allopurinol and Cardiomegaly

Topics: Animals; Cardiomegaly; Humans; Hypertension; Mitochondria, Heart; NADPH Oxidases; Nitric Oxide Synthase Type III; Nitroso Compounds; Oxidation-Reduction; Oxidative Stress; Oxidoreductases; Reactive Oxygen Species; Ventricular Remodeling; Xanthine Oxidase

Despite advances in treatment, chronic congestive heart failure carries a poor prognosis and remains a leading cause of cardiovascular death. Accumulating evidence suggests that reactive oxygen species (ROS) play an important role in the development and progression of heart failure, regardless of the etiology. Under pathophysiological conditions, ROS have the potential to cause cellular damage and dysfunction. Whether the effects are beneficial or harmful will depend upon site, source and amount of ROS produced, and the overall redox status of the cell. All cardiovascular cell types are capable of producing ROS, and the major enzymatic sources in heart failure are mitochondria, xanthine oxidases and the nonphagocytic NADPH oxidases (Noxs). As well as direct effects on cellular enzymatic and protein function, ROS have been implicated in the development of agonist-induced cardiac hypertrophy, cardiomyocyte apoptosis and remodelling of the failing myocardium. These alterations in phenotype are driven by redox-sensitive gene expression, and in this way ROS may act a potent intracellular second messengers. Recent experimental studies have suggested a possible causal role for increased ROS in the development of contractile dysfunction following myocardial infarction and pressure overload, however the precise contribution of different cellular and enzymatic sources involved remain under investigation.

Topics: Apoptosis; Cardiomegaly; Heart Failure; Humans; Mitochondria, Heart; Myocardial Infarction; NADH, NADPH Oxidoreductases; Oxidative Stress; Reactive Oxygen Species; Xanthine Oxidase

Oxidative stress is considered a central pathophysiological event in cardiovascular disease, including hypertension. Early age reduction in renal mass is associated with hypertension and oxidative stress in later life, which is aggravated by increased salt intake. The aim of the present study was to examine if renal sympathetic denervation can exert blood pressure lowering effects in uninephrectomized (UNX) rats (3-week old) fed with high salt (HS, 4%; w/w) diet for 4 weeks. Moreover, we investigated if renal denervation is associated with changes in NADPH and xanthine oxidase-derived reactive oxygen species. Rats with UNX + HS had reduced renal function, elevated systolic and diastolic arterial pressures, which was accompanied by increased heart weight, and cardiac superoxide production compared to sham operated Controls. UNX + HS was also associated with higher expression and activity of NADPH and xanthine oxidase in the kidney. Renal denervation in rats with UNX + HS attenuated the development of hypertension and cardiac hypertrophy, but also improved glomerular filtration rate and reduced proteinuria. Mechanistically, renal denervation was associated with lower expression and activity of both NADPH oxidase and xanthine oxidase in the kidney, but also reduced superoxide production in the heart. In conclusion, our study shows for the first time that renal denervation has anti-hypertensive, cardio- and reno-protective effects in the UNX + HS model, which can be associated with decreased NADPH oxidase- and xanthine oxidase-derived reactive oxygen species (i.e., superoxide and hydrogen peroxide) in the kidney.

Topics: Animals; Blood Pressure; Cardiomegaly; Denervation; Glomerular Filtration Rate; Heart; Hypertension, Renal; Kidney; Myocardium; NADP; Rats; Reactive Oxygen Species; Xanthine Oxidase

Clinical and experimental evidence demonstrates that hypertrophied cardiac tissue is more sensitive to ischemic injury than is normal myocardium. Recent studies indicate that cardiac ischemia-reperfusion injury involves the generation of toxic oxygen free radicals. We used the spontaneously hypertensive rat (SHR) model, with its otherwise genetically identical control (the Wistar-Kyoto [WKY] rat), to investigate the potential role of enzymes that generate and detoxify oxygen radicals in the sensitivity of hypertrophied heart to ischemia and reperfusion. Because hypertension develops progressively with age in SHRs, we assayed xanthine oxidase, superoxide dismutase, catalase, and glutathione peroxidase at three different time points and found significant fluctuations at different ages. At age 26 weeks, physiological measurements demonstrated hypertension and increased sensitivity to ischemia and reperfusion, measured as significantly decreased left ventricular recovery after injury. At this age, xanthine oxidase, which may generate oxygen radicals, was significantly increased in SHR compared with WKY rats (p = 0.003). Superoxide dismutase, which is a principal step in oxygen-radical detoxification, was significantly lower (p = 0.044). These data suggest that differences in the constitutive levels of oxygen-radical metabolic pathways are different in hypertrophied myocardium, and it is suggested that this finding may play a role in the response of these hearts to ischemia-reperfusion injury.

Topics: Animals; Cardiomegaly; Catalase; Free Radicals; Glutathione Peroxidase; Myocardial Reperfusion Injury; Myocardium; Oxygen; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxide Dismutase; Xanthine Oxidase

Effects of xanthine--xanthine oxidase produced oxygen radicals were studied in hypertrophied rat hearts in a Langendorff preparation. Heart hypertrophy was produced by banding of the abdominal aorta for 6 weeks. This resulted in a 22% increase in ventricle/body weight ratio compared with that of sham-operated controls. Perfusion with xanthine--xanthine oxidase caused contractile failure and a significant rise in the resting tension. Complete contractile failure in hypertrophied hearts was seen at 25.5 +/- 3.2 min, whereas in control hearts it happened at 14.4 +/- 5.6 min. Contractile failure due to oxygen radicals in both groups was associated with a decline in high energy phosphates, increased lipid peroxidation, and extensive structural damage. Sarcolemma in both groups became permeable to the extracellular tracer lanthanum. As compared with control, in hypertrophied hearts the malondialdehyde content, indicative of lipid peroxidation, was less by 40%; whereas superoxide dismutase, a free radical scavenger, was higher by a similar amount. These data show a greater capacity of the 6-week hypertrophied heart to withstand a free radical induced contractile failure. This delay in oxygen radical effect can be partially explained by the reduced lipid peroxide content and increased superoxide dismutase activity in the hypertrophied hearts.

Topics: Animals; Cardiomegaly; Free Radicals; Heart; In Vitro Techniques; Male; Malondialdehyde; Microscopy, Electron; Myocardial Contraction; Myocardium; Oxygen; Rats; Rats, Inbred Strains; Xanthine; Xanthine Oxidase; Xanthines

Topics: Adult; Allopurinol; Arrhythmias, Cardiac; Blood Glucose; Cardiomegaly; Cholesterol; Diphosphates; Electrocardiography; Heart Defects, Congenital; Humans; Lipids; Male; Orotic Acid; Phosphates; Phospholipids; Ribose; Triglycerides; Uric Acid; Uricosuric Agents