RESUMO
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.
Assuntos
Envelhecimento/metabolismo , Diástole/efeitos dos fármacos , Coração/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Mitocôndrias Cardíacas/metabolismo , Sulfetos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Testes de Função Cardíaca , Masculino , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos WistarRESUMO
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.
Assuntos
Envelhecimento/fisiologia , Alcinos/farmacologia , Diástole/efeitos dos fármacos , Glicina/análogos & derivados , Átrios do Coração/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Sístole/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Diástole/fisiologia , Glicina/farmacologia , Injeções Intramusculares , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Volume Sistólico/efeitos dos fármacos , Superóxidos/metabolismo , Sístole/fisiologia , Ácido Úrico/metabolismo , Rigidez Vascular/efeitos dos fármacosRESUMO
The objective of this study was to show the effect of H2S donor, NaHS on the endothelium-dependent vasorelaxation, free radical state and cNOS uncoupling in old rats. In the aorta of old rats a combined oxidative and nitrosative stress develops that leads to cNOS uncoupling and decreased constitutive synthesis of the NO. That biochemical changes correlate with lowering of the endothelium-dependent relaxation of aortic smooth muscles (7.5 ± 1.4%, compared with 64.9 ± 3.5% in adults). It was found that, due to the combined inhibition of oxidative and nitrosative stress, NaHS restores constitutive de novo synthesis of NO by restoring cNOS coupling. Additionally, NaHS improves endothelium-dependent vasorelaxation by increasing (by 6.5 times) Ach-induced relaxation of aortic smooth muscles.
Assuntos
Envelhecimento/fisiologia , Aorta/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Óxido Nítrico/biossíntese , Sulfetos/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta/fisiologia , Radicais Livres/metabolismo , Expressão Gênica , Sulfeto de Hidrogênio/química , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Sulfetos/química , Vasodilatadores/química , Vasodilatadores/farmacologiaRESUMO
In the study we investigated the effect of blockade cystathionine-gamma -lyase (CSE), an enzyme of hydrogen sulfide (H2S) (de novo) synthesis on the endothelium-dependent relaxation of aortic smooth muscle (SM) in old rats. It has been shown that an inhibition of CSE by propargylglycine (PAG) results in restoration of a decreased ACh-induced relaxation of aorta in old rats. This effect of PAG was removed by blocking nitric oxide (NO) synthesis in the endothelial cells. Age-related changes in the levels of H2S, NO2- and enzyme activity of the constitutive synthesis of NO (cNOS) in the heart, were determined. It has been shown that PAG introduction elevates a decreased levels of HzS, NO2- and stimulates the suppressed activity of cNOS in old rats. These results suggest that PAG activates alternative ways of H2S synthesis and stimulates the constitutive synthesis of NO. These actions of PAG restore endothelial function in old rats.