Murat Ayaz

Protective effect of selenium treatment on diabetes-induced myocardial structural alterations

One of the main causes leading to mortality in diabetes is myocardial disease. Using streptozotocin (STZ)-induced diabetic animals, it has been possible to characterize diabetes-induced myocardial abnormalities. Interstitial and microvascular disorders are known to be a characteristic part of the diabetic cardiomyopathy and partly resist insulin therapy. Because diabetic damage is partly attributed to oxidative stress, antioxidant treatment may be able to reduce this damage. The aim of this study was to investigate the cardioprotective effect of sodium selenite, known as an antioxidant agent. The diabetes was induced by ip injection of 50 mg/kg body wt STZ. The duration of diabetes was 5 wk. The protected group received (ip) 5 µmol/kg body wt/d sodium selenite (Na2SeO3) over 4 wk following diabetes induction. Electron and light microscopic morphometry of heart samples revealed typical diabetic alterations consisting in an increase in collagen content, vacuolation, diminishing of the cardiomyocyte diameter, alteration in myofilaments and Z-lines of myofibers, and myofibrillary degeneration. Sodium selenite treatment could prevent the loss of myofibrills and reduction of myocyte diameter. In the sodium-selenite-treated diabetic rat heart, alterations of the discus intercalaris and nucleus were corrected, and degenerations seen in myofilaments and Z-lines were reversed by this treatment. Under these findings, one can suggest that sodium selenite treatment may alleviate late diabetic complications when it is used under control conditions.

Selenium-Induced Changes on Rat Sciatic Nerve Fibers : Compound Action Potentials

The nervous system, through its important role as a communication network, governs reactions to stimuli, processes information and generates elaborate patterns of signals to control complex behaviors. Although selenium (Se) was shown to have some beneficial effects in pathological conditions, it is still a toxic element with a fairly small therapeutic window. In this study, the direct effects of Se ranging from 10(-8) to 10(-4) M were tested on rat sciatic nerve preparations. The toxicity started at 10(-8) M and the degree of alterations was found to be dose-dependent. In between the measured parameters, total compound action potential area (Astart = 3.70 +/- 0.16 ms x mV and A(-8) M = 3.04 +/- 0.14 ms x mV) and maximum depolarization points (MDstart = 6.70 +/- 0.22 mV and MD(-8) M = 6.04 +/- 0.18 mV) were the first to be affected from 10(-8) M. Latencies and conduction velocity distribution measurements have shown that nerve fibers having intermediate conduction velocities (20-35 m/s) are the first to be affected from this toxicity. Despite the fact that the new claims concluded the positive effects of the administrations, it is evident that the dose of supplementation must be fine-tuned to avoid possible side effects.

Resveratrol-induced depression of the mechanical and electrical activities of the rat heart is reversed by glyburide: evidence for possible KATP channels activation

Resveratrol, a natural phytoalexin found in wine, has been suggested to have benefits in preventing cardiovascular diseases. However, the direct effects of resveratrol on the activity of cardiac tissues and its mechanism of action have not been determined. This study examined the effects of resveratrol on the right and left atrium and left papillary muscle isolated from the rat heart. The contractile responses of the right atrium and papillary muscle and the action potential from the left atrium were recorded and the effects of resveratrol on these responses were observed. The resting force of the isolated right atrium and the peak developed force of the left papillary muscle were depressed by resveratrol (0.1 nM – 0.1 mM). Exposure to the KATP channel blocker glyburide (3 μM) prevented significantly the resveratrol-induced decrease. Resveratrol (0.1 mM) shortened the repolarization phase of action potential recorded from the left atrium and this effect of resveratrol was reversed by glyburide (3 μM). These results indicated that resveratrol depressed cardiac muscle contraction and shortened action potential duration probably due to the activation of KATP channels in the rat heart.

