二氧化硫对血管张力作用的信号转导机制及其与几种内源物质的联合作用
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摘要
二氧化硫(SO2)及其衍生物亚硫酸盐和亚硫酸氢盐是常见的污染物,以往的研究表明该化学物是可引起多种毒性作用的全身性毒物。流行病学研究指出,SO2及其衍生物污染与人群心血管疾病的发生有关联。研究发现,生物体内含硫氨基酸和细胞内的硫化氢(H2S)的正常代谢可产生内源性SO2及其衍生物亚硫酸盐和亚硫酸氢盐,亚硫酸氧化酶可促进亚硫酸盐氧化生成硫酸盐而排出体外。
从上世纪80年代以来,一氧化氮(NO)、一氧化碳(CO)、及硫化氢(H2S)等有毒气体分子先后被发现是生物气体信号分子,具有扩张血管、抑制细胞增殖等多种重要的生理学和毒理学作用。与这些有毒气体相比,设想同样作为有毒气体的SO2可能也是一种生物气体信号分子,在人和哺乳动物的心血管系统具有多种生理和毒理学作用。在以前的研究中,发现SO2及其衍生物亚硫酸盐和亚硫酸氢盐均可引起大鼠血压下降、SO2衍生物可引起离体大鼠胸主动脉血管环的舒张。然而,迄今作为亚硫酸盐和亚硫酸氢盐前体物的SO2的心血管效应尚未见报道,SO2对心血管效应的机制尚不了解,SO2对离体血管环的作用仍然有待阐明,SO2的心血管效应是否被血管内皮或周围神经末梢释放的血管活性因子所介导也未可知,SO2与血管组织中不同细胞信号途径之间的相互作用,例如cGMP途径和氧自由基,尚未见研究。此外,SO2与内源小分子化合物对血管张力的联合效应也很少研究。
本研究的目的是探讨SO2对血管张力的生理学和毒理学作用及其细胞和分子机制,为此我们全面地研究了在此过程中血管内皮的作用,进行了SO2对离体大鼠胸主动脉血管环的舒张实验及其有关信号转导途径的研究。为了探讨SO2与体内小分子化合物氨、乳酸、丙酮酸之间在对血管收缩性方面有无相互作用,以便正确评价SO2对人体的毒性作用,本论文还研究了这些化合物对血管张力的影响及其与SO2的联合作用。
在本研究中,采用将气态SO2或SO2生理盐水溶液加入孵育液的方法,使SO2直接作用于离体大鼠胸主动脉血管环,同时使用不同信号转导途径抑制剂和不同离子通道抑制剂,研究SO2诱发血管舒张的信号转导机制,并采用类比法研究SO2对溶液pH的影响及其与血管舒张的关系。除此之外,还应用组织病理和免疫化学分析,以及放射免疫测定、实时定量RT-PCR,酶活性测定等生物化学和分子生物学技术和方法,研究了SO2对大鼠血管组织中eNOS-NO-cGMP信号转导途径的调节作用。
研究结果显示：(1)静脉注入SO2 (20、60μmol·kg-1体重)可迅速引起大鼠血压剂量依赖性下降；(2) SO2 (1-2000μmol·L-1)对血管的舒张作用是剂量依赖性的,SO2在低浓度(<450μmol·L-1)下诱发的血管舒张作用是内皮依赖性的,而在高浓度(>500μmol·L-1)下引起的血管舒张作用是非内皮依赖性的。(3)SO2生理盐水溶液对大鼠血管的舒张作用是SO2分子直接作用引起的,而不是亚硫酸盐和亚硫酸氢盐引起的,SO2引起的血管舒张曲线特征与亚硫酸盐和亚硫酸氢盐引起的曲线不同；(4)SO2引起的血管舒张效应不是由于自主的或者非肾上腺素能的和类胆碱能的(NANC)神经末端对神经递质的释放,也不是由于血管组织产生的过氧化物和过氧化氢,也不涉及前列环素、PKC、β-肾上腺素及cAMP途径；(5)SO2在低浓度(<450μmol·L-1)下诱发的血管舒张作用是被cGMP途径所介导；(6)极低浓度的SO2(3μM)和NO(3 or 5nM)之间对血管平滑肌舒张存在协同效应。(7)SO2能增强血管内皮eNOS的活性,但不能增强iNOS的活性；SO2还能在转录水平和翻译水平促进大鼠血管eNOS基因的表达；(8)SO2能促进大鼠动脉血管NO的生成,引起血管cGMP水平增加,但不能引起cAMP水平的改变；(9)整体实验表明,静脉注入乳酸、丙酮酸(120、300μmol·kg-1体重)可迅速引起大鼠血压剂量依赖性下降；静脉注入氨水(8μmol·kg-1体重)大鼠血压显著升高,而静脉注射(20μmol·kg-1体重)剂量的氨水后引起大鼠血压迅速下降; (10)氨对大鼠胸主动脉血管环的作用比较复杂,在100μmol·L-1下对血管张力未见显著影响,在0.5-3mmol·L-1对血管有收缩效应且与低浓度SO2的舒张效应有拮抗作用；而高浓度氨(5-8mmol·L-1)能引起血管舒张,其与SO2的舒张效应具有独立联合作用；(11)乳酸在较低浓度和高浓度下均可以引起大鼠胸主动脉血管环舒张,其舒张血管的机制部分地与NO/cGMP信号转导途径和KATP离子通道有关,其与SO2舒张作用的机制有所不同,二者的联合作用可能属于独立联合作用。(12)丙酮酸在生理浓度时对大鼠胸主动脉血管环张力未见影响,在较低浓度和高浓度下均可以引起血管舒张,其机制均与L-型钙通道有关,但低浓度时的舒张血管效应还与NO/cGMP信号途径、小电导钙激活的钾离子通道(SKca)有关,而高浓度时还与ATP敏感的钾离子通道(KATP)有关。丙酮酸与SO2舒张效应的机制有所不同,二者的联合作用可能属于独立作用类型。
