二氧化硫及其衍生物光谱特性及对血管张力作用的离子通道与信号转导机制
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摘要
二氧化硫是常见的大气污染物,以往研究表明二氧化硫不仅对呼吸系统有影响,而且对心血管系统及其它系统均有一定的毒害作用,因此它不仅是一种呼吸系统毒物而是一种全身性的毒物。现有资料表明,心脑血管疾病已经成为威胁人类健康的第一杀手。而以往的流行病学调查结果表明,二氧化硫及其衍生物与心血管系统的健康密切相关,二氧化硫暴露可以增加缺血性心脏疾病、心律失常等心血管疾病的患病风险和死亡率。因此,科研工作者越来越关注环境污染物二氧化硫与心脑血管疾病的关系。有关二氧化硫诱发心脑血管系统疾病的流行病学研究已经很多,但二氧化硫影响心脑血管疾病的作用机制却不够深入。继NO、CO、H2S被证明是气体信号分子之后,近年来有关研究不断表明二氧化硫可能是第四种气体信号分子。然而,有关二氧化硫及其衍生物的光谱特性研究及二氧化硫供体的研究却很少。为此,本研究运用紫外可见光光谱法和离体血管环技术等方法,重点研究了二氧化硫及其衍生物亚硫酸钠(Na2SO3)、亚硫酸氢钠(NaHSO3)、焦亚硫酸钠(Na2S2O5, SMB)的光谱特性及亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠对离体大鼠血管环舒张作用的离子通道和信号转导机制。通过这些研究,以探讨亚硫酸氢钠、焦亚硫酸钠作为二氧化硫供体进行生物学研究的可能,为二氧化硫作为气体信号分子的设想增添新的依据。
本研究对二氧化硫溶于水和有机溶剂时的吸收光谱特征进行研究,同时也对二氧化硫衍生物亚硫酸钠、亚硫酸氢钠和焦亚硫酸钠水溶液的吸收光谱特征进行研究,并探讨盐酸(HCl)对二氧化硫及其衍生物光谱性质的影响。研究结果表明：(1)二氧化硫在水、乙醇、甘油(含20%水)、正丁醇具有特征吸收峰,分别为276、277、276和278nm,表明二氧化硫在溶剂中的吸收峰主要取决于二氧化硫分子本身的物理化学性质。(2)二氧化硫在水中的吸收峰值远低于在有机溶剂中的吸收峰值,表明水对二氧化硫分子的光谱吸收具有一定的淬灭作用。(3)二氧化硫水溶液的特征吸收峰为276nm,焦亚硫酸钠和亚硫酸氢钠水溶液的特征吸收峰均为257nm,而亚硫酸钠水溶液在200～800nm范围内不具特征吸收峰,这表明二氧化硫衍生物的水溶液不存在二氧化硫或二氧化硫浓度很低。(4)盐酸、硫酸、硝酸、磷酸和醋酸均能增强二氧化硫水溶液的吸光强度,且呈浓度依赖关系：而氯化钾、氯化镁、氯化钠和氯化钙对二氧化硫水溶液的吸光强度有下降作用。结果表明,盐酸对二氧化硫溶于水中的吸光强度的增强作用是H+的作用而不是Cl-的作用。(5)焦亚硫酸钠、亚硫酸氢钠和亚硫酸钠水溶液加入盐酸后,均在276nm出现特征性吸收峰,表明盐酸与二氧化硫衍生物进行化学反应生成二氧化硫。(6)二氧化硫水溶液对环境和生物(包括人体)的作用是二氧化硫或水合二氧化硫所引起；而亚硫酸氢钠和焦亚硫酸钠水溶液的作用是HSO3所引起,亚硫酸钠溶液的作用是S032-所引起,为了增强二氧化硫衍生物的作用,向其溶液中加入H+是一个简单适宜的途径。(7)应用二氧化硫及其衍生物在溶剂中具有特征性吸收峰这一特点,可以采用简便易行的光谱分析方法测定溶液中二氧化硫的浓度及其动态变化。(8)亚硫酸氢钠或焦亚硫酸钠溶液加入适当浓度的H+可以作为毒理学和生理学研究和实践的“二氧化硫供体”。
本文同时对亚硫酸钠和亚硫酸氢钠的舒张血管机制进行了比较研究,结果发现(1)亚硫酸氢钠可以引起离体大鼠血管环的舒张,且在100～4000μmol·L-1之间呈浓度依赖性。与亚硫酸氢钠的舒张效应不同,亚硫酸钠在200μmol·L-1之下对离体大鼠血管环未见明显影响,在500～1000μmol·L-1引起离体大鼠血管环收缩,在2000～4000μmol·L-1则可引起大鼠离体血管环舒张。(2)亚硫酸氢钠的EC5o为2326±78.56μmol·L-1加入盐酸后亚硫酸氢钠的ECso则为2078±88.57μmol·L-1,表明加入盐酸后可以显著增强亚硫酸氢钠对离体大鼠血管环的舒张效应。(3)在低浓度下,亚硫酸氢钠对离体大鼠血管环的舒张效应与内皮有关；而在高浓度下,亚硫酸氢钠的舒张效应与内皮无关。