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NEUROPHARMACOLOGY

Role of -Aminobutyric Acid (GABA)_A and GABA_B Receptors in Paraventricular Nucleus in Control of Sympathetic Vasomotor Tone in Hypertension

Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Division of Anesthesiology and Critical Care, University of Texas M.D. Anderson Cancer Center, Houston, Texas

The paraventricular nucleus (PVN) of the hypothalamus is involved in tonic regulation of sympathetic outflow. Impaired GABAergic control of PVN neurons may contribute to the elevated sympathetic drive in hypertension. In this study, we examined the function of GABA_A and GABA_B receptors in the PVN in control of sympathetic nerve activity and arterial blood pressure (ABP) in normotensive and hypertensive rats. Lumbar sympathetic activity (LSNA) and ABP were recorded from anesthetized spontaneously hypertensive rats (SHRs), Sprague-Dawley (SD) rats, and Wistar-Kyoto (WKY) rats. Bilateral microinjection of bicuculline (0.01–0.15 nmol), a GABA_A receptor antagonist, into the PVN increased LSNA and ABP in normotensive WKY and SD rats in a dose-dependent manner. This response was significantly attenuated in SHRs. Furthermore, the decrease in LSNA and ABP induced by a GABA_A receptor agonist, muscimol (0.05–1.5 nmol), in the PVN was significantly less in SHRs than in normotensive controls. In contrast, microinjection of the GABA_B receptor agonist baclofen (0.3–4.5 nmol) into the PVN decreased LSNA and ABP in SHRs. However, in WKY and SD rats, baclofen only decreased LSNA and ABP at the highest dose tested. In addition, blockade of GABA_B receptors in the PVN with CGP52432 (3-[[(3,4-dichlorophenyl)methyl]amino]propyl]diethoxymethyl)phosphinic acid) (0.15–3.0 nmol) dose-dependently increased LSNA and ABP in SHRs but not in normotensive controls. Collectively, this study provides new evidence that GABA_A receptor function is attenuated, whereas the function of GABA_B receptors is enhanced, in the PVN of SHRs.

Address correspondence to: Dr. Hui-Lin Pan, Division of Anesthesiology and Critical Care, Unit 409, University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030-4009. E-mail: huilinpan{at}mdanderson.org

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