Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Soluble guanylyl cyclase mediates concomitant coronary vasodilator and positive inotropic actions of the HNO donor Angeli's salt in the intact rat heart

  • Rebecca Ritchie1, 2Email author,
  • Kai Yee Chin1, 3,
  • Chengxue Qin1,
  • Nga Cao1,
  • Barbara Kemp-Harper4 and
  • Owen Woodman3
BMC Pharmacology and Toxicology201314(Suppl 1):P57

https://doi.org/10.1186/2050-6511-14-S1-P57

Published: 29 August 2013

Background

The NO redox sibling nitroxyl (HNO) elicits soluble guanylyl cyclase (sGC)-dependent vasodilatation. HNO has high reactivity with thiols (unlike NO), which is attributed with HNO-enhanced left ventricular (LV) function. The present study tested the hypothesis that the concomitant vasodilatation and inotropic actions induced by the HNO donor, Angeli’s salt (sodium trioxodinitrate), are sGC-dependent and sGC-independent, respectively.

Materials and methods

Haemodynamic responses to bolus doses of Angeli’s salt (10pmol - 10μmol), alone and in the presence of selective scavengers of HNO (L-cysteine, 4mM) or NO (hydroxocobalamin HXC, 50µM) or selective inhibitors of sGC (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one ODQ, 10μM), calcitonin gene-related peptide (CGRP) receptors (CGRP8-37, 0.1μM) or voltage-dependent potassium channels (4-aminopyridine 4-AP, 1mM) were determined in isolated adult male rat hearts.

Results

Angeli’s salt elicited concomitant, potent dose-dependent increases in coronary flow and LV systolic and diastolic function. Both L-cysteine and ODQ caused a rightward shift in the dose-response curve of each of these effects, implicating HNO and sGC in both the vasodilator and inotropic actions of Angeli’s salt. In contrast, neither HXC, CGRP8-37 nor 4-AP affected Angeli’s salt actions.

Conclusion

These data suggest that each of the vasodilator, inotropic and lusitropic actions of Angeli’s salt are mediated by L-cysteine-sensitive, HNO/sGC-dependent mechanisms. Our findings represent the first evidence that sGC specifically contributes a significant component of the inotropic and lusitropic actions of an HNO donor in the intact heart. Thus, HNO acutely enhances LV contractile function and LV relaxation, whilst concomitantly unloading the heart, potentially favourable properties for the failing heart.

Authors’ Affiliations

(1)
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute
(2)
Department of Medicine, Monash University
(3)
School of Medical Sciences, RMIT University
(4)
Department of Pharmacology, Monash University

Copyright

© Ritchie et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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