dimethylarginine and Necrosis

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates postexercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male

Topics: Amidohydrolases; Animals; Arginine; Cardiomyopathies; Coronary Circulation; Disease Models, Animal; Exercise Tolerance; Female; Heterozygote; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Transgenic; Muscular Dystrophy, Duchenne; Myocardium; Necrosis; Quadriceps Muscle; Ventricular Function, Left

CDP-choline exerts tissue protective effect in several ischemic conditions. Recently we have reported that the drug prevents cardiac arrhythmias and improves survival rate in short-term myocardial ischemia reperfusion in rats.. In the current study, we determined the effect of intravenously administered CDP-choline on myocardial tissue injury induced by 30-min ischemia followed by 3-h reperfusion in anesthetized rats.. Myocardial ischemia was produced by ligature of the left main coronary artery. CDP-choline (100-500 mg/kg) was intravenously injected in the middle of the ischemic period. Cardiovascular parameters were recorded through the experimental period. At the end of the reperfusion period, the hearts of the animals were removed and stained for the investigation of tissue necrosis and apoptosis. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by TUNEL assay. Also the blood samples of rats were collected for the measurement of M30-M65, ADMA, homocysteine, and lactate levels.. Ischemia/reperfusion caused serious injury in myocardium, increased blood ADMA and lactate levels without influencing other parameters. CDP-choline significantly reduced the infarct size and the number of apoptotic cells in the risk area. Blood pressure increased after CDP-choline injection; however, it returned back to the basal levels before the onset of reperfusion. CDP-choline failed to alter any other measured parameters.. The present results demonstrate that intravenously administered CDP-choline is able to protect myocardium from injury induced by long-term coronary occlusion-reperfusion in rats. The inhibition of apoptosis by the drug may contribute to its protective effect. But neither the increase in blood pressure in response to CDP-choline injection nor changes in plasma ADMA concentration appear to mediate the attenuation of the myocardial injury.

Topics: Animals; Apoptosis; Arginine; Blood Pressure; Cytidine Diphosphate Choline; Homocysteine; Lactic Acid; Male; Myocardial Reperfusion Injury; Myocardium; Necrosis; Rats; Rats, Wistar