从这些实验结果可以得出如下结论：(1)SO2在低浓度下可以引起大鼠主动脉内皮依赖性血管舒张,而在高浓度下引起的血管舒张作用是非内皮依赖性的。生理浓度的内源性SO2是血管活性因子,可以与NO起协同作用共同调节血管平滑肌的张力,血管组织中的SO2和NO可能存在着某种形式的“交叉对话”；(2)SO2(1-2000μmol·L-1)对血管的舒张作用是剂量依赖性的。SO2舒血管作用不仅远大于亚硫酸盐和亚硫酸氢盐,而且舒张机制也不同,表明亚硫酸盐和亚硫酸氢盐是SO2血管活性作用失活过程的产物；(3)SO2能够上调主动脉eNOS-NO-cGMP信号转导途径,对该通路既有急性效应又有延时效应；SO2所引起的血管舒张作用部分地被其对eNOS-NO-cGMP通路的急性效应所介导,而SO2对血管收缩的抑制作用部分地被其对eNOS-NO-cGMP通路的延时效应所介导；(4)氨对血管的效应比较复杂,低浓度氨引起的血管收缩作用可与SO2引起的血管舒张作用相互拮抗,共同调节血管张力；(5)乳酸和丙酮酸也能引起血管舒张,低浓度下对血管有保护作用,而高浓度下可与SO2对血管的舒张作用叠加。因此,在对SO2进行健康评价时应考虑其与内源性小分子化合物的联合作用。
Sulfur dioxide (SO2) and its derivatives sulfite and bisulfite are common gaseous pollutants in the atmosphere. The previous studies have revealed that SO2 and its derivatives are systemic toxins, which may cause many kinds of toxicological effects in multiple organs of mammals. The epidemiological studies found that SO2 and its derivatives are correlative with the cardiovascular diseases. SO2 and its derivatives are also, however, endogenously generated from sulfur-containing amino acids and the intracellular hydrogen sulfide (H2S) in vivo. SO2 derivatives sulfite and bisulfite can be oxidized by sulfite oxidase to sulfate and excreted in urine.
Since the early 1980s, Nitric oxide (NO), carbon monoxide (CO) and H2S are discovered to be biological gas transmitters, which play a number of important physiological and toxicological roles. By analogy to these gases, SO2 is hypothesized to have physiological and toxicological role in cardiovascular system in human and mammal. In a previous study, it was showed that rat blood pressure could be lowered by SO2 and its derivatives bisulfite and sulfite, SO2 derivatives caused the vasodilatory effect of isolated rat aortic rings in vitro. To date, however, the cardiovascular effects of SO2, a known precursor of bisulfite and sulfite have not been studied. The mechanisms underlying the vascular effect of SO2 are not understood yet. The effect of SO2 on isolated vascular rings in vitro remains to be elucidated. Whether the vascular effects of SO2 are mediated by vasoactive factors released from the endothelium or peripheral nerve endings, e.g., nonadrenergic and noncholinergic (NANC) nerves, is not clear. The interaction of SO2 with different cellular signaling pathways in vascular tissues, including cGMP and oxygen-derived free radicals, has not been examined. The combined effects of endogenous small molecular chemicals and SO2 on the ring tension were rarely studied.