Effect of selenite treatment on ultrastructural changes in experimental diabetic rat bones

It is known that streptozotocin (STZ)-induced diabetes causes functional and structural alterations in some types of tissue and organ. A number of methods have been used to characterize the properties of diabetic tissues and their diagnosis. Selenium compounds, playing an antioxidant role, can restore some altered metabolic parameters and diminished functions in experimental diabetes. The first aim of the present study was to investigate the effects of STZ-induced diabetes on structural properties of rat long bones. Electron and light microscopic observations showed deleterious alterations in the structure of the diabetic rat long bones, the most prominent effect being in osteocytic cells. Fine cytoplasmic processes of the osteocytes seemed to be shortened, and diabetes affected the normal cytoplasmic processes in a negative manner. The second aim of the present study was to evaluate the effects of sodium selenite treatment for 4 wk on the long bones of the diabetic rats. Electron and light microscopic observations demonstrated that sodium selenite treatment prevented the STZ-induced structural as well as ultrastructural changes in the long bones of the rats. In conclusion, this study first showed that a period of 5-wk diabetes was enough to cause some important and degenerative changes in the structure of the bone tissues, and, second, it demonstrated that sodium selenite treatment of the diabetic rats could normalize these alterations.

Coenzyme Q(10) and alpha-lipoic acid supplementation in diabetic rats: conduction velocity distributions.

Diabetic neuropathies are a family of nerve disorders caused by diabetes. Patients with diabetes can develop nerve problems at any time, but the longer a person has diabetes the greater the risk. This study aims to investigate diabetes- and coenzyme Q(10) (CoQ(10)) or alpha-lipoic acid (ALA) supplementation-induced changes in the conduction velocity (CV) distributions of rat sciatic nerve fibers. Sciatic nerve compound action potentials (CAPs) were recorded by suction electrode and CV distributions by the collision technique. Diabetes resulted in a significant increase in time to peak, rheobase and chronaxie values of these CAP waveforms, whereas the maximum depolarization, area, kinetics and CVs of both fast and slow nerve fiber groups were found to be decreased. Coenzyme Q(10) (CoQ(10)) supplementation was found to have some positive effect on the diabetes-induced alterations. CoQ(10) supplementation induced positive changes mainly in the area and fall-down phase of the kinetics of CAP waveforms, as well as rheobase, chronaxie and speed of the intermediately conducting groups ( approximately or equal to 40 m/s). alpha-Lipoic acid (ALA) supplementation did not produce statistically significant effects. This study has shown for the first time that diabetes induces a shift of actively contributing nerve fibers toward slower CVs, and supplementation with CoQ(10) not only stopped this shift but also tended to restore velocities toward those of the age-matched control group. In addition to its effects on mitochondrial alterations, these positive effects of CoQ10 on diabetic neuropathy can be attributed to its antioxidant activity.

Sodium selenite protects against diabetes-induced alterations in the antioxidant defense system of the liver.

Free radical genesis of disorder is one of the major subjects of discussion in the explanation of pathological conditions. In this study, the effects of micro molar quantities of sodium selenite treatment on diabetes‐induced alterations in the antioxidant defense system were investigated.

Toxic concentrations of selenite shortens repolarization phase of action potential in rat papillary muscle

Selenium (Se) has long been recognized as both an essential mammalian nutrient and a hazardous element. Sodium selenite is commonly used as a dietary supplement for the treatment of Se deficiency. On the other hand, chronic Se toxicity has been demonstrated to affect the major organs, including the heart, in experimental animals.This study examines the effects of high concentrations of extracellular selenite (in the range of 0.001–1 mM) application into the recording bath on the electrical properties of rat papillary muscles. Conventional glass semifloating microelectrodes were used to record intracellular action potentials (APs) in isolated rat papillary muscles. The amplitude of APs and the resting membrane potential of papillary muscles were not changed following a 20-min selenite (1 mM) application compared to the first minute of its application. Freshly isolated ventricular myocytes by an enzymatic method were used to determine the selenite-induced alterations in Na+ currents. Na+ currents, measured at 22°C, by the whole-cell patch-clamp technique, decreased by 38±8% in the presence of 1 mM selenite for 5 min. These selenite-induced effects were not reversed, but are restored by dithiothreitol (1 mM).These results demonstrated that toxic concentrations of selenite induced a significant shortening in AP duration as a result of an increase in the rate of repolarization. Our findings also suggest that a decrease in Na+ currents, in addition to Ca2+ currents, may play a role in the shortening of AP duration in rat papillary muscles.

Gender-dependent effects of selenite on the perfused rat heart: a toxicological study.