这提示我们,亚硫酸氢钠的舒张机制在低浓度和高浓度下是不同的。(4)L型钙离子通道阻断剂硝苯地平能够部分地抑带2000.4000μmol·L-1亚硫酸氢钠对离体大鼠血管环的舒张反应,而对400μmol·L-1亚硫酸氢钠引起的舒张反应无显著影响。(5)非特异性钾通道阻断剂TEA可部分地抑制400、2000及4000μmol·L-1亚硫酸氢钠对血管环的舒张反应；大电导钙激活的钾通道(BKca)阻断剂IbTx可部分地抑制400.2000μmol·L-1亚硫酸氢钠对血管环的舒张反应,而对4000μmol·L-1亚硫酸氢钠引起的舒张效应没有明显影响；小电导钙离子激活的钾通道(SKCa)抑制剂蜂毒明肽和电压依赖型的钾通道(Kv)阻断剂4-AP对亚硫酸氢钠的舒张效应没有影响。ATP敏感的钾通道(KATP)阻断剂格列本脲可部分地抑制4000μmol·L-1亚硫酸氢钠对离体大鼠血管环的舒张反应,而对400、2000μmol·L-1亚硫酸氢钠引起的舒张反应无显著影响。(6)一氧化氮合酶抑制剂(L-NNA)和sGC抑制剂(NS-2028)可部分地抑制低浓度亚硫酸氢钠导致的舒张效应,而对高浓度亚硫酸氢钠诱导的舒张效应无明显影响。(7)蛋白激酶C抑制剂十字孢碱、前列环素PGI2抑制剂吲哚美辛、p-肾上腺素受体抑制剂普萘洛尔对亚硫酸氢钠诱导的舒张效应没有明显影响。
本文研究了焦亚硫酸钠对离体大鼠血管环的效应,结果发现焦亚硫酸钠可浓度依赖性的引起血管环的舒张。去除内皮后发现,在低浓度下(<400μmol·L-1)焦亚硫酸钠不能引起血管环的舒张,而在高浓度下(>500μmol·L-1可以导致血管环的舒张。这说明焦亚硫酸钠的舒张效应在低浓度下是内皮依赖性的或是内皮起主要作用,而在高浓度下焦亚硫酸钠的舒张效应与内皮无关或内皮不起主要作用。在低浓度下内皮依赖性的舒张最大约为20%,而在高浓度下非内皮依赖性的舒张则可达到90%以上。我们研究了L型钙离子通道对焦亚硫酸钠诱导的血管环舒张效应的影响。结果表明,硝苯地平能够部分地抑制1000μmol·L-1焦亚硫酸钠对离体大鼠血管环(内皮完整及去内皮)的舒张反应,而对50、200μmol·L-1焦亚硫酸钠引起的舒张反应无显著影响。这说明在高浓度焦亚硫酸钠诱导的舒张效应中,L型钙离子通道起了一定的作用。我们同时也研究了PGI2合成酶抑制剂吲哚美辛对焦亚硫酸钠诱导的舒张效应的影响。结果发现,吲哚美辛对焦亚硫酸钠诱导的舒张效应没有明显影响。为了解钾离子通道在焦亚硫酸钠诱导的舒张效应中所起的作用,我们用多种不同的钾离子通道阻断剂TEA、4-AP、IbTx、蜂毒明肽和格列本脲预先温育血管环20min、然后观察其对焦亚硫酸钠诱导的舒张效应的影响。结果发现：(1)高浓度及低浓度焦亚硫酸钠诱导的舒张效应均部分地被TEA所抑制。(2) IbTx可以部分地抑制J50、200μmol·L-1焦亚硫酸钠诱导的舒张效应,表明BKca离子通道在低浓度焦亚硫酸钠诱导的舒张效应中可能有一定的作用,而对高浓度焦亚硫酸钠诱导的舒张效应不起作用或作用很小。蜂毒明肽对焦亚硫酸钠诱导的舒张效应没有明显影响,表明焦亚硫酸钠的舒张效应与小电导该激活钾离子通道无关。(3)KATP通道阻断剂格列本脲可部分地抑制1000μmol·L-1焦亚硫酸钠对离体大鼠血管环(内皮完整及去内皮)的舒张反应,而对50、200μmol·L-1焦亚硫酸钠引起的舒张反应无显著影响。这表明KATp通道与高浓度焦亚硫酸钠诱导的舒张效应有关,而对低浓度焦亚硫酸钠诱导的舒张效应无关或作用很小。(4)4-AP对焦亚硫酸钠诱导的舒张效应没有明显影响,表明Kv通道在焦亚硫酸钠诱导的舒张作用中不起作用或作用很小。我们分别用sGC抑制剂NS-2028和NOS抑制剂L-NNA预先温育血管环。结果发现,NS-2028和L-NNA对血管环的基础张力没有影响。而对低浓度焦亚硫酸钠诱导的舒张效应有部分抑制作用。这表明低浓度的焦亚硫酸钠舒张效应与cGMP途径有关,而高浓度的焦亚硫酸钠舒张效应与cGMP途径无关。焦亚硫酸钠的舒张效应与PKC, PGI2, β-1肾上腺素受体途径无关。