The objective of the present study is to explore the physiological and toxicological role of SO2 on vascular contractility and its underlying cellular and molecular mechanisms, we systematically examined the roles of the endothelium, and vasodilation experiment of isolated rat thoracic aortic rings by SO2 was carried out and the signal transduction pathways involved in the vascular effects of SO2 were investigated. Effects of the in vivo small molecular chemicals ammonia, lactic acid, or pyruvic acid on the ring tension and the combined effects of SO2 with these chemicals were studied in order to evaluate correctly the toxicological role of SO2 on human health.
In the present studies, isolated rat thoracic aortic rings were exposed directly to SO2 gas or SO2 gas-bubbled saline (SO2 stock solution), and effects of inhibitors of different signal transduction pathways and different ion channels for vasorelaxation of SO2 on the rings were investigated. At one time, relationship between vasorelaxation and pH decrease of Krebs solution caused by SO2 was studied using anology method. The vasodilatory effects of ammonia, lactic acid and pyruvic acid on the rings and its mechanisms were also studied with same methods mentioned above. Moreover, effects of SO2 on eNOS-NO-cGMP pathway in rat vascular tissues were studied with histopathological and immunohistochemical analysis, and biochemical and molecular biological technique and methods, for example, radioimmunoassay, real-time quantitative RT-PCR and so on.
The results show:(1) The venous transfusion of SO2 (20,60μmol·kg-1w.t.) lowered rapidly blood pressure in a dose-dependent manner in rats; (2) SO2 relaxed rat thoracic aortic rings in a dose-dependent manner (from 1 to 2000μmol·L-1). The vasorelaxant effect of SO2 at low concentrations (<450μmol·L-1) was endothelium-dependent, and at high concentrations (>500μmol·L-1) was endothelium-independent. (3) The vasorelaxation by addition of SO2 stock solution (final concentrations≤2 mM) was actually caused by SO2 molecules, not by sulfite or bisulfite, and the characteristic of vasorelaxation by SO2 were different from that of sulfite and bisulfite. (4) The vasorelaxant effect of SO2 was not due to the altered neurotransmitter release from the autonomous or nonadrenergic and noncholinergic (NANC) nerve endings, also not due to superoxide and hydrogen peroxide produced in the vascular tissues, also disapproving the involvement of prostaglandin, PKC,β-adrenoceptor and cAMP pathways. (5) The vasorelaxant effect of SO2 at low concentrations was mediated by the cGMP pathway. (6) There was the synergistic effect on smooth muscle relaxation between much lower concentrations of SO2 (3μM) and NO (3 or 5nM). (7) SO2 could increase activity of endothelial nitric oxide synthase (eNOS), but not of induced NOS (iNOS); Also it potentiated expression of eNOS gene on the transcription and translation levels in rat aorta; (8) SO2 enhanced nitric oxide (NO) formation in aortic tissue, level of cGMP in rat aorta, but no change of cAMP. (9) The venous transfusion of lactic acid or pyruvic acid (120、300μmol·kg-1w.t.) could rapidly cause a decrease of rat blood pressure in a dose-dependent manner in vivo; The venous transfusion of ammonia at 8μmol·kg-1w.t. caused obviously an increase of rat blood pressure, but at 20μmol·kg-1w.t. caused rapidly a decrease of rat blood pressure; (10) The role of ammonia on rat thoracic aortic rings was complexity, effect of ammonia at 100μmol·L-1 on the vascular tension was not notable, at 0.5-3mmol·L-1 caused a vasoconstriction response and the antagonistic effect to vasorelaxation by SO2 was observed; at higher concentrations(5-8mmol·L-1)caused vasorelaxation and the independent joint action between the vasorelaxations by higher ammonia and SO2 was found; (11) Lactic acid relaxed rat thoracic aortic rings in a dose-dependent manner, the vasorelaxation was partially mediated by the NO/cGMP pathway and ATP-Sensitive K+(KATP) Channels. The mechanisms of vasorelaxation by lactic acid were not whole similar to that of SO2, and the joint action of their vasorelaxation might be the independent joint action; (12) Effect of pyruvic acid at physiological concentrations on rat vascular ring tension was not found. Pyruvic acid at both lower and higher concentrations caused vasorelaxation, which was partially mediated by by L-type calcium-channels. However, the vasorelaxation by pyruvic acid at lower concentrations was also mediated by the NO/cGMP pathway and small-conductance Ca2+-activated K+(SKCa) channels, the vasorelaxation by pyruvic acid at higher concentrations was also mediated by KATP Channels. The mechanisms of vasorelaxation by pyruvic acid were not whole similar to that of SO2, and the joint action of their vasorelaxation might be the independent joint action.
