Effects Of Sulfur Dioxide On The Cardiovascular Functions And The Combined Effect With Several Substances

A large number of epidemiological studies have shown that sulfur dioxide (SO2) was correlative with the cardiovascular diseases at home and abroad. Long-term exposure to SO2 can increase the risk of cardiovascular disease and mortality, so the damage effect of SO2 on the cardiovascular system increasingly aroused the attention of scholars. Compared with epidemiological studies, little research has been made on the mechanism of SO2 induced cardiovascular diseases, which can not meet the need for cardiovascular disease prevention and treatment. In addition, lactic acid, pyruvic acid and ammonia are the body's endogenous substances and have important physiological roles in the human body. Studying their effects on cardiac function and the combined effects of them and SO2 has an important scientific significance. To this end, the methods of isolated vascular rings, Langendorff isolated heart perfusion, western blot and radioimmunoassay were used to study the effects of SO2 on cardiovascular function and its mechanisms, as well as the effects of lactic acid, pyruvic acid and ammonia on cardiac function and the combined effects of them with SO2, by these to clear the mechanism of the effects of SO2 on cardiovascular system and to provide toxicological and pathological basis for cardiovascular diseases induced by SO2.The present study was designed to investigate vasodilator effect of gaseous SO2 and roles of various ion channels in relaxations of SO2 on isolated rat aortic rings. The results showed that, SO2 could relax isolated aortic rings in a dose-dependent manner for both endothelium-intact and endothelium-denuded aortic rings. SO2 at physiological (110.34±35.22μM) and low concentrations (< 450μM) caused relaxation of endothelium-intact aortic rings, but not for endothelium-denuded aortic rings. For the endothelium-intact rings, the vasorelaxant effects induced by 30 and 300μM SO2 were partially inhibited by iberiotoxin, a big-conductance Ca2+-activated K+(BKCa) channel blocker, while the vasorelaxation of 1500μM SO2 on both endothelium-intact and endothelium-denuded aortic rings was partially inhibited by nifedipine, an L-type calcium-channel blocker and glibenclamide, an ATP-sensitive K+(KATP) channel blocker. The results suggested that SO2 was a vasoactive substance and the vasorelaxant effects of SO2 at physiological and low concentrations were endothelium-dependent, which might be partly related to BKCa channel. The mechanism of SO2-induced vasorelaxation at high concentrations was shown to be endothelium-independent, which might be related to KATP channel and L-type calcium-channel.The effects of SO2 and its derivatives on heart function in isolated perfused rat heart and the possible mechanisms involved in their effects was investigated. The results showed that SO2 and SO2 derivatives elicited a negative inotropic effect in a dose-dependent manner. And SO2 has a higher effect than SO2 derivatives. The negative inotropic effects induced by SO2 at low concentrations on the heart were partially inhibited by staurosporine, a protein kinase C (PKC) inhibitor, indomethacin, a cyclooxygenase inhibitor, L-NAME, a NO synthase inhibitor and NS-2028, a soluble guanylate cyclase inhibitor, respectively. While the negative inotropic effects induced by SO2 derivatives at low concentrations on the heart were partially inhibited by nifedipine, an L-type calcium channel blocker and glibenclamide, a KATP blocker; the negative inotropic effects induced by high concentrations of SO2 and SO2 derivatives on the heart were partially inhibited by nifedipine, glibenclamide, staurosporine, indomethacin and NS-2028. The results suggested that, at low concentrations, the mechanism of SO2-induced negative inotropic effects might occur through promoting the activities of PKC, cycloxygenase and NO-cGMP pathway, but the mechanism of SO2 derivatives-induced effects might be related to KATP channel and L-type calcium-channel. At high concentrations, the mechanisms of SO2 and SO2 derivatives-induced negative inotropic effects were similar, which might be related to KATP channel and L-type calcium-channel as well as possible alterations in PKC, cycloxygenase and cGMP.In order to thoroughly explore the effects of SO2 and its derivatives on isolated rat hearts and their mechanisms, the effects of SO2 and its derivatives on the PKC protein expression, ATP activity, cGMP, glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), NO, NOS and other indicators in isolated heart tissue and on creatine kinase (CK) and lactate dehydrogenase (LDH) levels in the heart perfusate were observed in this study. The results showed that different concentrations of SO2 and SO2 derivatives could significantly decrease the levels of GSH, SOD in the heart tissues and significantly increased the levels of PKC protein expression, cGMP, MDA, NO, NO synthase (NOS) in the heart tissues and the levels of CK, LDH in the heart perfusate. High concentrations of SO2 and SO2 derivatives could significantly decrease the levels of superoxide anion radical (O2-), Na+K+-ATP enzyme and Ca2+Mg2+-ATP enzyme in heart tissues and significantly increase the contents of H2O2,'OH. The results suggested that, SO2 and SO2 derivatives have significantly oxidative damage on isolated rat heart tissues (GSH, SOD, O2- significantly decreased and MDA, H2O2,'OH significantly increased). The activities of Na+K+-ATP enzyme and Ca2+Mg2+-ATP enzyme in myocardial membrane were decreased in its mediated. In addition, the results further showed that the negative inotropic effects induced by SO2 and SO2 derivatives on the heart were indeed correlative with the changes of PKC levels and the NO-cGMP pathway.The effects of lactic acid, pyruvic acid and ammonia on cardiac function and their mechanisms, as well as the combined effects of them with SO2 on cardiac function were observed. The results showed that lactic acid and pyruvic acid had negative inotropic effects, while ammonia had a significant positive inotropic effect on the hearts. Their impact on cardiac function was partly correlative with the change of the pH value of heart perfusate caused by them, but mainly caused by their own. The mechanism of the negative inotropic effect induced by lactic acid on the heart might be through opening of KATP channels and activation of PKC; the mechanism of the negative inotropic effect induced by pyruvic acid on the heart might be through opening of voltage-gated potassium channels (KV); the mechanism of the positive inotropic effect induced by ammonia on the heart might be through inhibiting the opening of KATP channel and activation of NO-cGMP pathway. The combined effects of lactic acid and pyruvic acid with SO2 on cardiac function were not synergistic but independent; the combined effect of ammonia with SO2 on cardiac function was antagonistical.In summary, different concentrations of SO2 have significant relaxation effect on the rat aortic ring and negative inotropic effects on the isolated rat heart. The mechanisms of relaxation effects on the rat aortic ring and negative inotropic effects on the isolated rat hearts induced by low concentrations of SO2 and high concentrations of SO2 were different. The combined effects of lactic acid and pyruvic acid with SO2 on the heart functions were independent; the combined effect of ammonia and SO2 on cardiac function was antagonistical.