Central GABA receptor stimulants as potential novel antihypertensive agents

Abstract

Abstractγ‐Aminobutyric acid (GABA) undoubtedly plays an important role as an inhibitory transmitter in the central nervous system. In recent years, evidence has accumulated which strongly suggests that GABA may specifically play a role in the central regulation of cardiovascular homeostasis. GABA apparently mediates a tonic hindbrain inhibition of vagal bradycardia, probably at nucleus ambiguus. In addition, evidence also suggests an additional GABA inhibitory input in the forebrain to sympathetic structures, possibly in the area of the periventricular hypothalamus. Thus, there appear to be at least two anatomically distinct and physiologically opposed GABAergic inhibitory mechanisms which function to control resting heart rate and reflex vagal activity. GABA also seems to be involved to some degree in the control of vasopressin release and respiratory function.Because of the physiological and pharmacological effects of centrally administered GABA or GABA mimetics, it is suggested that such agents might provide the basis for a new class of antihypertensive agents. Activation of central GABA receptors consistently reduces blood pressure and heart rate by a reduction in centrally mediated sympathetic nervous activity and, perhaps, a reduction in vasopressin release. Thus far, the GABA mimetics, THIP, imidazole‐4‐actic acid, muscimol, isoguvacine, isoarecaidine, kojic amine, as well as GABA itself, have all been shown to reduce blood pressure when centrally administered. Conversely, GABA antagonists, such as bicuculline and picrotoxin, raise blood pressure. Prodrugs of GABA or of other GABA mimetics can be used to allow for systemic administration of these agents with subsequent central penetration to provide an antihypertensive effect.Finally, it is suggested that the interaction of GABA with benzodiazepine receptors may allow for the development of new agents which, in addition to reducing stress‐induced cardiovascular responses, may prevent the development of hypertension.