These findings led to the conclusions:(1) SO2 at low concentrations might cause the endothelium-dependent vasodilation, at high concentrations caused the endothelium-independent vasodilation, which might be a toxic effect on vascular tissues. Endogenous SO2 at physiological concentrations was a vasoactive factor, which might regulate vascular smooth muscle tone in synergy with NO, suggesting there was some forms of "cross-talks" between SO2 and NO in vascular tissue; (2) The vasorelaxation effect was caused by SO2 (1-2000μmol·L-1) in a dose-dependent manner. Not only the effect by SO2 was much greater than that of sulfite and bisulfite, and that the mechanisms of their vasorelaxations were also different, suggesting sulfite and bisulfite were metabolic products in inactivity process of SO2 as a vasoactive substance; (3) There were acute and prolonged effects of SO2 on the NO/cGMP signalling pathway; SO2 could upregulate the eNOS-NO-cGMP pathway and at least partly by which the SO2 might cause vasodilation and inhibition to vasoconstriction; (4) The effect of ammonia on rat thoracic aortic rings was complicated, the vascular tension might be regulated together by the antagonistic effect between vasoconstriction by ammonia at lower concentrations and vasorelaxation by SO2, but ammonia at high concentrations could cause vasorelaxation and potentiate the vasorelaxation by SO2; (5) The vasorelaxation was also caused by lactic acid and pyruvic acid in a dose-dependent manner, the both endogenous chemicals at lower concentrations might execute a protective role on blood vessels, and at high concentrations might potentiate the vasorelaxation by SO2. Therefore, the combined toxic effects of SO2 and endogenous small molecular chemicals on the cardiovascular system should be considered when the influence of SO2 on human health is evaluated.
从上世纪80年代以来,一氧化氮(NO)、一氧化碳(CO)、及硫化氢(H2S)等有毒气体分子先后被发现是生物气体信号分子,具有扩张血管、抑制细胞增殖等多种重要的生理学和毒理学作用。与这些有毒气体相比,设想同样作为有毒气体的SO2可能也是一种生物气体信号分子,在人和哺乳动物的心血管系统具有多种生理和毒理学作用。在以前的研究中,发现SO2及其衍生物亚硫酸盐和亚硫酸氢盐均可引起大鼠血压下降、SO2衍生物可引起离体大鼠胸主动脉血管环的舒张。然而,迄今作为亚硫酸盐和亚硫酸氢盐前体物的SO2的心血管效应尚未见报道,SO2对心血管效应的机制尚不了解,SO2对离体血管环的作用仍然有待阐明,SO2的心血管效应是否被血管内皮或周围神经末梢释放的血管活性因子所介导也未可知,SO2与血管组织中不同细胞信号途径之间的相互作用,例如cGMP途径和氧自由基,尚未见研究。此外,SO2与内源小分子化合物对血管张力的联合效应也很少研究。
本研究的目的是探讨SO2对血管张力的生理学和毒理学作用及其细胞和分子机制,为此我们全面地研究了在此过程中血管内皮的作用,进行了SO2对离体大鼠胸主动脉血管环的舒张实验及其有关信号转导途径的研究。为了探讨SO2与体内小分子化合物氨、乳酸、丙酮酸之间在对血管收缩性方面有无相互作用,以便正确评价SO2对人体的毒性作用,本论文还研究了这些化合物对血管张力的影响及其与SO2的联合作用。