综合以上实验可得出如下结论：(1)二氧化硫及其衍生物的光谱特性是不同的,其中二氧化硫在水中的特征吸收峰为276nm,亚硫酸氢钠和焦亚硫酸钠水溶液的特征吸收峰均为257nm,亚硫酸钠水溶液在200～800nm之间未表现出特征吸收峰。(2)二氧化硫衍生物亚硫酸氢钠、亚硫酸钠和焦亚硫酸钠对离体大鼠血管环的舒张效应并不相同,其中亚硫酸钠表现为低浓度收缩,高浓度舒张；而亚硫酸氢钠和焦亚硫酸钠则均表现为舒张效应,且焦亚硫酸钠对离体大鼠血管环的舒张效应要大于亚硫‘酸氢钠。(3)亚硫酸氢钠或焦亚硫酸钠在低浓度下的舒张效应是内皮依赖性的,其舒张途径部分地与cGMP途径和BKO。离子通道有关；亚硫酸氢钠或焦亚硫酸钠在高浓度下的舒张效应与内皮无关,可能与KATP和L型Ca2+通道部分地有关。亚硫酸氢钠或焦亚硫酸钠的舒张效应与PKC, PGI2,p-肾上腺素受体途径无关。(4)在加入适当H+情况下,焦亚硫酸钠或亚硫酸氢钠可以用作二氧化硫供体进行毒理学等方面的研究。
As we know, sulfur dioxide (SO2) is a common gaseous pollutant. Our previous studies showed that SO2and its derivatives are systemic toxins, which may cause many kinds of toxicological effects not only in respiratory system but also other system of mammals. Epidemiological studies have shown that SO2was correlative with the cardiovascular diseases such as ischemic heart diseases, myocardial ischemia, spontaneous hypertension, and hypoxic pulmonary hypertension. Compared with epidemiological studies, little research has been made on the mechanism of SO2induced cardiovascular diseases. Our recent studies demonstrated that gaseous SO2had a biological role in regulating cardiovascular functions, and SO2could cause relaxation of rat thoracic aortic rings in a concentration-dependent manner. Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) were considered as gasotransmitters. Recent studies found that SO2was may be the fourth endogenous gaseous transmitter in the cardiovascular system. To the best of our knowledge, few publications tried to show the spectra of SO2and its derivatives. In present study, the absorption spectra of SO2, sodium sulfite (Na2SO3), sodium bisulfite (NaHSO5) and sodium metabisulfite (Na2S2O5, SMB) in aqueous solution were studied. At the same time, the vasodilator effects and its ion channel and signal transduction mechanisms of Na2SO3, Na2S2O5and NaHSO3on isolated rat aortic rings were investigated.
