NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits

doi:10.1016/j.cardiores.2007.04.006

Cardiovascular Research 2007 75(3):546-554; doi:10.1016/j.cardiores.2007.04.006

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NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits

Yu-Long Li, Lie Gao, Irving H. Zucker and Harold D. Schultz^*

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA

^* Corresponding author. Tel.: +1 402 559 7167; fax: +1 402 559 4438. hschultz{at}unmc.edu

Objective A previous study from this laboratory showed thatelevation of endogenous angiotensin II (Ang II) and upregulationof the angiotensin II type 1 (AT₁) receptor in the carotid body(CB) are involved in the enhanced peripheral chemoreceptor sensitivityin rabbits with chronic heart failure (CHF). NADPH oxidase-derivedsuperoxide anion mediates the effects of Ang II in many organs.We investigated whether this signaling pathway may mediate theenhanced peripheral chemoreceptor sensitivity induced by AngII in CHF rabbits.

Methods and results By recording single-unit activity from thecarotid sinus nerve in isolated preparations, we found thatphenylarsine oxide 2 µM (PAO, NADPH oxidase inhibitor)and TEMPOL 1 mM (superoxide dismutase mimetic) significantlydecreased not only the Ang II-enhanced CB chemoreceptor responsesto different levels of hypoxia in sham rabbits ( ${Delta}$ -12.5±0.8and ${Delta}$ -12.8±0.9 imp/s at 40.7±2.3 mm Hg of PO₂,and ${Delta}$ -5.6±0.5 and ${Delta}$ -5.3±0.4 imp/s at 60.2±3.1mm Hg of PO₂, p<0.05, respectively) but also the CHF-inducedelevation of CB chemoreceptor responses to different levelsof hypoxia ( ${Delta}$ -13.6±1.1 and ${Delta}$ -13.7±0.9 imp/s at 40.9±3.1mm Hg of PO₂, and ${Delta}$ -6.7±1.2 and ${Delta}$ -6.6±0.8 imp/sat 59.8±3.5 mm Hg of PO₂, p<0.05). In addition, mRNAand protein expressions of NADPH oxidase components (gp91^phox,p40^phox and p47^phox) were higher in the CB from CHF rabbitscompared to sham rabbits. Furthermore, 100 pM Ang II inducedan increase in superoxide production in CB homogenates fromsham rabbits, which was similar to that in CB homogenate fromCHF rabbits. PAO and Tempol inhibited the Ang II- and CHF-enhancedsuperoxide anion production.

Conclusions These results suggest that the enhanced peripheralchemoreceptor sensitivity mediated by Ang II in CHF rabbitsoccurs via a NADPH oxidase–superoxide signaling pathway.

KEYWORDS Angiotensin; Reactive oxygen species; Autonomic nervous system; Chemoreceptor; Heart failure

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