory pathway in rats. Neuropharmacology 31:259-69
Takahashi, H; Buccafusco, J J (1991) Spinal cholinergic modulation of cardiovascular tone and a somatosympathetic reflex response. Brain Res Bull 27:47-51
Buccafusco, J J; Wei, J; Kraft, K L (1991) The effect of the acetylcholine transport blocker vesamicol on central cholinergic pressor neurons. Synapse 8:301-6
Buccafusco, J J; Makari, N F; Hays, A C (1990) Pharmacological analysis of the enhanced pressor response to central cholinergic stimulation in spontaneously hypertensive rats. Jpn J Pharmacol 54:105-12
Buccafusco, J J; Magri, V (1990) The pressor response to spinal cholinergic stimulation in spontaneously hypertensive rats. Brain Res Bull 25:69-74
Buccafusco, J J; Magri, V (1989) Modification of spino-bulbar autonomic cholinergic systems by activation of alpha-adrenergic receptors. J Auton Nerv Syst 28:133-40
Makari, N F; Trimarchi, G R; Buccafusco, J J (1989) Contribution of pre- and post-synaptic components to heightened central cholinergic activity in spontaneously hypertensive rats. Neuropharmacology 28:379-86
Aronstam, R S; Marshall, D C; Buccafusco, J J (1988) Cholinergic false transmitters: physiological and biochemical actions in central and peripheral systems. Neuropharmacology 27:217-25

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