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Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in
Yanfeng Ding1, Yu-Long Li, Harold D Schultz
1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Abstract:
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 microg x kg(-1) x min(-1)) and the CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)(3)Cl(2)](2), 3.0 microg x kg(-1) x 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)(3)Cl(2)](2) was smaller than that induced by SNAP + [Ru(CO)(3)Cl(2)](2). Conversely, treatment with the NOS inhibitor N(omega)-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 beta-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.
Insights
Chronic heart failure (CHF) potentiates peripheral chemoreflex sensitivity due to reduced nitric oxide (NO) and carbon monoxide (CO) in the carotid body (CB). Supplementation with NO and CO attenuated hypoxia-induced nerve activity, suggesting their deficiency contributes to this heightened response in CHF.
Area of Science:
- Cardiovascular Physiology
- Neuroscience
- Biochemistry
Background:
- Peripheral chemoreflex sensitivity is heightened in chronic heart failure (CHF).
- Nitric oxide (NO) synthase (NOS) downregulation in the carotid body (CB) is implicated, but the role of carbon monoxide (CO) is unclear.
- Understanding these pathways is crucial for managing CHF-related autonomic dysfunction.
Purpose of the Study:
- To investigate the combined roles of NO and CO in modulating renal sympathetic nerve activity (RSNA) during hypoxia in a rabbit model of CHF.
- To determine if deficiencies in NO and CO contribute to augmented peripheral chemoreflex sensitivity in CHF.
Main Methods:
- Conscious rabbits with experimentally induced CHF and sham controls were subjected to graded hypoxia.
- Renal sympathetic nerve activity (RSNA) was measured.
- The effects of NO donor (SNAP) and CO-releasing molecule ([Ru(CO)3Cl2]2) administration, alone and combined, were assessed.
- Inhibitors of NOS and heme oxygenase (HO) were used.
- Immunostaining and Western blot analyzed NOS and HO-2 protein expression in CB tissue.
Main Results:
- Hypoxia-induced RSNA was significantly enhanced in CHF rabbits compared to sham rabbits.
- Administration of NO donor (SNAP) and CO-releasing molecule ([Ru(CO)3Cl2]2) individually attenuated RSNA increases in CHF rabbits.
- Combined SNAP and [Ru(CO)3Cl2]2 administration showed a greater attenuation of RSNA than individual treatments.
- NOS and HO-2 protein expression was significantly lower in the CBs of CHF rabbits compared to sham rabbits.
- NOS and HO inhibition augmented hypoxia-induced RSNA in sham rabbits, but not in CHF rabbits.
Conclusions:
- Deficiencies in both nitric oxide (NO) and carbon monoxide (CO) within the carotid body (CB) contribute to the augmented peripheral chemoreflex sensitivity observed in chronic heart failure (CHF).
- Restoring NO and CO levels may represent a therapeutic strategy for mitigating exaggerated sympathetic responses in CHF.
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