Ivan Srejovic, Vladimir Jakovljevic, Vladimir Zivkovic and Dragan Djuric
N-methyl-D-aspartate (NMDA) receptors belong to ionotropic glutamate receptor family, together with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainite receptors and δ-receptors. All of these receptors are tetramers composed of four subunits. NMDA receptors have several unique features in relation to other ionotropic glutamate receptors: requirement for simultaneous action of two coagonists, glutamate and glycine; dual control of receptor activation, ligand-dependent (by glutamate and glycine) and voltage-dependent (Mg2+ block) control; and influx of considerable amounts of Ca2+ following receptor activation. Increasing number of researches deals with physiological and pathophysiological roles of NMDA receptors outside of nerve tissues, especially in the cardiovascular system. NMDA receptors are found in all cell types represented in cardiovascular system, and their overstimulation in pathological conditions, such as hyperhomocysteinemia, is related to a range of cardiovascular disorders. On the other hand we demonstrated that blockade of NMDA receptors depresses heart function. There is a need for the intensive study of NMDA receptor in cardiovascular system as potential theraputical target both in prevention and treatment of cardiovascular disorders.
Jasmina Sretenovic, Vladimir Zivkovic, Ivan Srejovic and Zoran Milosavljevic
In recent decades, steroid abuse has become very popular and widespread among professional and recreational athletes. The aim of this study was to examine the chronic effects of training combined with high doses of nandrolone decanoate on cardiac muscle tissue. The study included 32 Wistar albino rats divided into 4 groups: control (T-N-), steroid (T-N+), exercisetraining (T+N-) and exercise plus steroid (T+N+) groups. The T+N- and T+N+ group swam for 4 weeks, 1 hour per day, 5 days per week. The N+ (nandrolone positive groups) received nandrolone decanoate (20 mg/kg) once per week, subcutaneously. After 4 weeks of training, the rats were sacrificed. Heart biopsy specimens were routinely fixed and embedded in paraffin. Fivemicrometre thick sections were stained with haematoxylin and eosin (H/E) and Masson-Trichrome dyes. Captured microscopic images were processed by special software for image analysis to quantify results. Our results showed that the combination of nandrolone and training causes left ventricular wall thickening of 30%. Average cardiac muscle cell longitudinal diameter was increased by 6% in the T-N+ group, by 16% in the T+N- group and by 25% in the T+N+ group. The cross sectional muscle cell area was increased in the T+N+ group by 33%. Heart collagen content was increased in the nandrolone group compared to the control group by 261%. Collagen content was decreased in the T+N+ group by 34%. High doses of AAS induced left ventricle hypertrophy and excessive heart collagen deposition.
Deniel Pesic, Ivan Srejovic, Djordje Stefanovic, Dusica Djordjevic, Dejan Cubrilo and Vladimir Zivkovic
Production of free radicals and oxidative damage during physical activity is a topic that is intensively studied and paid a lot of attention, first of all in professional sports. Marathon is categorized as extremely demanding sports discipline, as it induces high energy consumption and also requires special mental self-control. We presented cases of two athletes of different age, who have been on dissimilar level of sports readiness, and also had various approach to physical activity and exercise. During 10 days they ran out 10 marathons, partly on a fl at terrain, and partly on hilly, which produced different level of effort in conquering the terrain. Also, both athletes had complex supplementation scheme in order to prevent electrolyte imbalance and excessive production of free radicals. Blood samples were taken in the morning and immediately after the end of the marathon. Measured oxidative stress biomarkers changed without a noticeable pattern, but these changes did not vary greatly among themselves. Catalase activity in both marathon runners was higher after marathon almost after every race for 10 days. On the other hand, amount of reduced glutathione was lower after marathon in both athletes in the same manner. Based on the obtained results we can conclude that adequate supplementation could have crucial role in prevention of oxidative damage.
Dejan Simic, Aleksandar Spasic, Mirko Jovanovic, Predrag Maric, Radovan Milosevic and Ivan Srejovic
Phosphodiesterase-5 inhibitors (PDE5Is) represent a group of drugs that are registered for the treatment of erectile dysfunctions predominantly, but recently also for treatment of pulmonary hypertension and benign prostatic hypertrophy. However, more and more research deals with possible antitumor potential of PDE5Is in different types of cancers, including prostate cancer. Prostate cancer represents the one of the most common carcinoma in the male population, whose incidence is continuously increasing. Early detection combined with radical prostatectomy increases the survival rate, but also it is necessary to keep in mind the quality of life of patients undergoing prostatectomy in light of bladder control and erectile function. Authors of various clinical studies presented the results that often lead to totally opposing conclusions. For example, Chavez and colleagues have shown that use of PDE5Is in men with erectile dysfunction decreases the risk of developing prostate cancer, while, on the other hand, Michl and colleagues pointed out the adversely effect of PDE5Is on biochemical recurrence after bilateral nerve sparing radical prostatectomy. In that sense, the aim of this review was to present as many as possible of existing results dealing with of action of PDE5Is in the field of prostatic carcinoma. Taking into account all presented data, it can be concluded that eff ect of PDE5Is on formation, development and outcome of treatment in patients with prostate carcinoma is very intriguing question, whose response requires additional both experimental and clinical research.
