Cardiac function and tolerance to ischemia–reperfusion injury in chronic kidney disease

Abstract

Cardiac dysfunction is an independent risk factor of ischemic heart disease and mortality in chronic kidney disease (CKD) patients, yet the relationship between impaired cardiac function and tolerance to ischemia-reperfusion (IR) injury in experimental CKD remains unclear. Cardiac function was assessed in 5/6 ablation-infarction (AI) and sham male Sprague-Dawley rats at 20 weeks of age, 8 weeks post-surgery using an isolated working heart system. This included measures taken during manipulation of preload and afterload to produce left ventricular (LV) function curves as well as during reperfusion following a 15-min ischemic bout. In addition, LV tissue was used for biochemical tissue analysis. Cardiac function was impaired in AI animals during preload and afterload manipulations. Cardiac functional impairments persisted post-ischemia in the AI animals, and 36% of AI animals did not recover sufficiently to achieve aortic overflow following ischemia (versus 0% of sham animals). However, for those animals able to withstand the ischemic perturbation, no difference was observed in percent recovery of post-ischemic cardiac function between groups. Urinary NOx (nitrite + nitrate) excretion was lower in AI animals and accompanied by reduced LV endothelial nitric oxide synthase and NOx. LV antioxidants superoxide dismutase-1 and -2 were reduced in AI animals, whereas glutathione peroxidase-1/2 as well as NADPH-oxidase-4 and H(2)O(2) were increased in these animals. Impaired cardiac function appears to predispose AI rats to poor outcomes following short-duration ischemic insult. These findings could be, in part, mediated by increased oxidative stress via nitric oxide-dependent and -independent mechanisms.