Rebecca H.RITCHIE

(Heart Failure Pharmacology，Baker IDI Heart＆ Diabetes Institute，Melbourne 8008，Australia.E － mail:rebecca.ritchie@bakeridi.edu.au)

Systemic oxidative stress is defined as an imbalance between the generation of reactive oxygen species(ROS)and the body’s endogenous antioxidant capacity.Superoxide(·O2－)is regarded as the parent ROS，readily generating hydrogen peroxide(H2O2)，peroxynitrite(·ONOO－)，and hydroxyl(·OH).H2O2and·ONOO－are formed even under normal physiological conditions.Over the last decade，oxidative stress has been implicated as playing a causal role in the development of cardiac dysfunction and remodelling in a range of cardiac pathologies，ranging from pathological cardiac hypertrophy，cardiac fibrosis and reperfusion injury following myocardial ischaemia，as well as to heart failure.We have demonstrated that chronic administration of ROS － suppressing therapies(e.g.tempol，resveratrol and the natriuretic peptides ANP and BNP)is cardioprotective in rodent models of these disorders.Our own recent work also implicates ROS in the development of diabetic cardiomyopathy，analogous to their well－established role in the vascular complications of diabetes.The detrimental consequences of pathological ROS signalling in the diabetic heart are evident regardless of aetiology(across type 1 diabetes，type 2 diabetes and insulin resistance)or species(mouse，rat，human).In contrast to ROS，the impact of reactive nitrogen species(RNS)on the myocardium is less well－defined and is nitrogen species－dependent.Nitric oxide(NO·)is largely cardioprotective in settings of cardiac pathology.In contrast，·ONOO－，a mixed ROS/RNS that is generated from the rapid reaction of NO· with·O2－，is detrimental and is a major contributor to the loss of NO·bioavailability under settings of high·O2－generation(i.e.most cardiac pathologies).Nitroxyl(HNO)，the one－electron reduced and protonated form of NO·，has recently emerged as a novel regulator of cardiovascular function.We were the first to demonstrate that HNO retains the cGMP－mediated cardioprotective properties of its redox congener，including antihypertrophic and ROS － suppressing actions.HNO is particularly favourable for managing cardiac dysfunction and failure，as it is also impervious to both tolerance development and to reaction with·O－2，thus maintaining bioavailability under oxidative stress.Further，HNO elicits additional cGMP － independent enhancement of myocardial function.In conclusion，ROS play a causal role in multiple cardiac pathologies.Therapies that limit excess ROS generation thus represent exciting possibilities for treating the cardiac dysfunction that results from cardiac remodelling，myocardial ischaemia，diabetes and other causes of heart failure.In addition，approaches such as HNO donors，which exploit NO· cardioprotection yet remain bioavailable under settings of oxidative stress，are equally attractive for managing these disorders，alone or in combination with standard care.