Role of γ-Aminobutyric Acid (GABA)A and GABAB Receptors in Paraventricular Nucleus in Control of Sympathetic Vasomotor Tone in Hypertension

• Published in: The Journal of pharmacology and experimental therapeutics 2007-02, Vol.320 (2), p.615-626
• Main Authors: Li, De-Pei, Pan, Hui-Lin
• Format: Article
• Language: English
• Subjects: Animals; Baclofen - pharmacology; Bicuculline - pharmacology; Blood Pressure - drug effects; Heart Rate - drug effects; Hypertension - physiopathology; Male; Microinjections; Muscimol - pharmacology; Paraventricular Hypothalamic Nucleus - physiology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, GABA-A - physiology; Receptors, GABA-B - physiology; Sympathetic Nervous System - physiopathology
• ISSN: 0022-3565
• DOI: 10.1124/jpet.106.109538

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 GABAA and GABAB 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 GABAA 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 GABAA 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 GABAB 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 GABAB 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 GABAA receptor function is attenuated, whereas the function of GABAB receptors is enhanced, in the PVN of SHRs.