在本研究中,采用将气态SO2或SO2生理盐水溶液加入孵育液的方法,使SO2直接作用于离体大鼠胸主动脉血管环,同时使用不同信号转导途径抑制剂和不同离子通道抑制剂,研究SO2诱发血管舒张的信号转导机制,并采用类比法研究SO2对溶液pH的影响及其与血管舒张的关系。除此之外,还应用组织病理和免疫化学分析,以及放射免疫测定、实时定量RT-PCR,酶活性测定等生物化学和分子生物学技术和方法,研究了SO2对大鼠血管组织中eNOS-NO-cGMP信号转导途径的调节作用。
研究结果显示：(1)静脉注入SO2 (20、60μmol·kg-1体重)可迅速引起大鼠血压剂量依赖性下降；(2) SO2 (1-2000μmol·L-1)对血管的舒张作用是剂量依赖性的,SO2在低浓度(<450μmol·L-1)下诱发的血管舒张作用是内皮依赖性的,而在高浓度(>500μmol·L-1)下引起的血管舒张作用是非内皮依赖性的。(3)SO2生理盐水溶液对大鼠血管的舒张作用是SO2分子直接作用引起的,而不是亚硫酸盐和亚硫酸氢盐引起的,SO2引起的血管舒张曲线特征与亚硫酸盐和亚硫酸氢盐引起的曲线不同；(4)SO2引起的血管舒张效应不是由于自主的或者非肾上腺素能的和类胆碱能的(NANC)神经末端对神经递质的释放,也不是由于血管组织产生的过氧化物和过氧化氢,也不涉及前列环素、PKC、β-肾上腺素及cAMP途径；(5)SO2在低浓度(<450μmol·L-1)下诱发的血管舒张作用是被cGMP途径所介导；(6)极低浓度的SO2(3μM)和NO(3 or 5nM)之间对血管平滑肌舒张存在协同效应。(7)SO2能增强血管内皮eNOS的活性,但不能增强iNOS的活性；SO2还能在转录水平和翻译水平促进大鼠血管eNOS基因的表达；(8)SO2能促进大鼠动脉血管NO的生成,引起血管cGMP水平增加,但不能引起cAMP水平的改变；(9)整体实验表明,静脉注入乳酸、丙酮酸(120、300μmol·kg-1体重)可迅速引起大鼠血压剂量依赖性下降；静脉注入氨水(8μmol·kg-1体重)大鼠血压显著升高,而静脉注射(20μmol·kg-1体重)剂量的氨水后引起大鼠血压迅速下降; (10)氨对大鼠胸主动脉血管环的作用比较复杂,在100μmol·L-1下对血管张力未见显著影响,在0.5-3mmol·L-1对血管有收缩效应且与低浓度SO2的舒张效应有拮抗作用；而高浓度氨(5-8mmol·L-1)能引起血管舒张,其与SO2的舒张效应具有独立联合作用；(11)乳酸在较低浓度和高浓度下均可以引起大鼠胸主动脉血管环舒张,其舒张血管的机制部分地与NO/cGMP信号转导途径和KATP离子通道有关,其与SO2舒张作用的机制有所不同,二者的联合作用可能属于独立联合作用。(12)丙酮酸在生理浓度时对大鼠胸主动脉血管环张力未见影响,在较低浓度和高浓度下均可以引起血管舒张,其机制均与L-型钙通道有关,但低浓度时的舒张血管效应还与NO/cGMP信号途径、小电导钙激活的钾离子通道(SKca)有关,而高浓度时还与ATP敏感的钾离子通道(KATP)有关。丙酮酸与SO2舒张效应的机制有所不同,二者的联合作用可能属于独立作用类型。
从这些实验结果可以得出如下结论：(1)SO2在低浓度下可以引起大鼠主动脉内皮依赖性血管舒张,而在高浓度下引起的血管舒张作用是非内皮依赖性的。生理浓度的内源性SO2是血管活性因子,可以与NO起协同作用共同调节血管平滑肌的张力,血管组织中的SO2和NO可能存在着某种形式的“交叉对话”；(2)SO2(1-2000μmol·L-1)对血管的舒张作用是剂量依赖性的。SO2舒血管作用不仅远大于亚硫酸盐和亚硫酸氢盐,而且舒张机制也不同,表明亚硫酸盐和亚硫酸氢盐是SO2血管活性作用失活过程的产物；(3)SO2能够上调主动脉eNOS-NO-cGMP信号转导途径,对该通路既有急性效应又有延时效应；SO2所引起的血管舒张作用部分地被其对eNOS-NO-cGMP通路的急性效应所介导,而SO2对血管收缩的抑制作用部分地被其对eNOS-NO-cGMP通路的延时效应所介导；(4)氨对血管的效应比较复杂,低浓度氨引起的血管收缩作用可与SO2引起的血管舒张作用相互拮抗,共同调节血管张力；(5)乳酸和丙酮酸也能引起血管舒张,低浓度下对血管有保护作用,而高浓度下可与SO2对血管的舒张作用叠加。因此,在对SO2进行健康评价时应考虑其与内源性小分子化合物的联合作用。
Sulfur dioxide (SO2) and its derivatives sulfite and bisulfite are common gaseous pollutants in the atmosphere. The previous studies have revealed that SO2 and its derivatives are systemic toxins, which may cause many kinds of toxicological effects in multiple organs of mammals. The epidemiological studies found that SO2 and its derivatives are correlative with the cardiovascular diseases. SO2 and its derivatives are also, however, endogenously generated from sulfur-containing amino acids and the intracellular hydrogen sulfide (H2S) in vivo. SO2 derivatives sulfite and bisulfite can be oxidized by sulfite oxidase to sulfate and excreted in urine.
