Nazmi Yaras

Protective action of doxycycline against diabetic cardiomyopathy in rats

Reactive oxygen and nitrogen species play an important role in the development of diabetic cardiomyopathy. They can activate matrix metalloproteinases (MMPs), and MMP‐2 in particular is known to mediate early consequences of oxidative stress injury in the heart. Therefore, we investigated the role of MMP‐2 and the effect of the MMP inhibitor doxycycline on the changes of heart function caused by diabetes.

Interpretation of relevance of sodium-calcium exchange in action potential of diabetic rat heart by mathematical model.

Sarcolemmal Na+–Ca2+ exchange plays a central role in ion transport of the myocardium and the current carried with it contributes to the late phase of the action potential (AP) besides the contribution of outward K+-currents. In this study, the mathematical model for AP of the diabetic rat ventricular myocytes [34] was modified and used for the diabetic rat papillary muscle. We used our experimentally measured values of two K+-currents; transient outward current, Ito and steady-state outward current, Iss, as well as L-type Ca2+-current, ICaL, then compared with the simulated values. We have demonstrated that the prolongation in the AP of the papillary muscle of the diabetic rats are not due to the alteration of ICaL but mainly due to the inhibition of the K+-currents and also the Na+–Ca2+ exchanger current, INa–Ca. In combination with our experimental data on sodium-selenite-treated diabetic rats, our simulation results provide new information concerning plausible ionic mechanisms, and second a possible positive effect of selenium treatment on the altered INa–Ca for the observed changes in the AP duration of streptozotocin-induced diabetic rat heart. (Mol Cell Biochem 269: 121–129, 2005)

EFFECT OF IMMOBILIZATION AND COLD STRESS ON VISUAL EVOKED POTENTIALS

The main aim of our research was to study the effects of immobilization and/or cold stress on amplitudes and latencies of visual evoked potentials (VEPs) and thiobarbituric acid reactive substances (TBARS). Forty healthy male albino rats, aged three months, were used. The rats were equally divided into four groups: Control group (C), the group exposed to cold stress (CS), the group exposed to immobilization stress (IS), and the group exposed to both cold and immobilization stress (CIS). Plasma corticosterone concentrations were significantly increased in all stress groups. Lipid peroxidation was increased in brain and retina of all stress groups as indicated by the significant increase in TBARS levels compared to the C group. Glutathione peroxidase (GSH-Px) activity in brain and retina increased in the CS group, but decreased in the IS group relative to the C group. GSH-Px activity also increased in the brain, but not in the retina in the CIS group with respect to the C group. The mean latencies of P1, N1, P2, N2, and P3 components were significantly prolonged in all stress groups compared with the C group. The results suggest that stress induced lipid peroxidation may influence VEPs.

THE EFFECT OF PERGOLIDE ON COGNITIVE PERFORMANCE OF YOUNG AND MIDDLE-AGED RATS

In this study, we investigated the effect of pergolide, a dopaminergic agonist, on cognitive ability in young and middle-aged rats using the Morris Water Maze (MWM). Pergolide 0.5/mg/day IP was administered to young and middle-aged rats, whereas only vehicle was given to their age-matched controls. During the acquisition period of 6 days, young rats showed normal escape latency pattern, which was not affected by pergolide. Middle-aged rats, however, showed poor escape latency pattern, and this poor pattern was also not affected by pergolide. On the 7th day, pergolide decreased retention time of young rats compared to control values. Middle-aged rats also showed reduced retention time. In contrast to the findings of young rats, retention time was not affected by pergolide in middle-aged rats. We concluded that pergolide does not alter escape latency at any age. It has a negative effect on retention time of young rats, whereas it has no effect on middle-aged ones.

Serum lipid peroxidation markers are correlated with those in brain samples in different stress models.

Objective Stress can stimulate increased production of oxygen radicals. We investigated the correlations between serum levels of lipid peroxidation markers and those in brain samples in different stress models. Methods Animals (n = 96) were divided equally into eight groups: a control group and groups treated with vitamin E (Vit E); exposed to immobilisation stress; exposed to immobilisation stress and treated with Vit E; exposed to cold stress; exposed to cold stress and treated with Vit E; exposed to both immobilisation and cold stress; and a final group exposed to both immobilisation and cold stress and treated with Vit E. Thiobarbituric acid-reactive substance (TBARS) in brain samples and levels of TBARS, corticosterone, conjugated dienes (CD), lipids, and paraoxonase-1 (PON1) activity in serum were analysed. Results Serum corticosterone (p < 0.001), CD (p < 0.05), lipid (p < 0.05) levels, and brain TBARS (p < 0.05) levels were significantly higher in all stress groups than in controls, and the elevated levels were reversed in the Vit E-treated stress groups (p < 0.05). Serum PON1 activity was not different among the groups (p > 0.05). Serum TBARS levels increased significantly in all stress groups (p < 0.05), but this elevation was only reversed in the group exposed to both immobilisation and cold stress and treated with Vit E (p < 0.001). Conclusion These results suggest that serum levels of lipid peroxidation markers can be determined readily and may be useful as indicators to evaluate the effects of oxidative stress in the brain.

