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

Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling
Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling
Nitroxyl anion (NO(-)) is the one-electron reduction product of nitric oxide (NO( small middle dot)) 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, Na(2)N(2)O(3)) 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.
0027-8424
10463-10468
Paolocci, Nazareno
d674c5c7-7f14-462d-bda9-1ee8a4ab5b8a
Saavedra, Walter F.
9e0c6c3c-87af-48a5-af8a-dbf61f0985fb
Miranda, Katrina M.
128fa814-eb00-472f-a5e7-5657e59ac9b9
Martignani, Cristian
642188f2-22e6-4957-bf71-ad60eba8389b
Isoda, Takayoshi
54caa940-1e7d-4b58-a544-9226de0fd4a7
Hare, Joshua M.
da8f76d3-ec0b-4725-8f68-d4dc9849f822
Espey, Michael G.
ee9fa59b-ebe3-46cd-a86c-cd1659f99331
Fukuto, Jon M.
222058bd-beef-4b4e-856c-54b1fc7eb4a9
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Wink, David A.
008b5aec-8c2b-4035-8912-fb6fd530413c
Kass, David A.
9858ecbf-227d-4774-95d8-1b886c7ef05c
Paolocci, Nazareno
d674c5c7-7f14-462d-bda9-1ee8a4ab5b8a
Saavedra, Walter F.
9e0c6c3c-87af-48a5-af8a-dbf61f0985fb
Miranda, Katrina M.
128fa814-eb00-472f-a5e7-5657e59ac9b9
Martignani, Cristian
642188f2-22e6-4957-bf71-ad60eba8389b
Isoda, Takayoshi
54caa940-1e7d-4b58-a544-9226de0fd4a7
Hare, Joshua M.
da8f76d3-ec0b-4725-8f68-d4dc9849f822
Espey, Michael G.
ee9fa59b-ebe3-46cd-a86c-cd1659f99331
Fukuto, Jon M.
222058bd-beef-4b4e-856c-54b1fc7eb4a9
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Wink, David A.
008b5aec-8c2b-4035-8912-fb6fd530413c
Kass, David A.
9858ecbf-227d-4774-95d8-1b886c7ef05c

Paolocci, Nazareno, Saavedra, Walter F., Miranda, Katrina M., Martignani, Cristian, Isoda, Takayoshi, Hare, Joshua M., Espey, Michael G., Fukuto, Jon M., Feelisch, Martin, Wink, David A. and Kass, David A. (2001) Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling. Proceedings of the National Academy of Sciences, 98 (18), 10463-10468. (doi:10.1073/pnas.181191198). (PMID:11517312)

Record type: Article

Abstract

Nitroxyl anion (NO(-)) is the one-electron reduction product of nitric oxide (NO( small middle dot)) 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, Na(2)N(2)O(3)) 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.

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e-pub ahead of print date: 21 August 2001
Published date: 28 August 2001
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337869
URI: https://eprints.soton.ac.uk/id/eprint/337869
ISSN: 0027-8424
PURE UUID: 6948ffd8-192f-4393-80dd-ed1ba0a9fe37
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 22 Jun 2012 13:46
Last modified: 06 Jun 2018 12:29

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Contributors

Author: Nazareno Paolocci
Author: Walter F. Saavedra
Author: Katrina M. Miranda
Author: Cristian Martignani
Author: Takayoshi Isoda
Author: Joshua M. Hare
Author: Michael G. Espey
Author: Jon M. Fukuto
Author: Martin Feelisch ORCID iD
Author: David A. Wink
Author: David A. Kass

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