Biljana Jakovljevic, Sasa Plecevic, Anica Petkovic, Tamara Nikolic Turnic, Isidora Milosavljevic, Kristina Radoman and Ivan Srejovic
The investigation was aimed to evaluate the effects of 3-weeks swimming exercise on blood pressure and redox status in high-salt-induced hypertensive rats. Male Wistar albino rats (n=40, 6 weeks old) were divided into 4 groups: 1. hypertensive rats that swam for 3 weeks; 2. sedentary hypertensive control rats; 3. normotensive rats that swam for 3 weeks; 4. sedentary normotensive control rats. Hypertensive animals were on high concentrated sodium (8% NaCl) solution for 4 weeks (period of induction of hypertension). After sacrificing, hearts were isolated and perfused according to Langendorff technique at gradually increased coronary perfusion pressure from 40-120 cmH2O. The oxidative stress markers were determined in coronary venous effluent: the index of lipid peroxidation (measured as TBARS), nitrites (NO2-), superoxide anion radical (O2-) and hydrogen peroxide (H2O2). Swimming did not lead to significant changes in levels of TBARS, NO2-, O2- in any of compared groups while levels of H2O2 were significantly higher in swimming hypertensive group comparing to swimming normotensive group at coronary perfusion pressure of 80-120 cmH2O. Our results indicate that the short-term swimming start to reduce blood pressure. In addition it seems that this type of swimming duration does not promote cardiac oxidative stress damages.
Irena Pusica, Ivan Srejovic, Jovana Bradic, Jelena Smigic, Stefani Bolevich, Sergey Bolevich, Vladimir Jakovljević and Dusica Djordjevic
Energy drinks (EDs) contain caffeine and other active ingredients which affect cardiovascular system. The aims of this study were to examine direct effects of Red Bull (RB) on cardiodynamics and oxidative stress in isolated hearts of rats. The rats were divided into four groups: untrained rats who never consumed ED (dED-UT); untrained rats who consumed ED 5 days a week during 4 weeks (ch+dED-UT); rats trained 5 times a week for 4 weeks, but did not consume ED (dED-T); rats trained and consumed ED 5 times a week for 4 weeks (ch+dED-T). After sacrificing, hearts were isolated and perfused according to Langendorff technique. Through the isolated heart of all rats in each group, RB was administered. The parameters of cardiac function were recorded, and the levels of prooxidants were measured in the coronary effluent during coronary autoregulation. Rats in ch+dED-UT group had significantly lower rates of myocardial contraction and relaxation compared to rats in dED-UT group. The same effect was recorded in the dED-T group compared to dED-UT group. The levels of hydrogen peroxide were significantly higher in trained rats. Rats in ch+dED-T group also had significantly higher levels of superoxide anion radical and index of lipid peroxidation, as well as lower levels of nitrites when compared to ch+dED-UT group, while opposite effect was recorded in rats in dED-T group compared to dED-UT group. The RB could have a potentially negative inotropic effect in chronic consumers. Prooxidative effect of RB was most pronounced in trained chronic consumers.
Tanja Sobot, Amela Matavulj, Vladimir Jakovljevic, Tamara Nikolic, Vladimir Zivkovic, Ivan Srejovic, Nevena Jeremic and Dragan Djuric
The aim of this experimental study was to assess the effects of the acute administration of L-arginine alone and in combination with L-NAME (a non-selective NO synthase inhibitor) on the coronary flow and oxidative stress markers in isolated rat hearts. The experimental study was performed on hearts isolated from Wistar albino rats (n=12, male, 8 weeks old, body mass of 180-200 g). Retrograde perfusion of the isolated preparations was performed using a modified method according to the Langendorff technique with a gradual increase in the perfusion pressure (40–120 cmH2O). The following values were measured in the collected coronary effluents: coronary flow, released nitrites (NO production marker), superoxide anion radical and the index of lipid peroxidation (measured as thiobarbiturate reactive substances). The experimental protocol was performed under controlled conditions, followed by the administration of L-arginine alone (1 mmol) and L-arginine (1 mmol) + L-NAME (30 μmol). The results indicated that L-arginine did not significantly increase the coronary flow or the release of NO, TBARS and the superoxide anion radical. These effects were partially blocked by the joint administration of L-arginine + L-NAME, which indicated their competitive effect. Hence, the results of our study do not demonstrate significant effects of L-arginine administration on the coronary flow and oxidative stress markers in isolated rat hearts.
