Modulation of hydrogen sulfide synthesis improves heart function and endothelium-dependent vasorelaxation in diabetes.

Diabetes dramatically increases the risk of cardiovascular complications. The endothelial dysfunction and diastolic heart dysfunction are associated with a decreasing level of hydrogen sulfide (H2S) and inhibition of the activity of endothelial nitric oxide synthase (NOS) in diabetes. The aim of this study is to investigate the effect of modulation of H2S synthesis on heart functions and vasorelaxation in diabetes. The dl-propargylglycine and l-cysteine were administered intraperitoneally. H2S content in the heart tissue, markers of oxidative stress, inducible NOS and constitutive NOS (cNOS) activities, endothelium-dependent vasorelaxation of the aortic rings, and heart function were studied. We demonstrate that our combination increased H2S synthesis 13 times and cNOS activity 5 times in the heart tissue of diabetic rats. Increasing NO and H2S production caused improvement and restoration of endothelium-dependent relaxation of aorta, effective arterial elastance, and diastolic heart function in diabetic rats. The endothelium-dependent relaxation increased 2.4 times; effective arterial elastance decreased by 47%. The end-diastolic myocardial stiffness decreased 2.2 times. Thus, modulation of H2S synthesis leads to increased cNOS activity by up to 5 times in the cardiovascular system. Increasing NO and H2S production restored endothelium-dependent relaxation of aorta and improved heart function in diabetes.

The role of hydrogen sulfide in diastolic function restoration during aging.

The objective of the study was to examine the effect of exogenous hydrogen sulde donor; sodium hydrosulfide (NaHS), on thefree radical generation, cNOS uncoupling in the myocardium, and diastolicfunction in old rats. To evaluate diastolic function of the heart, we used pressure-volume (PV) conductance catheter system (Millar Instruments, USA). It was shown that H2S levels in. the isolated mitochondria and whole heart homogenates obtained from old age rats were significantly lower comparing with adult animals. The markers of combined oxidative and nitrosative stress (the rate of 0 2° H generation, pools of H202, diene conjugates, malondialdehyde, uric acid, the activity of iNOS, nitrate reductase, and NO pools) were increased in the old hearts in line with cNOS uncoupling. Such changes in NOS coupling resulted in the loss of diastolic relaxation (decrease of the rate of relaxation of the left ventricle (dp/dtmin) by 33%, 3-times increase of the end-diastolic pressure, 1.5-time increase of the time constant of left ventricular relaxation (Tau g) and 2-time increase of the end-diastolic stiffness). It has been found that NaHS inhibits oxidative and nitrosative stress, restores cNOS coupling and constitutive de novo synthesis of nitric oxide (NO), which promotes an improvement of the diastolic function (increase of the dp/dtmin by 20% and decrease of Tau g by 13%) . Key words: aging; cNOS uncoupling; heart; hydrogen sulfide; nitrosative stress; oxidative stress.

[PHYSICAL EXERCISE TRAINING CAN- CELS CONSTITUTIVE NOS UNCOUPLING AND INDUCED VIOLATIONS OF CARDIAC HEMODYNAMICS IN HYPERTENSION (PART III)].

In the heart and heart mitochondria spontaneously hypertensive rats investigated the effect of physical exercise training (swimming in a moderate and excessive training mode) on the physiological indicators of cardiac hemodynamics and biochemical parameters that characterize the level of oxidative and nitrosative stress. The index of coupling Ca(2+)-dependent constitutive NO-synthases (cNOS = eNOS + nNOS) and biochemical index of dysfunction were calculated. It turned out that both modes of training is completely restored, and even exceed the reference values in untrained rats Wistar conjugate cNOS state and Ca(2+)-dependent synthesis of nitric oxide (NO). Intensity regime of exercise on the border of functionality have been ineffective for improving the functional state of the cardiovascular system and hypertension can provoke it further. Moderate physical training regime, on the contrary, improves the diastolic function of the heart due to an increase dP/dtmin, reducing end-diastolic pressure and a significant reduction in end-diastolic stiffness. Moderate exercise decreased peripheral resistance and cardiac afterload, as indicated by the decrease in end-systolic pressure and arterial stiffness, which contributed to more efficient and energy-saving of heart work. Improve physiological indicators of cardiac hemodynamics and functional state of the heart in moderate mode of training correlated with changes in both the calculated indices. Moderate mode of training is recommended as a simple physiological preconditioning method for the prevention of cardiac dysfunction, hypertension as a result of state uncoupling cNOS and the resulting excessive generation of superoxide and, conversely, inhibition of Ca(2+)-dependent synthesis of NO.