In present paper, we investigated the absorption spectra of SO2, sodium sulfite, sodium bisulfite and sodium metabisulfite in aqueous solution. In the meanwhile, the effects of HCl on spectral properties of SO2and its derivatives were also investigated. The results showed that:(1) Sulfur dioxide in water, ethanol, n-butyl-alcohol and glycerol had a characteristic absorption peak at276,277,276and278nm respectively.(2) The absorption value of SO2in water was much smaller than in ethanol, n-butyl-alcohol and glycerol. We attributed the absorbing power of SO2to SO2molecule, rather than hydrated sulfur dioxide.(3) Na2S2O5and NaHS03exhibited a characteristic absorption peak at257nm. Na2SO3solution did not show a characteristic absorption from200to800nm.(4) The absorption of SO2at276nm was strongly enhanced in the presence of HC1, H2SO4, HNO3, H3PO4and HAc but not KC1, MgCl2, NaCl and CaCl2solution. The absorption of SO2strongly enhanced by HCl at276nm was due to H+, instead of the formation of a complex SO2Cl-.(5) NaHSO3, Na2SO3and Na2S2O5also exhibited an absorption at276nm with the addition of HC1, which was enhanced with the increase of HCl concentration.(6) NaHSO3and Na2S2O5solution in presence of H+may be acted as a donor of SO2in biology and other area.
To study the biological role of bisulfite on vascular contractility and its underlying cellular and molecular mechanisms, and to explore whether bisulfite can be used as a SO2donor in the biological experiments, the vasorelaxant effects of sodium bisulfite and sodium sulfite on isolated rat thoracic aortic rings were compared; and the signal transduction pathways and the ion channels involved in the vascular effects of bisulfite were investigated. The results showed that:(1) Sodium bisulfite relaxed rat thoracic aortic rings in a concentration-dependent manner (from100to4000μM); however, sodium sulfite at500and1000μM caused vasoconstriction, and only at higher concentrations (from2000to4000μM) it caused vasorelaxation in a concentration-dependent manner.(2) The EC50values of vasorelaxation effects induced by NaHSO3solution with and without200μM HCl were2078±88.57μM and2326±78.56μM, respectively. The vasorelaxation of isolated rat thoracic aortic rings induced by NaHSO3solution with HCl added was stronger than that of NaHSO3solution without HC1.(3) The vasorelaxation caused by the bisulfite at low concentrations (<500μM) was endothelium-dependent, but at high concentrations (>1000μM) it was endothelium-independent.(4) The vasorelaxant effects induced by the high concentrations (2000,4000μM) NaHSO3solution were partially inhibited by nifedipine (an L-type Ca2+channel blocker). But the vasorelaxant effects induced by the low concentration (400μM) NaHSO3solution were not affected by nifedipine.(5) The vasorelaxant effects induced by NaHSO3at low concentration were partially inhibited by TEA (many different types of K+channel inhibitor) or iberiotoxin (BKCa channel inhibitor), but not by glibenclamide (KATP channel inhibitor). The vasorelaxant effects induced by NaHSO3at high concentrations were partially inhibited by TEA or glibenclamide, but not by iberiotoxin.(6) The vasorelaxation induced by NaHSO3at low concentrations was virtually abolished by L-NNA or NS-2028. However, the vasorelaxation induced by NaHSO3at high concentrations was not altered by L-NNA or NS-2028.(7) Indomethacin (an inhibitor of cycloxygenase, one of PGl2-synthetases) or staurosporine (an inhibitor of PKC) or propranolol (an antagonist of P-noradrenoceptor) did not change the vasorelaxation effect of NaHSO3on isolated rat aortic rings.
