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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 28, 2005; DOI: 10.1124/jpet.104.082495


0022-3565/05/3133-1035-1045$20.00
JPET 313:1035-1045, 2005
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CELLULAR AND MOLECULAR

Angiotensin II Attenuates Synaptic GABA Release and Excites Paraventricular-Rostral Ventrolateral Medulla Output Neurons

De-Pei Li, and Hui-Lin Pan

Department of Anesthesiology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania

The hypothalamic paraventricular nucleus (PVN) neurons regulate sympathetic outflow through projections to the spinal cord and rostral ventrolateral medulla (RVLM). Although the PVN-RVLM pathway is important for the action of brain angiotensin II (Ang II) on autonomic control, the cellular mechanisms involved are not fully known. In this study, we examined the effect of Ang II on the excitability and synaptic inputs to RVLM-projecting PVN neurons. PVN neurons were retrogradely labeled by FluoSpheres injected into the RVLM of rats. Whole-cell patch-clamp recordings were performed on labeled PVN neurons in brain slices. Ang II significantly increased the firing rate of PVN neurons from 3.63 ± 0.65 to 6.10 ± 0.75 Hz (P < 0.05, n = 9), and such an effect was eliminated by an AT1 receptor antagonist, losartan. Furthermore, inclusion of a G protein inhibitor, guanosine 5'-O-(2-thiodiphosphate, in the pipette internal solution did not alter the excitatory effect of Ang II on labeled PVN neurons. Application of 0.5 to 5 µM Ang II significantly decreased the amplitude of evoked GABAergic inhibitory postsynaptic currents (IPSCs) in a dose-dependent manner. Also, 2 µM Ang II significantly decreased the frequency of miniature IPSCs (mIPSCs) from 3.89 ± 0.84 to 2.06 ± 0.45 Hz (P < 0.05, n = 11), but did not change the amplitude and decay time constant of mIPSCs. By contrast, Ang II had no significant effect on glutamatergic excitatory postsynaptic currents at the concentrations that inhibited IPSCs. In addition, Ang II failed to excite PVN neurons in the presence of bicuculline. Collectively, this study provides important new information that Ang II excites RVLM-projecting PVN neurons through attenuation of GABAergic synaptic inputs.


Received December 20, 2004; accepted January 26, 2005.

Address correspondence to: Dr. Hui-Lin Pan, Department of Anesthesiology, H187, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail: hpan{at}psu.edu




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