Nevena Jeremic, Vladimir Zivkovic, Ivan Srejovic, Jovana Jeremic, Anica Petkovic, Jovana Bradic and Vladimir Jakovljevic
Aim of present study was to determine the participation of various biomarkers of oxidative damage: nitrite (NO2−), superoxide anion radicals (O2−), index of lipid peroxidation (TBARS) and hydrogen peroxide (H2O2) in coronary circulation after application of the different models of preconditioning such as ischemic and preconditioning with proton pump inhibitors.
Examining a biochemical markers of oxidative damage we did not notice any increased production values of any parameter, according to that we can hypothesize that possible occurrence of reperfusion injury after ischemia and PPIs preconditioning is not mediated by this mechanism.
Due to the very difficult and controversial application of ischemic preconditioning in clinical practice, the results of this study suggest that in the future proton pump inhibitors can contribute to the prevention of myocardial damage following ischemia
Marko Ravic, Vladimir Jakovljevic, Petar Ristic, Ivan Srejovic, Aleksandra Vranic, Goran Babic and Sergey Bolevich
Diabetes mellitus is a major risk factor for cardiovascular diseases, while cardiovascular diseases are a leading cause of morbidity and mortality worldwide. The renin-angiotensin- aldosterone system controls renal, cardiovascular, adrenal function and regulates fluid and electrolyte balance as well as blood pressure. Because of his role, inhibition of reninangiotensin- aldosteron system is another therapy approach that reduces the risk of diabetes and cardiovascular disease. In this study, our goal was to evaluate effect of valsartan,as inhibitor of angiotensin II receptor type 1, on cardiac tissue and function, with focus on cardiodynamic and oxidative stress. The present study was carried out on 20 adult male Wistar albino rats (8 week old and with body masses of 180- 200 g). Rats were divided randomly into 2 groups (10 animals per group). Healthy animals treated with 1 μM of valsartan and streptozotocin-induced diabetic animals perfused with 1 μM of valsartan 4 weeks after the induction of diabetes. Our results demonstrated that acute application of valsartan has different effect on cardiodynamics in rat heart of diabetic and healthy animals but did not improve cardiac function in hyperglycemia- induced changes. A challenge for further investigations are studies with chronic or acute administration, alone or in combination with other angiotensin-converting-enzyme inhibitor in various models of diabetes.
Maja Jevdjevic, Ivan Srejovic, Vladimir Zivkovic, Nevena Barudzic, Anica Petkovic, Jovana Bradic, Dragan Djuric and Vladimir Jakovljevic
Eicosanoids lead to the promotion of inflammation, cause fever and pain and have many other eff ects. NSAIDs block the action of cyclooxygenase (COX) during the process of converting arachidonic acid into inflammatory mediators, thus reducing the symptoms of inflammation. Investigations focusing on nonselective COX inhibitors, used in high doses, revealed harmful eff ects on myocardial function. Th e aim of our study was to assess the eff ects of two nonselective NSAIDs, diclofenac and ibuprofen, on cardiodynamic parameters, coronary flow and oxidative stress biomarkers in isolated rat hearts. Th e hearts of male Wistar albino rats were excised and retrogradely perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40-120 cm H2O). Th e experiments were performed under controlled conditions (Krebs-Henseleit physiological solution). Th e hearts were perfused with 10 μmol/l diclofenac and 10 μmol/l ibuprofen. Th e heart function parameters, including the maximum rate of pressure development (dp/dt max), minimum rate of pressure development (dp/dt min), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean perfusion pressure (MBP) and heart rate (HR), were continuously registered. Coronary flow (CF) was measured flowmetrically. Oxidative stress markers, including the index of lipid peroxidation measured as TBARS, nitric oxide measured through nitrites (NO2 -), superoxide anion radical (O2 -), and hydrogen peroxide (H2O2) in the coronary venous effluent, were assessed spectrophotometrically. Our results showed that diclofenac aff ected cardiodynamic parameters more significantly than did ibuprofen. Furthermore, the present data indicate that both estimated COX inhibitors do not promote the production of reactive oxygen species.