In the present paper, the vasodilator effects of Na2S2O5and roles of Ca2+and K+channels as well as the cGMP pathway on isolated rat aortic rings were studied. The results show that the removal of functional endothelium abolished the relaxation response to Na2S2O5at low concentrations (<400μM), indicating that vasorelaxation was endothelium-dependent. However, Na2S2O5at high concentrations (>500μM) caused vasorelaxation of both endothelium-intact and endothelium-denuded rings, indicating that the vasorelaxation was endothelium-independent. The maximal endothelium-dependent vasorelaxation of Na2S2O5was rather smaller, approximately20%in comparison with those not depending on the presence of the endothelium was more than90%. We also studied the role of L-type calcium channels in Na2S2O5-induced vasorelaxation. The result showed that the vasorelaxant effects of1000μM Na2S2O5on both endothelium-intact and endothelium-denuded rings were partially inhibited by nifedipine. The relaxation effect induced by1000μM Na2S2O5in presence of1μM nifedipine was lower than that in absence of1μM nifedipine, which suggested a possible involvement of L-type Ca2+channels. We investigated the role of indomethacin in the vasorelaxation effect of Na2S2O5. The result showed that the treatment of indomethacin did not affect the vasorelaxation of Na2S2O5at low and high concentrations, which suggested that the vasorelaxant effect of Na2S2O5was not mediated by PGI2. To clarify the potential involvement of K+channels, aortic rings were pre-incubated with10mM TEA,2.5mM4-AP,100nM iberiotoxin,50nM apamin and10μM glibenclamide for20min prior to the application of Na2S2O5, respectively. The results showed that (1) The Na2S2O5-induced vasorelaxation was partially inhibited by TEA that blocked many K+channels in vascular SMCs, including Kca, Kv and KATP channels. Blocker of Kv channel failed to affect the vascular effects of Na2S2O5.(2) Iberiotoxin partially inhibited the50,200μM Na2S2O5-induced vasorelaxation for the endothelium-intact rings, suggesting that BKCa channels might be responsible for the low concentrations Na2S2O5-induced vasorelaxation. The Na2S2O5-induced vasorelaxation was not affected by apamin, suggesting that small-conductance KCa channels might not be responsible for the Na2S2O5-induced vasorelaxation.(3) Glibenclamide partially inhibited the1000μM Na2S2O5-induced vasorelaxation for both endothelium-intact and endothelium-denuded rings, showing that KATP channel might be attributed to the high concentrations Na2S2O5-induced vasorelaxation.(4) The relaxant effect of Na2S2O5was not affected by4-AP. These results suggested that opening of K+channels (BKCa and KATP) might contribute to the vasorelaxant effect of Na2S2O5. To examine whether the Na2S2O5-induced vasorelaxation was mediated by cGMP pathway, we studied the vascular effect of Na2S2O5in the presence of the sGC inhibitors NS-2028and the NO synthase inhibitor L-NNA, respectively. Relaxation induced by low concentrations Na2S2O5was virtually abolished by L-NNA or NS-2028. However, the high concentrations Na2S2O5-induced relaxation was not altered by L-NNA or NS-2028.
In summary, these findings led to the conclusions:(1) Spectral properties of sulfur dioxide and its derivatives dissolved in water were different. Sulfur dioxide in water had a characteristic absorption peak at276rm. And the characteristic aborption peak of Na2S2O5and NaHSO3were257nn. Na2SO3solution did not show a characteristic absorption from200to800nm.(2) The vasodilator effects of Na2SO3, Na2S2O5and NaHSO3on isolated rat aortic rings were different. Na2S2O5or NaHSO3caused relaxation of isolated rat thoracic aortic rings in a concentration-dependent manner. However, Na2SO3could cause constriction in low concentration (<2mM) and relaxation in high concentration.(3) The vasorelaxation of Na2S2O5or NaHSO3at low concentrations was endothelium-dependent and mediated by the cGMP pathway and BKca channel, but that at high concentrations was endothelium-independent and mediated by KATP and L-type Ca2+channels. The vasorelaxant effect of Na2S2O5or NaHSO3was disproved the involvement of PKC, PGI2and β-adrenoceptor pathways.(4) Na2S2O5or NaHSO3in presence of H+can be used as a SO2donor for the study of SO2biology.
