Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling

N. Paolocci, W. F. Saavedra, Katrina M Miranda, C. Martignani, T. Isoda, J. M. Hare, M. G. Espey, J. M. Fukuto, M. Feelisch, D. A. Winkt, D. A. Kass

Research output: Contribution to journalArticle

226 Citations (Scopus)

Abstract

Nitroxyl anion (NO-) is the one-electron reduction product of nitric oxide (NO') and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO- in vivo remains unknown. The NO- generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO- was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8-37) prevented this effect but not systemic vasodilation. Thus, NO- is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO- to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO- may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.

Original languageEnglish (US)
Pages (from-to)10463-10468
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number18
DOIs
StatePublished - Aug 28 2001
Externally publishedYes

Fingerprint

Calcitonin Gene-Related Peptide
Calcitonin Gene-Related Peptide Receptors
Oxidation-Reduction
Anions
Vasodilation
Blood Vessels
Reflex
Hexamethonium
Cardiac Volume
Venous Pressure
Baroreflex
Acetylcysteine
Nitric Oxide Synthase
Dilatation
Nitric Oxide
Cardiovascular Diseases
Dogs
Electrons
Blood Pressure
Pressure

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling. / Paolocci, N.; Saavedra, W. F.; Miranda, Katrina M; Martignani, C.; Isoda, T.; Hare, J. M.; Espey, M. G.; Fukuto, J. M.; Feelisch, M.; Winkt, D. A.; Kass, D. A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 18, 28.08.2001, p. 10463-10468.

Research output: Contribution to journalArticle

Paolocci, N, Saavedra, WF, Miranda, KM, Martignani, C, Isoda, T, Hare, JM, Espey, MG, Fukuto, JM, Feelisch, M, Winkt, DA & Kass, DA 2001, 'Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 18, pp. 10463-10468. https://doi.org/10.1073/pnas.181191198
Paolocci, N. ; Saavedra, W. F. ; Miranda, Katrina M ; Martignani, C. ; Isoda, T. ; Hare, J. M. ; Espey, M. G. ; Fukuto, J. M. ; Feelisch, M. ; Winkt, D. A. ; Kass, D. A. / Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 18. pp. 10463-10468.
@article{3fae310ea8a947b7903c75f791a09900,
title = "Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling",
abstract = "Nitroxyl anion (NO-) is the one-electron reduction product of nitric oxide (NO') and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO- in vivo remains unknown. The NO- generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO- was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8-37) prevented this effect but not systemic vasodilation. Thus, NO- is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO- to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO- may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.",
author = "N. Paolocci and Saavedra, {W. F.} and Miranda, {Katrina M} and C. Martignani and T. Isoda and Hare, {J. M.} and Espey, {M. G.} and Fukuto, {J. M.} and M. Feelisch and Winkt, {D. A.} and Kass, {D. A.}",
year = "2001",
month = "8",
day = "28",
doi = "10.1073/pnas.181191198",
language = "English (US)",
volume = "98",
pages = "10463--10468",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling

AU - Paolocci, N.

AU - Saavedra, W. F.

AU - Miranda, Katrina M

AU - Martignani, C.

AU - Isoda, T.

AU - Hare, J. M.

AU - Espey, M. G.

AU - Fukuto, J. M.

AU - Feelisch, M.

AU - Winkt, D. A.

AU - Kass, D. A.

PY - 2001/8/28

Y1 - 2001/8/28

N2 - Nitroxyl anion (NO-) is the one-electron reduction product of nitric oxide (NO') and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO- in vivo remains unknown. The NO- generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO- was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8-37) prevented this effect but not systemic vasodilation. Thus, NO- is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO- to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO- may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.

AB - Nitroxyl anion (NO-) is the one-electron reduction product of nitric oxide (NO') and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO- in vivo remains unknown. The NO- generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO- was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8-37) prevented this effect but not systemic vasodilation. Thus, NO- is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO- to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO- may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.

UR - http://www.scopus.com/inward/record.url?scp=17944372317&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17944372317&partnerID=8YFLogxK

U2 - 10.1073/pnas.181191198

DO - 10.1073/pnas.181191198

M3 - Article

VL - 98

SP - 10463

EP - 10468

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -