The HNO donor Angeli’s salt offers potential haemodynamic advantages over NO· or dobutamine in ischaemia–reperfusion injury in the rat heartex vivo

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Abstract

Graphical abstract

In contrast to the β1-adreneoceptor (β1-AR) agonist dobutamine and the NO· donor diethylamine NONOate (DEA/NO), the vasodilation properties of the nitroxyl (HNO) donor Angeli’s salt were preserved after ischaemia–reperfusion (I–R) injury. Although I–R injury blunted the inotropic effects of both Angeli’s salt and dobutamine, the HNO donor did not increase heart rate (HR). Improved recovery of left ventricular function (LVF) and reduced incidence of arrhythmias was also observed. HNO donors may thus offer haemodynamic advantages over existing pharmacotherapy in acute heart failure. AC, adenylyl cyclase; ·O2−, superoxide; ONOO−, peroxynitrite; PKA, protein kinase A, PKG, protein kinase G; sGC, soluble guanylyl cyclase, SH, thiol. Blue and red text represent beneficial and detrimental effects, respectively. Grey arrows indicate more modest effects than black arrows.

Available inotropic pharmacotherapy for acute heart failure (HF) remains largely ineffective at ameliorating marked impairments in contractile function. Nitroxyl (HNO), the redox sibling of NO•, has recently attracted interest as a therapeutic approach for acute HF. We now compare the impact of ischaemia–reperfusion (I–R) injury on acute haemodynamic responsiveness of the HNO donor, Angeli’s salt (AS), to that of NO· and dobutamine. Dose-response curves to bolus doses of AS, diethylamine NONOate (DEA/NO, both 0.001–μmol) and dobutamine (0.1–100 nmol) were performed in rat isolated hearts, following I–R or normoxic perfusion. An additional 10 μmol dose of Angeli’s salt was included, to permit roughly equivalent inotropic responses to dobutamine. Changes in cardiac contraction, heart rate and coronary flow (CF) were determined. Although AS and DEA/NO elicited comparable dose-dependent increases in CF in normoxic hearts, only AS vasodilation was preserved after I–R. AS and dobutamine elicited dose-dependent inotropic responses in normoxic hearts and I–R blunted inotropic responses to both. Dobutamine however increased heart rate, which was exacerbated by I–R; this was not evident with AS. Further, AS infusion during reperfusion (1 μM), in a separate cohort of rat hearts, improved recovery of cardiac contractility, with lower incidence of I–R-induced ventricular fibrillation. In conclusion, these observations suggest that HNO offers haemodynamic advantages over NO· following I–R. Although I–R suppresses inotropy to both agents, residual contractile responses to AS following I–R is likely free of concomitant pro-arrhythmic events. HNO donors may thus offer haemodynamic advantages over existing pharmacotherapy in acute HF.

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