本研究对二氧化硫溶于水和有机溶剂时的吸收光谱特征进行研究,同时也对二氧化硫衍生物亚硫酸钠、亚硫酸氢钠和焦亚硫酸钠水溶液的吸收光谱特征进行研究,并探讨盐酸(HCl)对二氧化硫及其衍生物光谱性质的影响。研究结果表明：(1)二氧化硫在水、乙醇、甘油(含20%水)、正丁醇具有特征吸收峰,分别为276、277、276和278nm,表明二氧化硫在溶剂中的吸收峰主要取决于二氧化硫分子本身的物理化学性质。(2)二氧化硫在水中的吸收峰值远低于在有机溶剂中的吸收峰值,表明水对二氧化硫分子的光谱吸收具有一定的淬灭作用。(3)二氧化硫水溶液的特征吸收峰为276nm,焦亚硫酸钠和亚硫酸氢钠水溶液的特征吸收峰均为257nm,而亚硫酸钠水溶液在200～800nm范围内不具特征吸收峰,这表明二氧化硫衍生物的水溶液不存在二氧化硫或二氧化硫浓度很低。(4)盐酸、硫酸、硝酸、磷酸和醋酸均能增强二氧化硫水溶液的吸光强度,且呈浓度依赖关系：而氯化钾、氯化镁、氯化钠和氯化钙对二氧化硫水溶液的吸光强度有下降作用。结果表明,盐酸对二氧化硫溶于水中的吸光强度的增强作用是H+的作用而不是Cl-的作用。(5)焦亚硫酸钠、亚硫酸氢钠和亚硫酸钠水溶液加入盐酸后,均在276nm出现特征性吸收峰,表明盐酸与二氧化硫衍生物进行化学反应生成二氧化硫。(6)二氧化硫水溶液对环境和生物(包括人体)的作用是二氧化硫或水合二氧化硫所引起；而亚硫酸氢钠和焦亚硫酸钠水溶液的作用是HSO3所引起,亚硫酸钠溶液的作用是S032-所引起,为了增强二氧化硫衍生物的作用,向其溶液中加入H+是一个简单适宜的途径。(7)应用二氧化硫及其衍生物在溶剂中具有特征性吸收峰这一特点,可以采用简便易行的光谱分析方法测定溶液中二氧化硫的浓度及其动态变化。(8)亚硫酸氢钠或焦亚硫酸钠溶液加入适当浓度的H+可以作为毒理学和生理学研究和实践的“二氧化硫供体”。
本文同时对亚硫酸钠和亚硫酸氢钠的舒张血管机制进行了比较研究,结果发现(1)亚硫酸氢钠可以引起离体大鼠血管环的舒张,且在100～4000μmol·L-1之间呈浓度依赖性。与亚硫酸氢钠的舒张效应不同,亚硫酸钠在200μmol·L-1之下对离体大鼠血管环未见明显影响,在500～1000μmol·L-1引起离体大鼠血管环收缩,在2000～4000μmol·L-1则可引起大鼠离体血管环舒张。(2)亚硫酸氢钠的EC5o为2326±78.56μmol·L-1加入盐酸后亚硫酸氢钠的ECso则为2078±88.57μmol·L-1,表明加入盐酸后可以显著增强亚硫酸氢钠对离体大鼠血管环的舒张效应。(3)在低浓度下,亚硫酸氢钠对离体大鼠血管环的舒张效应与内皮有关；而在高浓度下,亚硫酸氢钠的舒张效应与内皮无关。这提示我们,亚硫酸氢钠的舒张机制在低浓度和高浓度下是不同的。(4)L型钙离子通道阻断剂硝苯地平能够部分地抑带2000.4000μmol·L-1亚硫酸氢钠对离体大鼠血管环的舒张反应,而对400μmol·L-1亚硫酸氢钠引起的舒张反应无显著影响。(5)非特异性钾通道阻断剂TEA可部分地抑制400、2000及4000μmol·L-1亚硫酸氢钠对血管环的舒张反应；大电导钙激活的钾通道(BKca)阻断剂IbTx可部分地抑制400.2000μmol·L-1亚硫酸氢钠对血管环的舒张反应,而对4000μmol·L-1亚硫酸氢钠引起的舒张效应没有明显影响；小电导钙离子激活的钾通道(SKCa)抑制剂蜂毒明肽和电压依赖型的钾通道(Kv)阻断剂4-AP对亚硫酸氢钠的舒张效应没有影响。