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(Hypertension. 2005;45:276.)
© 2005 American Heart Association, Inc.

Scientific Contributions

Mechanisms of Angiotensin II–Mediated Decreases in Intraneuronal Ca²⁺ in Calcium-Loaded Stellate Ganglion Neurons

Stanley F. Fernandez; Ming-He Huang; Bruce A. Davidson; Paul R Knight, III; Joseph L. Izzo, Jr

From the Departments of Pharmacology (S.F.F., J.L.I.), Medicine (S.F.F., J.L.I.) and Anesthesiology (B.A.D., P.R.K.), School of Medicine and Biomedical Sciences, State University of New York at Buffalo; Department of Internal Medicine, Division of Cardiology (M.-H.H.), University of Texas Medical Branch, Galveston.

Correspondence to Joseph L. Izzo, Jr, MD, Department of Medicine, Erie County Medical Center, 462 Grider St, Buffalo, NY 14214. E-mail JIzzo{at}ams.ecmc.edu

Our laboratory has reported previously that angiotensin II, type-1 (AT₁) receptor stimulation in isolated stellate ganglion neurons decreases intraneuronal calcium concentration ([Ca²⁺]i) acutely if baseline [Ca²⁺]i is high and increases [Ca²⁺]i if baseline [Ca²⁺]i is low. Part of the angiotensin II (Ang II) effect in high Ca²⁺ neurons is mediated through stimulation of Na⁺–Ca²⁺ exchange. Current experiments were conducted to identify additional steps in the signaling pathways. In Ca²⁺-loaded neurons, Ang II–induced decreases in [Ca²⁺]i were attenuated by phospholipase C inhibition (U73122) or nitric oxide (NO) synthase inhibition (L-NMMA) and were mimicked by the cGMP analogue 8-Br-cGMP. Protein kinase C (PKC) inhibition (bisindolylmaleimide I or Go6976) and protein kinase G (PKG) inhibition (KT5823) partially blocked Ang II–mediated decreases in [Ca²⁺]i, but complete blockade of Ang II effects was obtained with combined PKC and PKG inhibition. Modulation of inositol triphosphate (IP₃)-inducible ER Ca²⁺ release by [Ca²⁺]i was investigated using furaptra, an ER-retaining dye. IP₃-mediated ER Ca²⁺ release in ß-escin–permeabilized neurons was measured after clamping of [Ca²⁺]i from 50 nM to 800 nM. Maximal ER Ca²⁺ release was observed at 200 nM [Ca²⁺]i, with noted blunting of release at higher [Ca²⁺]i. Steady-state mRNA transcript and protein levels revealed that the principal IP₃R isoform expressed was IP₃R-II. These results suggest that Ca²⁺ loading in stellate ganglion neurons promotes Ang II-mediated decreases in [Ca²⁺]i via PKC and NO/cGMP/PKG pathways and inhibits IP₃R-II–mediated ER Ca²⁺ release.

Key Words: angiotensin II • calcium • signal transduction