March 21, 2008
Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits
Key Result
In conscious rabbits with heart failure, administration of NO and CO donors attenuated hypoxia-induced increases in renal sympathetic nerve activity (P<0.05).
Structured PICO
Does supplementation or inhibition of NO and CO alter renal sympathetic nerve activity in response to hypoxia in a rabbit model of heart failure?
P
Population
Conscious rabbits with chronic heart failure or sham, evaluated for renal sympathetic nerve activity in response to graded hypoxia.
I
Intervention
NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1.2 microg x kg(-1) x min(-1)) and CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)(3)Cl(2)](2), 3.0 microg x kg(-1) x min(-1)}; NOS inhibitor N(omega)-nitro-L-arginine (30 mg/kg) + HO inhibitor Cr (III) mesoporphyrin IX chloride (0.5 mg/kg)
C
Comparator
Sham rabbits; individual treatments versus combination
O
Outcome
Renal sympathetic nerve activity (RSNA) in response to graded hypoxiasurrogate
Deficiency of both nitric oxide and carbon monoxide in the carotid bodies contributes to augmented peripheral chemoreflex sensitivity to hypoxia in heart failure.
Main Result
p-value: p=<0.05
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.