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(Hypertension. 2008;52:708.)
© 2008 American Heart Association, Inc.

Original Articles

Imbalance of Angiotensin Type 1 Receptor and Angiotensin II Type 2 Receptor in the Rostral Ventrolateral Medulla

Potential Mechanism for Sympathetic Overactivity in Heart Failure

From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.

Correspondence to Lie Gao, MD, PhD, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850. E-mail lgao{at}unmc.edu

Upregulation of angiotensin II type 1 receptors (AT₁R) in the rostral ventrolateral medulla (RVLM) contributes to the sympathoexcitation in the chronic heart failure (CHF). However, the role of angiotensin II type 2 receptor (AT₂R) is not clear. In this study, we measured AT₁R and AT₂R protein expression in the RVLM and determined their effects on renal sympathetic nerve activity, blood pressure, and heart rate in anesthetized sham and CHF rats. We found that (1) although AT₁R expression in the RVLM was upregulated, the AT₂R was significantly downregulated (CHF: 0.06±0.02 versus sham: 0.15±0.02, P<0.05); (2) simultaneously stimulating RVLM AT₁R and AT₂R by angiotensin II evoked sympathoexcitation, hypertension, and tachycardia in both sham and CHF rats with greater responses in CHF; (3) stimulating RVLM AT1R with angiotensin II plus the specific AT₂R antagonist PD123319 induced a larger sympathoexcitatory response than simultaneously stimulating AT₁R and AT₂R in sham rats, but not in CHF; (4) activating RVLM AT₂R with CGP42112 induced a sympathoinhibition, hypotension, and bradycardia only in sham rats (renal sympathetic nerve activity: 36.4±5.1% of baseline versus 102±3.9% of baseline in artificial cerebrospinal fluid, P<0.05); (5) pretreatment with 5,8,11,14-eicosatetraynoic acid, a general inhibitor of arachidonic acid metabolism, into the RVLM attenuates the CGP42112-induced sympathoinhibition. These results suggest that AT₂R in the RVLM exhibits an inhibitory effect on sympathetic outflow, which is, at least partially, mediated by an arachidonic acid metabolic pathway. These data implicate a downregulation in the AT₂R as a contributory factor in the sympathoexcitation in CHF.

Key Words: angiotensin II type 1 receptor • angiotensin II type 2 receptor • rostral ventrolateral medulla • sympathetic outflow

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