Chronic central GABAergic stimulation attenuates hypothalamic hyperactivity and development of spontaneous...

To determine whether chronic central gamma-aminobutyric acid (GABA) stimulation would attenuate development of hypertension, tail-cuff systolic pressures were measured in male spontaneously hypertensive rats (SHR) treated with either an inhibitor of GABA breakdown (valproate, VPA), or a GABA-receptor agonist (muscimol). When VPA was injected intraperitoneally (i.p.) daily for 4 weeks, tail-cuff systolic pressures were decreased during the last 2 weeks. On the other hand, continuous infusion of muscimol into the lateral cerebral ventricle for 14 days using an osmotic minipump decreased systolic pressures throughout the 10-day observation period. During terminal experiments under urethane anesthesia, pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were reduced in VPA- or muscimol-treated SHR. Pressor responses to intravenously (i.v.) injected norepinephrine (NE) were unaltered by either treatment, indicating that diminished pressor responsiveness to hypothalamic stimulation was not due to diminished cardiovascular reactivity. Regardless of either VPA acid or muscimol treatment, basal blood pressure (BP), heart rate (HR), and responses to hypothalamic stimulation were lower in normotensive Wistar-Kyoto controls (WKY) than in SHR. In addition, chronic treatment with either drug had weaker hypotensive and hypothalamic depressant effects in WKY than in SHR. Our results suggest that in SHR the central GABAergic system is impaired and that chronic treatment with GABAergic stimulants can attenuate development of spontaneous hypertension by reducing hypothalamic overactivity.