Gene transfer of Cu‐Zn superoxide dismutase to the carotid body reverses enhanced chemoreceptor function in heart failure rabbits

Abstract

Peripheral chemoreflex sensitivity is potentiated in both clinical and experimental chronic heart failure (CHF). NADPH oxidase‐derived superoxide anion mediates angiotensin II‐enhanced carotid body (CB) chemoreceptor sensitivity in CHF rabbits, and tempol, the superoxide dismutase (SOD) mimetic, inhibits this Ang II‐ and CHF‐enhanced superoxide anion effect (Cardiovasc Res. 2007, 75:546–54). Here we investigated the effect of adenoviral Cu‐Zn SOD gene transfer in the CB on chemoreceptor activity and function in CHF rabbits. Ad Cu‐Zn SOD (1×108 pfu/ml) gene transfer to the CBs significantly reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits. Baseline single‐fiber discharge from CB chemoreceptors during normoxia and the response to hypoxia were enhanced in CHF vs. sham rabbits. Ad Cu‐Zn SOD decreased the baseline discharge (2.9 ± 1.1 vs. 8.1 ± 0.8 imp/s at 104 ± 2.4 mm Hg PO2) and the response to hypoxia (16.4 ± 2.3 vs. 38.7 ± 2.3 imp/s at 41 ± 2.6 mm Hg PO2, p<0.05) in CHF rabbits. In addition, Ad Cu‐Zn SOD normalized the blunted IK in CB glomus cells from CHF rabbits (1020 ± 142 vs. 2156 ± 230 pA at +70 mV, p<0.05). Ad SOD did not affect CB afferent discharge and IK of CB glomus cells in sham rabbits. These results suggest that Cu‐Zn SOD activity in the CB may be involved in the enhanced activity of the CB chemoreceptors and peripheral chemoreflex function in CHF rabbits.