Disruption of chronic cariporide treatment abrogates myocardial ion homeostasis during acute ischemia reperfusion.

Cariporide, an Na/H exchanger inhibitor, is a drug with cardioprotective properties. However, chronic treatment with cariporide may modify the protein phenotype of the cardiomyocytes. Disruption of the equilibrium between a cariporide-modified phenotype and the supply of cariporide could be deleterious. The aim of this study was to test the effects of this equilibrium rupture (EqR) on cardiac function at baseline and acute ischemia reperfusion. Rats were chronically treated with cariporide (2.5 mg·kg·d) or with placebo for 21 days, after which isolated Langendorff-mode heart perfusion experiments utilized cariporide-free buffer. During this type of perfusion, the drug is rapidly cleared from the cellular environment. After 30 minutes of stabilization, the hearts were subjected to global zero-flow ischemia (25 minutes) followed by reperfusion (45 minutes). Measures of mechanical function, oxygen consumption, lactate plus pyruvate, CO2 and proton release into the coronary effluent were determined. The gene and protein expression of proton extruders was also evaluated. Chronic cariporide administration followed by EqR reduced the expression of the Na/H exchanger, increased the expression of the HCO3 or Na exchanger, decreased monocarboxylate/H carrier expression, reduced the lactate plus pyruvate release but did not change the glucose oxidation rate and mechanical function compared with baseline conditions. The resulting low glycolytic rate was associated with a stronger contracture during ischemia. During reperfusion, the early release of acidic forms was higher and redirected toward the use of the Na/H and HCO3 /Na exchangers to the detriment of the safe monocarboxylate/H carrier. Both phenomena were assumed to increase the Na uptake and activate the Na/Ca exchanger, resulting in Na and Ca overload and further cellular damage. This explains the impaired recovery of the contractile function observed in the EqR group during reperfusion. In conclusion, although cariporide is usually cardioprotective, a disruption of its chronic treatment followed by an ischemia/reperfusion event can become deleterious.

Functional changes of the coronary microvasculature with aging regarding glucose tolerance, energy metabolism, and oxidative stress.

This study was aimed at characterizing the functional progression of the endothelial (ECs) and smooth muscle cells (SMCs) of the coronary microvasculature between youth and old age, as well as at determining the mechanisms of the observed changes on the basis of the glucose tolerance, mitochondrial energy metabolism, and oxidative stress. Male rats were divided into four age groups (3, 6, 11, and 17 months for the young (Y), young adult (YA), middle-aged (MA), and old (O) animals). The cardiac mechanical function, endothelial-dependent dilatation (EDD) and endothelial-independent dilatation (EID) of the coronary microvasculature were determined in a Langendorff preparation. The mitochondrial respiration and H2O2 production were evaluated and completed by ex vivo measurements of oxidative stress. EDD progressively decreased from youth to old age. The relaxation properties of the SMCs, although high in the Y rats, decreased drastically between youth and young adulthood and stabilized thereafter, paralleling the reduction of mitochondrial oxidative phosphorylation. The ECs dilatation activity, low at youth, was stimulated in YA animals and returned to their initial level at middle age. That parameter followed faithfully the progression of the amount of active cardiac endothelial nitric oxide synthase and whole body glucose intolerance. In conclusion, the progressive decrease in EDD occurring with aging is due to different functional behaviors of the ECs and SMCs, which appear to be associated with the systemic glucose intolerance and cardiac energy metabolism.

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion.

Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10- or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H(2)O(2) release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H(2)O(2) when they oxidize FADH(2)-linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.