[EFFECT OF PROPARGYLGLYCINE UPON CARDIOHEMODYNAMICS IN OLD RATS].

Aging increases the risk of cardiovascular diseases. The objective of this study was to show the effect of propargylg- lycine (PPG) upon cardiohemodynamics in old rats. We used pressure-volume (PV) conductance catheter system (Millar Instruments, USA) in order to evaluate systolic and diastolic function in vivo. It has been shown that introducted PPG (11,31 mg/kg) decrises both arterial stiffness (by 1,5 times) and end-diastolic stiffness (by 2,1 times) in old rats. Using PPG in heart mitochondria resulted in increasing levels of H2S (by 112%), NO2- (by 162%) and in growing activity of cNOS (by 3 times). Additionally, PPG decreased the mitochondrial pools of the uric acid, the marker of the superoxide (*O2-) formation and of the ATP degradation. These results suggest that PPG activates alternative ways of H2S synthesis, stimulates the NO and H2S synthesis and suppresses the ATP degradation and *O2 formation. These actions of PPG improve arterial stiffness and end-diastolic stiffness.

[NOS UNCOUPLING IS ACCOMPANIED WITH INDUCTION OF THE OXIDATIVE STRESS AND THE CARDIOHEMODYNAMICS DISTURBANCES IN HYPERTENSION].

We compared the performance of cardiaohemodynamics and indicators of oxidative and nitrosative stress in the heart and aorta in normotensive Wistar rats (WKR) and spontaneously hypertensive rats (SHR). On the basis of experimentally determined parameters to calculate cNOS uncoupling index and biochemical index of function (BIF) in these organs of the cardiovascular system. In the heart, and especially in the aorta of SHR develop a combined oxidative and nitrosative stress that leads to cNOS uncoupling, BIF lowering that correlate with lowering of systolic and diastolic functions, inhibition of the efficiency Frank-Starling mechanism, oxygen consumption of the heart and increasing arterial stiffness. We made the assumption of the existence of the vicious circle of enhancing oxidative stress in organs of the cardiovascular system due to additional superoxide generation by uncoupling cNOS.

[ENDOTHELIAL MONOCYTEACTIVATING FACTOR II CANCELS OXIDATIVE STRESS, CONSTITUTIVE NOS UNCOUPLING AND INDUCED VIOLATIONS OF CARDIAC HEMODYNAMICS IN HYPERTENSION (PART II)].

The purpose of this study was to investigate the effect of EMAP II on free radical state of the heart and blood vessels, to restore cNOS coupling and cardiac hemodynamics in spontaneously hypertensive rats. It was found that, due to the combined inhibition of oxidative and nitrosative stress, EMAP I quickly restores impaired in hypertension constitutive de novo synthesis of NO by restoring cNOS coupling. Restoration by EMAP II of constitutive de novo synthesis NO abolished cardiac and endothelial dysfunction in spontaneously hypertensive rats. In hypertension, the introduction of EMAP II helped to improve the performance of the pumping function of the heart (stroke volume increased by 18.2 %, cardiac output -22 %), an arterial stiffness decreased by 23.2 %, process of relaxation of the left ventricle improved, due to decreased in 4,7 times myocardial end-diastolic stiffness.