Copyright © 2007, European Society of Cardiology
NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits
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 that elevation of endogenous angiotensin II (Ang II) and upregulation of the angiotensin II type 1 (AT1) receptor in the carotid body (CB) are involved in the enhanced peripheral chemoreceptor sensitivity in rabbits with chronic heart failure (CHF). NADPH oxidase-derived superoxide anion mediates the effects of Ang II in many organs. We investigated whether this signaling pathway may mediate the enhanced peripheral chemoreceptor sensitivity induced by Ang II in CHF rabbits.
Methods and results By recording single-unit activity from the carotid sinus nerve in isolated preparations, we found that phenylarsine oxide 2 µM (PAO, NADPH oxidase inhibitor) and TEMPOL 1 mM (superoxide dismutase mimetic) significantly decreased not only the Ang II-enhanced CB chemoreceptor responses to different levels of hypoxia in sham rabbits (
-12.5±0.8 and -12.8±0.9 imp/s at 40.7±2.3 mm Hg of PO2, and -5.6±0.5 and -5.3±0.4 imp/s at 60.2±3.1 mm Hg of PO2, p<0.05, respectively) but also the CHF-induced elevation of CB chemoreceptor responses to different levels of hypoxia (-13.6±1.1 and -13.7±0.9 imp/s at 40.9±3.1 mm Hg of PO2, and -6.7±1.2 and -6.6±0.8 imp/s at 59.8±3.5 mm Hg of PO2, p<0.05). In addition, mRNA and protein expressions of NADPH oxidase components (gp91phox, p40phox and p47phox) were higher in the CB from CHF rabbits compared to sham rabbits. Furthermore, 100 pM Ang II induced an increase in superoxide production in CB homogenates from sham rabbits, which was similar to that in CB homogenate from CHF rabbits. PAO and Tempol inhibited the Ang II- and CHF-enhanced superoxide anion production.
Conclusions These results suggest that the enhanced peripheral chemoreceptor sensitivity mediated by Ang II in CHF rabbits occurs via a NADPH oxidase–superoxide signaling pathway.
KEYWORDS Angiotensin; Reactive oxygen species; Autonomic nervous system; Chemoreceptor; Heart failure
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