Since the early 1980s, Nitric oxide (NO), carbon monoxide (CO) and H2S are discovered to be biological gas transmitters, which play a number of important physiological and toxicological roles. By analogy to these gases, SO2 is hypothesized to have physiological and toxicological role in cardiovascular system in human and mammal. In a previous study, it was showed that rat blood pressure could be lowered by SO2 and its derivatives bisulfite and sulfite, SO2 derivatives caused the vasodilatory effect of isolated rat aortic rings in vitro. To date, however, the cardiovascular effects of SO2, a known precursor of bisulfite and sulfite have not been studied. The mechanisms underlying the vascular effect of SO2 are not understood yet. The effect of SO2 on isolated vascular rings in vitro remains to be elucidated. Whether the vascular effects of SO2 are mediated by vasoactive factors released from the endothelium or peripheral nerve endings, e.g., nonadrenergic and noncholinergic (NANC) nerves, is not clear. The interaction of SO2 with different cellular signaling pathways in vascular tissues, including cGMP and oxygen-derived free radicals, has not been examined. The combined effects of endogenous small molecular chemicals and SO2 on the ring tension were rarely studied.
The objective of the present study is to explore the physiological and toxicological role of SO2 on vascular contractility and its underlying cellular and molecular mechanisms, we systematically examined the roles of the endothelium, and vasodilation experiment of isolated rat thoracic aortic rings by SO2 was carried out and the signal transduction pathways involved in the vascular effects of SO2 were investigated. Effects of the in vivo small molecular chemicals ammonia, lactic acid, or pyruvic acid on the ring tension and the combined effects of SO2 with these chemicals were studied in order to evaluate correctly the toxicological role of SO2 on human health.
In the present studies, isolated rat thoracic aortic rings were exposed directly to SO2 gas or SO2 gas-bubbled saline (SO2 stock solution), and effects of inhibitors of different signal transduction pathways and different ion channels for vasorelaxation of SO2 on the rings were investigated. At one time, relationship between vasorelaxation and pH decrease of Krebs solution caused by SO2 was studied using anology method. The vasodilatory effects of ammonia, lactic acid and pyruvic acid on the rings and its mechanisms were also studied with same methods mentioned above. Moreover, effects of SO2 on eNOS-NO-cGMP pathway in rat vascular tissues were studied with histopathological and immunohistochemical analysis, and biochemical and molecular biological technique and methods, for example, radioimmunoassay, real-time quantitative RT-PCR and so on.
