Previous studies involving drugs which stimulate or block GABA receptors suggest that this inhibitory neurotransmitter plays an important role in brain centers involved in automatic cardiovascular control. The proposed research, to be performed in anesthetized cats, rats, and guinea pigs, is aimed at expanding our knowledge in this area in several directions and assessing the potential impact on cardiovascular function of pharmacologically manipulating the GABA receptor complex using the benzodiazepines and related compounds. First, the site in the periventricular forebrain at which GABA antagonists elicit sympathetically-mediated hypertension, tachycardia, and ventricular arrhythmias will be more precisely localized. This will be accomplished by systematically exploring this area using a stereotaxic intracerebral microinjection technique to apply various GABAergic drugs as well as appropriate control substances while monitoring cardiovascular function. Second, the cardiovascular effects of D- and L- allylglycine, an in vivo inhibitor of GABA synthesis, as well as the associated effects on regional brain GABA levels will be examined and compared. It is expected that these effects will (1) reflect the ability of the stereoisomers to compromise GABAergic mechanisms, and (2) differ for each of the two isomers since GABA levels are lowered by either agent in the brainstem but only by the L isomer in the forebrain. Third, the effects of drugs thought to influence GABAergic mechanisms by acting at the benzodiazepine receptor will be investigated, including [1] the cardiovascular response evoked in anesthetized animals by the Beta-carbolines, a class of compounds thought to elicit the affective and physiological components of anxiety, and [2] the effects and interactions of benzodiazepines and other agents which act at the benzodiazepine receptor on baroreflex bradycardia and how they might be altered by pharmacologic manipulation of GABAergic inhibition. Not only should these studies yield important new insights into CNS GABAergic mechanisms involved in cardiovascular regulation but they might also suggest new strategies for the development of novel centrally acting drugs to be used in the treatment of cardiovascular disorders as well as new therapeutic indications for the benzodiazepines, a class of agents presently in wide clinical use.
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