Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons.
The hypothalamic paraventricular nucleus (PVN) is an important site for the regulation of sympathetic outflow. Angiotensin II (Ang II) can activate AT(1) receptors to stimulate PVN presympathetic neurons through inhibition of GABAergic input. However, little is known about the downstream pathway involved in this presynaptic action of Ang II in the PVN. In this study, using whole cell recording from retrogradely labeled PVN neurons in rat brain slices, we determined the signaling mechanisms responsible for the effect of Ang II on synaptic GABA release to spinally projecting PVN neurons. Bath application of Ang II reproducibly decreased the frequency of GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in fluorescence-labeled PVN neurons. Ang II failed to change the frequency of mIPSCs in labeled PVN neurons treated with pertussis toxin. However, Ang II-induced inhibition of mIPSCs persisted in the presence of either CdCl(2), a voltage-gated Ca(2+) channel blocker, or 4-aminopyridine, a blocker of voltage-gated K(+) channels. Interestingly, inhibition of superoxide with superoxide dismutase or Mn(III) tetrakis (4-benzoic acid) prophyrin completely blocked Ang II-induced decrease in mIPSCs. By contrast, inhibition of hydroxyl radical formation with the ion chelator deferoxamine did not significantly alter the effect of Ang II. These findings suggest that the presynaptic action of Ang II on synaptic GABA release in the PVN is mediated by the pertussis toxin-sensitive G(i/o) proteins but not by voltage-gated Ca(2+) and K(+) channels. Ang II attenuates GABAergic input to PVN presympathetic neurons through reactive oxygen species, especially superoxide anions.
Chen
Qian
Q
Department of Anesthesiology and Pain Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Pan
Hui-Lin
HL
D015761:4-Aminopyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D007796:Laminectomy / Q000379:methods; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D008665:Metalloporphyrins; D026902:Potassium Channel Blockers; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D000804:Angiotensin II; D005680:gamma-Aminobutyric Acid; D015761:4-Aminopyridine; D003676:Deferoxamine; D001640:Bicuculline