The central nervous system is thought to play an important role in regulating cardiovascular function. Increasingly, this role is appreciated in causing or exacerbating disorders of the cardiovascular system in man. In spite of this, relatively little is known about the pathways in the brain that regulate functions ultimately impacting on regulation of blood pressure and heart rate and rhythm. this is particularly true with regard to forebrain mechanisms that integrate and generate the responses to environmental or emotional stress which have been implicated in such catastrophic clinical events as sudden death, myocardial infarction and hypertension. The long range goal of this research is to elucidate the central nervous system pathways and mechanisms which influence cardiovascular control though the autonomic nervous system or through neuroendocrine factors. The approach taken is to study the effects of drugs which interact with the inhibitory neurotransmitter gamma aminobutyric acid (GABA), commonly thought to be the most prevalent neurotransmitter in the mammalian central nervous system. By examining the changes resulting from pharmacologically modifying GABA function in discrete regions of the brain in anesthetized and conscious rats, different roles for this substance in controlling sympathetic and parasympathetic activity to the heart and vasculature or in regulating the release of neuroendocrine factors with cardiovascular effects can be inferred. Specifically, this research proposes to: (1) investigate and characterize the pattern of cardiovascular and other associated changes resulting from altering GABA function in the posterior hypothalamus in anesthetized and conscious rats, and to determine the role that this region and local GABAergic inhibition may play in the physiological changes associated with stress and emotion; (2) determine the site in the forebrain where GABAergic drugs act to influence the release of vasopressin, a hypothalamic neurohormone with important cardiovascular effects;and (3) study the interaction of benzodiazepines, a widely used class of drugs now thought to exert their characteristic effects primarily by interacting with endogenous GABA, and other agents acting at benzodiazepine receptors with the mechanisms elucidated in (1) and (2) above. The results of these studies may enhance our understanding of the neural basis for certain cardiovascular disorders and suggest specific strategies for drug development and therapy aimed at their treatment or prevention.
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