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Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite

Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite
Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite
BACKGROUND AND PURPOSE: Nitrite (NO2-) has recently been shown to represent a potential source of nitric oxide (NO), in particular under hypoxic conditions. The aim of the current study was to compare the hemodynamic effects of nitrite in healthy volunteers and patients with stable congestive heart failure (CHF).

EXPERIMENTAL APPROACH: The acute hemodynamic effects of brachial artery infusion of nitrite (0.31 to 7.8?moles/min) was assessed in normal subjects (n=20) and CHF patients (n=21).

KEY RESULTS: NO2- infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF-patients at NO2- infusion rates which induced no changes in normal subjects (ANOVA: F=5.5; p=0.02). Unstressed venous volume (UVV) increased even with the lowest NO2- infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (ANOVA: F=6.2; p=0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO2- infusion. Venous plasma NO2- concentrations were lower in CHF-patients at baseline, and rose substantially less with NO2- infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF-patients than normal subjects at baseline. This difference was attenuated during NO2- infusion. Prolonged nitrite exposure in-vivo did not induce oxidative stress, nor did it induce tolerance in vitro.

CONCLUSIONS AND IMPLICATIONS: The findings of arterial hyper-responsiveness to infused NO2- in CHF-patients, with evidence of accelerated transvascular NO2- clearance (presumably with concomitant NO release) suggests that NO2- effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO2- as a therapeutic modality in CHF.
sodium nitrite, vascular effects, heart failure
0007-1188
659-670
Maher, Abdul R.
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Arif, Sayqa
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Madhani, Melanie
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Abozguia, Khalid
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Ahmed, Ibrar
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Fernandez, Bernadette O.
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Feelisch, Martin
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O'Sullivan, A.G.
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Christopoulos, Arthur
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Sverdlov, Aaron L.
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Ngo, Doan
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Dautov, Rustem
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James, Philip E.
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Horowitz, John D.
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Frenneaux, Michael P.
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Maher, Abdul R.
7350a8c4-6d9c-4439-b077-8ff6249d8c6e
Arif, Sayqa
ed43541d-4eaf-4397-9028-88b9571effff
Madhani, Melanie
63a48cca-67b7-41ae-bc79-0f4a166f0750
Abozguia, Khalid
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Ahmed, Ibrar
41ef717d-481b-4519-af34-d9d51397af7f
Fernandez, Bernadette O.
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Feelisch, Martin
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O'Sullivan, A.G.
8897e0e2-dee5-4c9d-acf4-23193a4c07b5
Christopoulos, Arthur
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Sverdlov, Aaron L.
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Ngo, Doan
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Dautov, Rustem
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James, Philip E.
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Horowitz, John D.
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Frenneaux, Michael P.
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Maher, Abdul R., Arif, Sayqa, Madhani, Melanie, Abozguia, Khalid, Ahmed, Ibrar, Fernandez, Bernadette O., Feelisch, Martin, O'Sullivan, A.G., Christopoulos, Arthur, Sverdlov, Aaron L., Ngo, Doan, Dautov, Rustem, James, Philip E., Horowitz, John D. and Frenneaux, Michael P. (2013) Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite. British Journal of Pharmacology, 169 (3), 659-670. (doi:10.1111/bph.12152). (PMID:23472879)

Record type: Article

Abstract

BACKGROUND AND PURPOSE: Nitrite (NO2-) has recently been shown to represent a potential source of nitric oxide (NO), in particular under hypoxic conditions. The aim of the current study was to compare the hemodynamic effects of nitrite in healthy volunteers and patients with stable congestive heart failure (CHF).

EXPERIMENTAL APPROACH: The acute hemodynamic effects of brachial artery infusion of nitrite (0.31 to 7.8?moles/min) was assessed in normal subjects (n=20) and CHF patients (n=21).

KEY RESULTS: NO2- infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF-patients at NO2- infusion rates which induced no changes in normal subjects (ANOVA: F=5.5; p=0.02). Unstressed venous volume (UVV) increased even with the lowest NO2- infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (ANOVA: F=6.2; p=0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO2- infusion. Venous plasma NO2- concentrations were lower in CHF-patients at baseline, and rose substantially less with NO2- infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF-patients than normal subjects at baseline. This difference was attenuated during NO2- infusion. Prolonged nitrite exposure in-vivo did not induce oxidative stress, nor did it induce tolerance in vitro.

CONCLUSIONS AND IMPLICATIONS: The findings of arterial hyper-responsiveness to infused NO2- in CHF-patients, with evidence of accelerated transvascular NO2- clearance (presumably with concomitant NO release) suggests that NO2- effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO2- as a therapeutic modality in CHF.

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e-pub ahead of print date: 16 May 2013
Published date: June 2013
Keywords: sodium nitrite, vascular effects, heart failure
Organisations: Faculty of Medicine

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Local EPrints ID: 352610
URI: http://eprints.soton.ac.uk/id/eprint/352610
ISSN: 0007-1188
PURE UUID: 8f1db949-2a8c-456d-a54c-3ad0941ef462
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 16 May 2013 13:39
Last modified: 18 Feb 2021 17:20

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Contributors

Author: Abdul R. Maher
Author: Sayqa Arif
Author: Melanie Madhani
Author: Khalid Abozguia
Author: Ibrar Ahmed
Author: Bernadette O. Fernandez ORCID iD
Author: Martin Feelisch ORCID iD
Author: A.G. O'Sullivan
Author: Arthur Christopoulos
Author: Aaron L. Sverdlov
Author: Doan Ngo
Author: Rustem Dautov
Author: Philip E. James
Author: John D. Horowitz
Author: Michael P. Frenneaux

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