The results show:(1) The venous transfusion of SO2 (20,60μmol·kg-1w.t.) lowered rapidly blood pressure in a dose-dependent manner in rats; (2) SO2 relaxed rat thoracic aortic rings in a dose-dependent manner (from 1 to 2000μmol·L-1). The vasorelaxant effect of SO2 at low concentrations (<450μmol·L-1) was endothelium-dependent, and at high concentrations (>500μmol·L-1) was endothelium-independent. (3) The vasorelaxation by addition of SO2 stock solution (final concentrations≤2 mM) was actually caused by SO2 molecules, not by sulfite or bisulfite, and the characteristic of vasorelaxation by SO2 were different from that of sulfite and bisulfite. (4) The vasorelaxant effect of SO2 was not due to the altered neurotransmitter release from the autonomous or nonadrenergic and noncholinergic (NANC) nerve endings, also not due to superoxide and hydrogen peroxide produced in the vascular tissues, also disapproving the involvement of prostaglandin, PKC,β-adrenoceptor and cAMP pathways. (5) The vasorelaxant effect of SO2 at low concentrations was mediated by the cGMP pathway. (6) There was the synergistic effect on smooth muscle relaxation between much lower concentrations of SO2 (3μM) and NO (3 or 5nM). (7) SO2 could increase activity of endothelial nitric oxide synthase (eNOS), but not of induced NOS (iNOS); Also it potentiated expression of eNOS gene on the transcription and translation levels in rat aorta; (8) SO2 enhanced nitric oxide (NO) formation in aortic tissue, level of cGMP in rat aorta, but no change of cAMP. (9) The venous transfusion of lactic acid or pyruvic acid (120、300μmol·kg-1w.t.) could rapidly cause a decrease of rat blood pressure in a dose-dependent manner in vivo; The venous transfusion of ammonia at 8μmol·kg-1w.t. caused obviously an increase of rat blood pressure, but at 20μmol·kg-1w.t. caused rapidly a decrease of rat blood pressure; (10) The role of ammonia on rat thoracic aortic rings was complexity, effect of ammonia at 100μmol·L-1 on the vascular tension was not notable, at 0.5-3mmol·L-1 caused a vasoconstriction response and the antagonistic effect to vasorelaxation by SO2 was observed; at higher concentrations(5-8mmol·L-1)caused vasorelaxation and the independent joint action between the vasorelaxations by higher ammonia and SO2 was found; (11) Lactic acid relaxed rat thoracic aortic rings in a dose-dependent manner, the vasorelaxation was partially mediated by the NO/cGMP pathway and ATP-Sensitive K+(KATP) Channels. The mechanisms of vasorelaxation by lactic acid were not whole similar to that of SO2, and the joint action of their vasorelaxation might be the independent joint action; (12) Effect of pyruvic acid at physiological concentrations on rat vascular ring tension was not found. Pyruvic acid at both lower and higher concentrations caused vasorelaxation, which was partially mediated by by L-type calcium-channels. However, the vasorelaxation by pyruvic acid at lower concentrations was also mediated by the NO/cGMP pathway and small-conductance Ca2+-activated K+(SKCa) channels, the vasorelaxation by pyruvic acid at higher concentrations was also mediated by KATP Channels. The mechanisms of vasorelaxation by pyruvic acid were not whole similar to that of SO2, and the joint action of their vasorelaxation might be the independent joint action.
These findings led to the conclusions:(1) SO2 at low concentrations might cause the endothelium-dependent vasodilation, at high concentrations caused the endothelium-independent vasodilation, which might be a toxic effect on vascular tissues. Endogenous SO2 at physiological concentrations was a vasoactive factor, which might regulate vascular smooth muscle tone in synergy with NO, suggesting there was some forms of "cross-talks" between SO2 and NO in vascular tissue; (2) The vasorelaxation effect was caused by SO2 (1-2000μmol·L-1) in a dose-dependent manner. Not only the effect by SO2 was much greater than that of sulfite and bisulfite, and that the mechanisms of their vasorelaxations were also different, suggesting sulfite and bisulfite were metabolic products in inactivity process of SO2 as a vasoactive substance; (3) There were acute and prolonged effects of SO2 on the NO/cGMP signalling pathway; SO2 could upregulate the eNOS-NO-cGMP pathway and at least partly by which the SO2 might cause vasodilation and inhibition to vasoconstriction; (4) The effect of ammonia on rat thoracic aortic rings was complicated, the vascular tension might be regulated together by the antagonistic effect between vasoconstriction by ammonia at lower concentrations and vasorelaxation by SO2, but ammonia at high concentrations could cause vasorelaxation and potentiate the vasorelaxation by SO2; (5) The vasorelaxation was also caused by lactic acid and pyruvic acid in a dose-dependent manner, the both endogenous chemicals at lower concentrations might execute a protective role on blood vessels, and at high concentrations might potentiate the vasorelaxation by SO2. Therefore, the combined toxic effects of SO2 and endogenous small molecular chemicals on the cardiovascular system should be considered when the influence of SO2 on human health is evaluated.
引文
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