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

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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 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)3Cl 2]2 was smaller than that induced by SNAP + [Ru(CO) 3Cl2]2. Conversely, treatment with the NOS inhibitor Nω-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.

Original languageEnglish (US)
Pages (from-to)14-23
Number of pages10
JournalJournal of Applied Physiology
Volume105
Issue number1
DOIs
StatePublished - Jul 1 2008

Fingerprint

Carbon Monoxide
Hypersensitivity
Nitric Oxide
Down-Regulation
Heart Failure
Nitric Oxide Synthase
Rabbits
Kidney
S-Nitroso-N-Acetylpenicillamine
Heme Oxygenase (Decyclizing)
Carotid Body
Nitric Oxide Donors
Tubulin
Arginine
Chlorides
Proteins
Western Blotting
Hypoxia

Keywords

  • Carotid body
  • Chronic heart failure
  • Renal sympathetic nerve activity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

@article{846291daa0274c5ca92b0af33a6cb55b,
title = "Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits",
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 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)3Cl 2]2 was smaller than that induced by SNAP + [Ru(CO) 3Cl2]2. Conversely, treatment with the NOS inhibitor Nω-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.",
keywords = "Carotid body, Chronic heart failure, Renal sympathetic nerve activity",
author = "Yanfeng Ding and Yulong Li and Schultz, {Harold D}",
year = "2008",
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T1 - Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits

AU - Ding, Yanfeng

AU - Li, Yulong

AU - Schultz, Harold D

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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)3Cl 2]2 was smaller than that induced by SNAP + [Ru(CO) 3Cl2]2. Conversely, treatment with the NOS inhibitor Nω-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.

AB - 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)3Cl 2]2 was smaller than that induced by SNAP + [Ru(CO) 3Cl2]2. Conversely, treatment with the NOS inhibitor Nω-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.

KW - Carotid body

KW - Chronic heart failure

KW - Renal sympathetic nerve activity

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