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The novel NO redox sibling, nitroxyl (HNO), prevents cardiomyocyte hypertrophy and superoxide generation via cGMP

We have previously shown that NO/cGMP signalling is an important antihyper-trophic mechanism in the heart [13]. HNO is the one electron reduction of NO•, thought to elicit cardiovascular actions via cGMP and/or calcitonin gene-related peptide (CGRP) [4]; we have recently shown that the HNO donor Angeli's salt inhibits cardiomyocyte hypertrophy and superoxide generation [5]. We now test the hypothesis that isopropylamine/NO (IPA/NO) elicits concentration-dependent anti-hypertrophic and antioxidant actions via HNO/sGC/cGMP-dependent signalling. IPA/NO (0.1–3 μM, replenished 3×/day over 48 h) elicited concentration-dependent inhibition of endothelin-1 (ET1, 60 nM)-stimulated neonatal rat cardiomyocyte (NRCM) hypertrophy (on two dimensional area of live cells). At 3 μM, IPA/NO decreased cell size from 255 ± 28% to 96 ± 27% of paired control (n = 4, p < 0.001). This antihypertrophic action of IPA/NO was significantly attenuated in the presence of the HNO scavenger L-cysteine (3 mM) or the cGMP-dependent protein kinase inhibitor Rp-8 PCTP cGMPS (10 μM, both n = 4, p < 0.05), but was unaffected by the NO scavenger carboxy-PTIO (200 μM) or the CGRP antagonist, CGRP8–37 (1 μM, both n = 4). For comparison, the NO• donor DEA/NO elicited similar concentration-dependent inhibition of ET1-induced cardiomyocyte hypertrophy; this was inhibited by carboxy-PTIO and Rp-8 PCTP cGMPS (10 μM, both n = 4, p < 0.05), but was unaffected by L-cysteine. Both IPA/NO and DEA/NO also blocked ET1-induced cardiomyocyte superoxide generation (both n = 4, p < 0.001, on NADPH-driven lucigenin-enhanced chemiluminescence), a key trigger of hypertrophy [3]. IPA-NO stimulated purified cell-free sGC activity by 3.2 ± 0.6-fold, and elevated NRCM cGMP content by 3.5 ± 0.4-fold (both n = 5, p < 0.05 via cGMP ELISA, as previously described [2, 3]. None of these agents alone, or their respective vehicles, elicited any effect on NRCM. Finally, using an NO•-sensing electrode, we demonstrated that IPA/NO (in contrast to DEA/NO), does not release NO• under these conditions, even at supra-pharmacological concentrations. In conclusion, these results provide convincing evidence that IPA/NO prevents cardiomyocyte hypertrophy via HNO activation of sGC. Although the antihypertrophic and antioxidant efficacy of IPA/NO was comparable to NO•, there is no role for extracellular oxidation of HNO to NO• or CGRP-mediated signalling in these IPA/NO actions. These studies may ultimately facilitate the development of HNO donors such as IPA/NO as novel antihypertrophic therapy for patients at risk of heart failure.


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Correspondence to Rebecca Ritchie.

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

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Ritchie, R., Irvine, J., Gossain, S. et al. The novel NO redox sibling, nitroxyl (HNO), prevents cardiomyocyte hypertrophy and superoxide generation via cGMP. BMC Pharmacol 9 (Suppl 1), P58 (2009).

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