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Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits

Departments of ¹Cellular and Integrative Physiology and ²Emergency Medicine, University of Nebraska Medical Center, Omaha, Nebraska

Submitted 18 December 2007 ; accepted in final form 17 March 2008

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Downregulation of nitric oxide (NO) synthase (NOS) in the carotid body (CB) is involved in this effect. However, it remains poorly understood whether carbon monoxide (CO) also contributes to the altered peripheral chemoreflex sensitivity in CHF. This work highlights the effect of NO and CO on renal sympathetic nerve activity (RSNA) in response to graded hypoxia in conscious rabbits. Renal sympathetic nerve responses to graded hypoxia were enhanced in CHF rabbits compared with sham rabbits. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1.2 µg·kg^–1·min^–1) and the CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)₃Cl₂]₂, 3.0 µg·kg^–1·min^–1} each attenuated hypoxia-induced RSNA increases in CHF rabbits (P < 0.05), but the degree of attenuation of RSNA induced by SNAP or [Ru(CO)₃Cl₂]₂ was smaller than that induced by SNAP + [Ru(CO)₃Cl₂]₂. Conversely, treatment with the NOS inhibitor N-nitro-L-arginine (30 mg/kg) + the heme oxygenase (HO) inhibitor Cr (III) mesoporphyrin IX chloride (0.5 mg/kg) augmented the renal sympathetic nerve response to hypoxia in sham rabbits to a greater extent than treatment with either inhibitor alone and was without effect in CHF rabbits. In addition, using immunostaining and Western blot analyses, we found that expression of neuronal NOS, endothelial NOS, and HO-2 protein (expressed as the ratio of NOS or HO-2 expression to β-tubulin protein expression) was lower in CBs from CHF (0.19 ± 0.04, 0.17 ± 0.06, and 0.15 ± 0.02, respectively) than sham (0.63 ± 0.04, 0.56 ± 0.06, and 0.27 ± 0.03, respectively) rabbits (P < 0.05). These results suggest that a deficiency of NO and CO in the CBs augments peripheral chemoreflex sensitivity to hypoxia in CHF.

carotid body; renal sympathetic nerve activity; chronic heart failure

This article has been cited by other articles:

				Y. Ding, Y.-L. Li, M. C. Zimmerman, R. L. Davisson, and H. D. Schultz Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits Cardiovasc Res, March 1, 2009; 81(4): 678 - 685. [Abstract] [Full Text] [PDF]

				S. W. Mifflin NO and CO have got to GO for enhanced chemoreceptor sympathoexcitation in heart failure J Appl Physiol, July 1, 2008; 105(1): 1 - 2. [Full Text] [PDF]