The HNO donor Angeli’s salt offers potential haemodynamic advantages over NO or dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo
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- 作者：Kai Yee China ; b ; Lisa Michela ; Cheng Xue Qina ; Nga Caoa ; Owen L. Woodmanb ; 1 ; Rebecca H. Ritchiea ; c ; 1 ; rebecca.ritchie@bakeridi.edu.au" class="auth_mail" title="E-mail the corresponding author
- 关键词：AC ; adenylyl cyclase ; AS ; Angeli&rsquo ; s salt ; β1-AR ; β1-adrenoceptor ; CGRP ; calcitonin gene-related peptide ; CK ; creatine kinase ; DEA/NO ; diethylamine NONOate ; DOB ; dobutamine ; DRC ; dose-response curve ; HF ; heart failure ; HNO ; nitroxyl ; I&ndash ; R ; ischaemia&ndash ; reperfusion ; LV ; left ventricle ; LVDP ; left ventricular developed pressure ; LVEDP ; left ventricular end-diastolic pressure ; LV± ; dP/dt ; first derivative of LV pressure ; MI ; myocardial infarction ; NO ; nitric oxide ; O2 ; -superoxide
- 刊名：Pharmacological Research
- 出版年：2016
- 出版时间：February 2016
- 年：2016
- 卷：104
- 期：Complete
- 页码：165-175
- 全文大小：2765 K
文摘
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.
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.