Effect of magnesium supplementation on blood rheology in NOS inhibition-induced hypertension model

This study investigated the effects of magnesium on blood rheological properties and blood pressure in nitric oxide synthase (NOS) inhibition-induced hypertension model. Hypertension was induced by oral administration of the nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/day) for 6 weeks and systolic blood pressure was measured by the tail-cuff method. The groups receiving magnesium supplementation were fed with rat chow containing 0.8% magnesium oxide during the experiment. At the end of experiment, blood samples were obtained from abdominal aorta, using ether anesthesia. Plasma and erythrocyte magnesium levels were determined by the atomic absorption spectrometer. RBC deformability and aggregation were determined by rotational ektacytometry. Plasma fibrinogen concentration was evaluated by ELISA. Whole blood and plasma viscosities were determined by viscometer and intracellular free Ca++ level was measured by using spectroflurometric method. Blood pressure was elevated in hypertensive groups and suppressed by magnesium therapy. Plasma viscosity and RBC aggregation were found to be higher in hypertensive rats than control animals and these parameters significantly decreased in magnesium supplemented hypertensive animals. Other measurements were not different between experimental groups. These results confirm that blood pressure, plasma viscosity and RBC aggregation increased in NOS inhibition-induced hypertension model and oral magnesium supplementation improved these parameters.

Extracellular ATP activates eNOS and increases intracellular NO generation in Red Blood Cells

BACKGROUND It has been well documented that ATP activates NOS enzymes and causes increased NO production in several cell types. Although RBC known to possesses eNOS enzyme activity, it has not been investigated whether RBC eNOS could be induced by extracellular ATP. OBJECTIVE The aim of the present study is to evaluate extracellular ATP mediated eNOS activation and NO production in RBC. METHODS RBC packed were isolated from healthy volunteers and re-suspended in Hepes solution at a hematocrit of 0.01 l/l. Intracellular NO and Ca+2 levels and eNOS activation measured by flow cytometry in response to P2X receptor agonist, Bz-ATP, in the absence and presence of NOS, P2 receptors and PI3K inhibitors. RESULTS P2X receptor agonist Bz-ATP found to increase intracellular NO, Ca+2 and serine 1177 phosphorylated eNOS levels and these responses have shown to be suppressed by NOS enzyme, P2 receptors and PI3K inhibitors. CONCLUSIONS The results of the study clearly demonstrated extracellular ATP induced NO generation in RBC through intracellular Ca+2 and PI3K/Akt pathways. The mechanism we described here might be important at basal conditions and also in conditions with increased ATP release.

Sex Differences and Diabetes Mellitus in Cardiovascular Function

Diabetes is an increasingly widespread epidemic disease, with type 2 diabetes accounting for most of the cases. Cardiovascular complications are the most common cause of morbidity and mortality in diabetic patients. Some studies have also reported that gender difference has a profound impact in the pathogenesis, development, and severity of cardiovascular diseases in diabetic patients, although this assertion was not documented and reviewed in detail. Indeed, cardiovascular diseases are the leading cause of death among women in developed countries. Similarly, results of human and animal studies have shown that sex differences cannot be ruled out in diabetes-induced cardiovascular abnormalities. The proposed underlying mechanisms of gender-related differences in response to different stimuli in healthy and diabetic subjects are the distinction in regulation of cytosolic Ca2+ levels and the varied rate of oxidative damage. The female rat myocardium is more resistant to diabetes-induced cardiac dysfunction than that of male rats, but this female advantage is canceled in postmenopausal individuals. Therefore, it is possible to suggest that estrogen can exert protective effects against diabetes through modulation of altered Ca2+ dynamics and reduction of oxidative damage in the heart. Although the current findings provide convincing evidence about the sex-related differences in diabetes-induced cardiovascular pathology, further studies are needed to clarify the underlying mechanisms of this distinction.