GABAB-ergic stimulation in hypothalamic pressor area induces larger sympathetic and cardiovascular depression in spontaneously hypertensive rats

Abstract

To determine whether central GABA (γ-aminobutyric acid) B receptor stimulation would affect the sympathetic and cardiovascular activities, baclofen (a GABAB receptor agonist) was injected into lateral cerebral ventricles (intracerebroventricularly, ICV) in urethaneanesthetized normotensive rats. Intracerebroventricular injections of GABAA agonist (muscimol, 1 μg) consistently decreased blood pressure and heart rate. In contrast ICV injections of baclofen (2 μg) increased blood pressure (BP) and heart rate with initial transient cardiovascular depression, and these effects of baclofen were abolished by ICV pretreatment with GABAB antagonist (saclofen, 100 μg). To determine whether the cardiovascular effects of ICV injections were elicited by activating GABA receptors in the hypothalamus, we injected baclofen or muscimol directly into various hypothalamic areas. Baclofen (100 and 800 ng) injected into the ventromedialhypothalamus (VMH) or posterior hypothalamus (PH) of normotensive rats produced dose-related decreases in sympathetic nerve activity, blood pressure, and heart rate. These effects of baclofen were larger in VMH injections than in PH injections. The depressor responses elicited by VMH injections of baclofen were abolished by intravenous pretreatment with α-blocker, but unaffected by parasympathetic blocker, further indicating that the depressor responses of baclofen (VMH) were not due to parasympathetic activation, but due to peripheral sympathetic depression. Muscimol (400 ng) and baclofen (800 ng) injected into VMH produced similar amplitude of sympathetic depressant, depressor and bradycardic responses. In contrast, BP was increased by the same dose of baclofen injected into the hypothalamic depressor area (anterior hypothalamus, AH), but was unaffected by muscimol. Final experiments were performed to determine whether these sympathetic and cardiovascular effects to hypothalamic GABAB stimulations would be altered in hypertension. In spontaneously hypertensive rats (SHR), basal BP and heart rate were already higher than in normotensive controls (Wistar-Kyoto rat, WKY). Baclofen injected into VMH reduced sympathetic nerve activity, BP, and heart rate in both groups of rats, and these effects were significantly larger in SHR than in WKY. This enhanced depressor response induced by baclofen (VMH) in SHR persisted even after sinoaortic denervation, which indicates that the enhanced depressor response is not due to reduced peripheral baroreflex sensitivity in SHR. On the other hand, baclofen injected into AH increased BP and heart rate in both WKY and SHR, but the magnitude of these responses did not differ between two groups. In summary, GABA reduces sympathetic nerve activity, BP, and heart rate through both GABAA and B receptors in VMH. The GABAB system acts on the depressor area, AH, to further regulate the cardiovascular activities. In SHR, the GABAB-ergic system in VMH but not in AH is altered, and this might contribute to the development of hypertension.