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

J Appl Physiol (1985). 2008 Jul;105(1):14-23. doi: 10.1152/japplphysiol.01345.2007. Epub 2008 Mar 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Blotting, Western
  • Body Weight / drug effects
  • Carbon Monoxide / metabolism*
  • Chemoreceptor Cells / drug effects
  • Chemoreceptor Cells / physiology*
  • Down-Regulation
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Antibody Technique
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology*
  • Heart Rate / drug effects
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Kidney / innervation
  • Kidney / physiology
  • Male
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Organ Size / drug effects
  • Organometallic Compounds / pharmacology
  • Pacemaker, Artificial
  • Rabbits
  • Reflex / drug effects
  • Reflex / physiology*
  • Sympathetic Nervous System / physiology


  • Enzyme Inhibitors
  • Nitric Oxide Donors
  • Organometallic Compounds
  • tricarbonyldichlororuthenium (II) dimer
  • Nitric Oxide
  • Carbon Monoxide
  • Nitric Oxide Synthase
  • Heme Oxygenase (Decyclizing)