Abstract 14489: Inhibition of NO-Mediated GABA Release by Reactive Oxygen Species in the Rostral Ventrolateral Medulla Results in Sympathoexcitation in Hypertensive Rats
Background: The rostral ventrolateral medulla (RVLM) in the brainstem is known to regulate the activity of sympathetic nervous system (SNS). In the RVLM, increased reactive oxygen species (ROS) activates SNS and contributes to hypertension, whereas nitric oxide (NO) suppresses SNS by promoting the release of gamma-amino butyric acid (GABA). It remains unknown whether the inhibition of NO-mediated GABA release by ROS in the RVLM activates SNS in hypertensive rats. Objective: The aim of this study was to determine, in hypertensive rats, whether the sympathoexcitation induced by ROS in the RVLM is mediated by the decreased GABA release in the RVLM, and, if so, to determine whether this mechanism is involved in decreased bioavailability of NO due to ROS in the RVLM.
Methods and Results: We used stroke-prone spontaneously hypertensive rats (SHRSP). Microinfusion of a superoxide scavenger (tempol, 10 nmol for 10 min) into the RVLM decreased mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), while increased GABA releases (in vivo microdialysis). Prior microinfusion of an NO synthase inhibitor (L-NMMA, 100 nmol for 10 min) into the RVLM attenuated the tempol-induced decreases in MAP (-6.2±0.7 vs. -11.3±1.3%), HR (-3.0±0.4 vs. -5.1±0.5%), and RSNA (-8.2±1.2 vs. -15.7±1.0%), as well as the increase in GABA release (23.4±3.2 vs. 57.9±12.4%, n=5 for each, p<0.05). Microinjection of the GABA-A receptor antagonist (bicuculline, 200 pmol) into the RVLM was performed before microinjection of tempol or L-NMMA. Blockade of GABA-A receptors attenuated the tempol-induced changes in MAP (-5.1±0.8% vs. -17.8±3.7%), HR (-2.6±0.6% vs. -7.7±1.0%) and RSNA (-7.8±0.6% vs. -19.5±2.8%, n=4 for each, p<0.05). It also attenuated the L-NMMA- induced changes in MAP (3.0±0.3 vs. 7.6±1.1%), HR (1.7±0.2 vs. 3.5±0.2%) and RSNA (4.7±0.4 vs. 14.8±1.2%, n=4 for each, p<0.05).
Conclusion: Superoxide-induced suppression of bioavailability of NO and NO-mediated GABA release in the RVLM would play a pivotal role in the sympathoexcitation in SHRSP.
- © 2011 by American Heart Association, Inc.