Both GABA_A And GABA_B Receptor-mediated Inhibition On Sympathetic Outflow In The Paraventricular Nucleus Is Blunted In Chronic Heart Failure

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 heart failure. To determine the role ofγ-aminobutyric acid (GABA)A and GABAB receptor in mediating the tonic inhibitory influence on the paraventricular nucleus (PVN) in rats with heat failure.Heart failure animal model was induced by coronary artery ligation. Inα-chloralose- and urethane-anaesthetized rats, microinjection of bicuculline(a GABA antagonist ) and muscimol(a GABA agonist ) into PVN was performed,and arterial blood pressure (BP) , heart rate (HR) and renal sympathetic nerve discharge (RSND) were observed in both sham-operated control and heart failure (HF) rats.The PCR determined that the mRNA expression levels of the GABAA receptorα1 subunit and the GABAB receptor 1a and 1b subtypes in the PVN were in CHF and sham rats. Microinjection of bicuculline (0.01-0.15 nmol), a GABAA receptor antagonist, into the PVN increased RSNA and ABP in Sham and HF rats in a dose dependent manner. This response was significantly attenuated in HF rats. Furthermore, the decrease in RSNA and ABP induced by a GABAA receptor agonist, muscimol (0.05-1.5 nmol), in the PVN was significantly less in HF rats than in sham-operated controls. In contrast, microinjection of GABAB receptor antagonist CGP35348 (0.15-3.0 nmol) into the PVN produced a dose-dependent increase in RSND, BP, and HR in both shamoperated control and HF rats. CGP35348 attenuated the increase in RSND and BP in HF rats compared with control rats. Alternatively, microinjection of the GABAB receptor agonist baclofen (0.3-4.5 nmol) into the PVN produced a dose-dependent decrease in RSND, BP, and HR in both control and HF rats. Baclofen was also less effective in decreasing RSND, BP, and HR in HF rats than in control rats. The PCR data showed that the mRNA expression levels of the GABAA receptorα1 subunit and the GABAB receptor 1a and 1b subtypes in the PVN were significantly lower in CHF than in sham rats. GABAA receptor and GABAB receptor mediates the tonic inhibitory influence on PVN,the inhibitory tonic influence mediated by GABAA receptor and GABAB receptor is smaller in HF rats.The current data suggest that the tonic inhibition mediated by both GABAA and GABAB receptors in the PVN on sympathetic outflow is blunted in CHF, which may be an important mechanism responsible for sympathetic hyperactivity in CHF.