Volume 14 Supplement 1

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

Open Access

The nitroxyl donor isopropylamine-NONOate elicits soluble guanylyl cyclase-dependent antihypertrophic actions: comparison of the potential therapeutic advantages of HNO over NO•

  • Rebecca Ritchie1, 2Email author,
  • Jennifer Irvine1,
  • Nga Cao1,
  • Swati Gossain1, 3,
  • Amy Alexander1,
  • Jane Love1,
  • Chengxue Qin1,
  • John D Horowitz4 and
  • Barbara K Kemp-Harper3
BMC Pharmacology and Toxicology201314(Suppl 1):P56

https://doi.org/10.1186/2050-6511-14-S1-P56

Published: 29 August 2013

Background

Nitroxyl (HNO) is a redox congener of NO•. We now directly compare the antihypertrophic efficacy of HNO and NO• donors in cardiomyocytes in vitro, and compare their contributing mechanisms of actions in this setting. In addition, the ability of the HNO donor isopropylamine-NONOate to acutely limit hypertrophic responses in the intact, beating rat heart was also determined.

Results

IPA-NO elicited concentration-dependent inhibition of endothelin-1 (ET1)-induced increases in neonatal rat cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic IPA-NO actions were significantly attenuated by L-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (cGMP-dependent protein kinase inhibitor), and ODQ (to target soluble guanylyl cyclase, sGC), but were unaffected by carboxy-PTIO (NO• scavenger) or CGRP8-37 (calcitonin gene-related peptide antagonist). Furthermore, IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an L-cysteine-sensitive effect), and stimulated sGC activity 3-fold, without detectable NO• release. IPA-NO also suppressed ET1-induced cardiomyocyte superoxide generation. The pure NO• donor, DEA-NO, reproduced these IPA-NO actions, but were sensitive to carboxy-PTIO rather than L-cysteine. Although IPA-NO stimulation of purified sGC was preserved under pyrogallol oxidant stress (in direct contrast to DEA-NO), cardiomyocyte sGC activity after either donor were attenuated by this stress. Excitingly IPA-NO also exhibited acute antihypertrophic actions in response to acute pressure-overload in the intact heart, at doses that did not affect coronary perfusion pressure or LV function.

Conclusion

Our results demonstrate that the antihypertrophic actions of HNO are broad, and not donor-specific, and are likely independent of its vasodilator and other hemodynamic actions. Given that HNO is impervious to reactivity with superoxide, HNO donors may offer therapeutic advantages over NO• donors. These studies further strengthen the therapeutic promise of HNO donors and other non-nitrovasodilator means of cGMP-elevation as a novel strategy for cardiac pathologies, as stand-alone and/or add-on therapy to standard care.

Authors’ Affiliations

(1)
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute
(2)
Department of Medicine, Monash University
(3)
Department of Pharmacology, Monash University
(4)
The Queen Elizabeth Hospital

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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