Gender differences are related to the manner in which the heart responds to chronic and acute stress conditions of physiological and pathological nature. Depending on dose, sodium selenite acts as an antioxidant proven to have beneficial effects in several pathological conditions G. Drasch, J. Schopfer, and G. N. Schrauzer, Selenium/cadmium ratios in human prostates: indicators of prostate cancer risk of smokers and non-smokers, and relevance to the cancer protective effects of selenium,Biol. Trace Element Res.103(2), 103–107 (2005); R. G. Kasseroller and G. N. Schrauzer, Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review,Am. J. Ther.7(4), 273–279 (2000); G. N. Schrauzer, Anticarcinogenic effects of selenium,Cell. Mol. Life Sci.57(13–14), 1864–1873 (2000); I. S. Palmer and O. E. Olson, Relative toxicities of selenite and selenate in the drinking water of rats,J. Nutr.104(3), 306–314 (1974). To date, little is known about the gender-dependent direct effects of toxic doses of selenite on electrophysiology of the cardiovascular system H. A. Schroeder and M. Mitchener, Selenium and tellurium in rats: effect on growth, survival and tumors,J. Nutr.101(11), 1531–1540 (1971); G. N. Schrauzer, The nutritional significance, metabolism and toxicology of selenomethionine,Adv. Food Nutr. Res.47, 73–112 (2003). In the present study, the effects of in vitro toxic concentrations of sodium selenite ranging from 10-6 M to 10-3 M were tested on both male and female rat heart preparations. The toxic effects seen in an electrocardiogram and left ventricular pressure were dose and sex dependent at most of the tested concentrations. The present study clearly shows that at toxic doses, stress conditions are induced by selenite, resulting in gender-dependent modifications of the heart function. This modification is more pronounced in the contraction cascade of female rats. Males, on the other hand, had been much more affected in excitation-related parameters.

A Critical Balance Between Oxidative Stress and Antioxidant Defense in Cardiovascular System Under Hyperglycemia: A Summary of Experimental Studies

Diabetes mellitus is a disorder resulting from a lost in control of blood glucose level by insufficient insulin release (type 1), impaired insulin function, or insulin resistance (type 2). The main etiology for mortality and a great percent of the morbidity in patients with diabetes is cardiovascular disease. In addition to hyperglycemia, enhanced oxidative stress plays a major role in the pathogenesis of diabetes. Although reactive oxygen species (ROS) are known to be mediators of intracellular signaling pathways under physiological conditions, excessive production of ROS can be detrimental to the cells as a result of increased oxidative stress and thereby cellular dysfunction. Hence, well-tuned, balanced, and responsive antioxidant systems are vital for proper regulation of the redox status of the cells. Studies have reported valuable effects of antioxidant agents, including trace elements, on diabetes-induced cardiovascular system dysfunctions, either directly or indirectly. Thus, several approaches have been carried out to either diminish an elevated ROS production or improve the endogenous levels of antioxidants. Indeed, reduced fatty acid oxidation and use of trace elements in treatment strategies result in promising prevention hints for diabetes-induced cardiovascular dysfunctions. Our scope here is to review the important role of antioxidants, particularly selenium, as cardioprotective agents in several types of disease states including diabetes, presenting our research results on cardiac function by using experimental animal models for diabetes. Although the paradigm that inhibiting overproduction of superoxides and peroxides would prevent cardiac dysfunction diabetes-induced damage has been difficult to verify using conventional antioxidants such as selenium, of special note is that its role as hyperglycemia controller, insulin sensitizer, or antioxidant therapy remains to be further explored as well as the effect of hypolipidemic therapy.

A small GTPase RhoA and its downstream effectors Rho-associated protein kinases (ROCK) signaling pathway activation mediate smooth muscle contraction. ROCKs inhibit myosin light chain phosphatase (MLCP) dephosphorylation and therefore reduce relaxation. H

A small GTPase RhoA and its downstream effectors Rhoassociated protein kinases (ROCK) signaling pathway activation mediate smooth muscle contraction. ROCKs inhibit myosin light chain phosphatase (MLCP) dephosphorylation and therefore reduce relaxation. However, nitric oxide (NO) that is produced and released from endothelial cells has an inhibitory effect on the ROCK pathway in vasculature. Studies in which ROCK activity was inhibited by variety of pharmacological agents (HA1077 or Y-27632) have shown that it has some critical effects on systemic diseases like hypertension or diabetes mellitus. Indeed this activity may show isoform specificity (ROCK1 or ROCK2) dependent on the pathology. Therefore, in vascular pathogenesis ROCK pathway with its isoforms also need to be considered due to its direct effects on the vasoconstriction.