Chin Kai Yee, Michel Lisa, Qin Cheng Xue, Cao Nga, Woodman Owen L, Ritchie Rebecca H
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; The School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia.
Pharmacol Res. 2016 Feb;104:165-75. doi: 10.1016/j.phrs.2015.12.006. Epub 2015 Dec 30.
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 10μmol 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 (1μM), 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.
目前用于急性心力衰竭（HF）的有正性肌力作用的药物治疗在改善明显的收缩功能损害方面大多无效。硝酰（HNO）是NO•的氧化还原同类物，最近作为急性HF的一种治疗方法引起了关注。我们现在比较缺血再灌注（I-R）损伤对HNO供体安吉利盐（AS）与NO和多巴酚丁胺急性血流动力学反应性的影响。在大鼠离体心脏中，在I-R或常氧灌注后，对AS、二乙胺亚硝酸盐（DEA/NO，均为0.001 μmol）和多巴酚丁胺（0.1 - 100 nmol）的推注剂量进行剂量反应曲线实验。还加入了10 μmol剂量的安吉利盐，以使对多巴酚丁胺的正性肌力反应大致相当。测定心脏收缩、心率和冠状动脉血流（CF）的变化。虽然在常氧心脏中AS和DEA/NO引起了类似的CF剂量依赖性增加，但I-R后仅AS的血管舒张作用得以保留。AS和多巴酚丁胺在常氧心脏中引起剂量依赖性正性肌力反应，I-R使两者的正性肌力反应减弱。然而，多巴酚丁胺增加心率，I-R使其加剧；而AS没有这种情况。此外，在另一组大鼠心脏中，再灌注期间输注AS（1 μM）可改善心脏收缩力的恢复，降低I-R诱导室颤的发生率。总之，这些观察结果表明，I-R后HNO比NO具有血流动力学优势。虽然I-R抑制了两种药物的正性肌力作用，但I-R后对AS的残余收缩反应可能没有伴随的促心律失常事件。因此，在急性HF中，HNO供体可能比现有药物治疗具有血流动力学优势。