ATP敏感的钾通道(KATP)阻断剂格列本脲可部分地抑制4000μmol·L-1亚硫酸氢钠对离体大鼠血管环的舒张反应,而对400、2000μmol·L-1亚硫酸氢钠引起的舒张反应无显著影响。(6)一氧化氮合酶抑制剂(L-NNA)和sGC抑制剂(NS-2028)可部分地抑制低浓度亚硫酸氢钠导致的舒张效应,而对高浓度亚硫酸氢钠诱导的舒张效应无明显影响。(7)蛋白激酶C抑制剂十字孢碱、前列环素PGI2抑制剂吲哚美辛、p-肾上腺素受体抑制剂普萘洛尔对亚硫酸氢钠诱导的舒张效应没有明显影响。
本文研究了焦亚硫酸钠对离体大鼠血管环的效应,结果发现焦亚硫酸钠可浓度依赖性的引起血管环的舒张。去除内皮后发现,在低浓度下(<400μmol·L-1)焦亚硫酸钠不能引起血管环的舒张,而在高浓度下(>500μmol·L-1可以导致血管环的舒张。这说明焦亚硫酸钠的舒张效应在低浓度下是内皮依赖性的或是内皮起主要作用,而在高浓度下焦亚硫酸钠的舒张效应与内皮无关或内皮不起主要作用。在低浓度下内皮依赖性的舒张最大约为20%,而在高浓度下非内皮依赖性的舒张则可达到90%以上。我们研究了L型钙离子通道对焦亚硫酸钠诱导的血管环舒张效应的影响。结果表明,硝苯地平能够部分地抑制1000μmol·L-1焦亚硫酸钠对离体大鼠血管环(内皮完整及去内皮)的舒张反应,而对50、200μmol·L-1焦亚硫酸钠引起的舒张反应无显著影响。这说明在高浓度焦亚硫酸钠诱导的舒张效应中,L型钙离子通道起了一定的作用。我们同时也研究了PGI2合成酶抑制剂吲哚美辛对焦亚硫酸钠诱导的舒张效应的影响。结果发现,吲哚美辛对焦亚硫酸钠诱导的舒张效应没有明显影响。为了解钾离子通道在焦亚硫酸钠诱导的舒张效应中所起的作用,我们用多种不同的钾离子通道阻断剂TEA、4-AP、IbTx、蜂毒明肽和格列本脲预先温育血管环20min、然后观察其对焦亚硫酸钠诱导的舒张效应的影响。结果发现：(1)高浓度及低浓度焦亚硫酸钠诱导的舒张效应均部分地被TEA所抑制。(2) IbTx可以部分地抑制J50、200μmol·L-1焦亚硫酸钠诱导的舒张效应,表明BKca离子通道在低浓度焦亚硫酸钠诱导的舒张效应中可能有一定的作用,而对高浓度焦亚硫酸钠诱导的舒张效应不起作用或作用很小。蜂毒明肽对焦亚硫酸钠诱导的舒张效应没有明显影响,表明焦亚硫酸钠的舒张效应与小电导该激活钾离子通道无关。(3)KATP通道阻断剂格列本脲可部分地抑制1000μmol·L-1焦亚硫酸钠对离体大鼠血管环(内皮完整及去内皮)的舒张反应,而对50、200μmol·L-1焦亚硫酸钠引起的舒张反应无显著影响。这表明KATp通道与高浓度焦亚硫酸钠诱导的舒张效应有关,而对低浓度焦亚硫酸钠诱导的舒张效应无关或作用很小。(4)4-AP对焦亚硫酸钠诱导的舒张效应没有明显影响,表明Kv通道在焦亚硫酸钠诱导的舒张作用中不起作用或作用很小。我们分别用sGC抑制剂NS-2028和NOS抑制剂L-NNA预先温育血管环。结果发现,NS-2028和L-NNA对血管环的基础张力没有影响。而对低浓度焦亚硫酸钠诱导的舒张效应有部分抑制作用。这表明低浓度的焦亚硫酸钠舒张效应与cGMP途径有关,而高浓度的焦亚硫酸钠舒张效应与cGMP途径无关。焦亚硫酸钠的舒张效应与PKC, PGI2, β-1肾上腺素受体途径无关。
综合以上实验可得出如下结论：(1)二氧化硫及其衍生物的光谱特性是不同的,其中二氧化硫在水中的特征吸收峰为276nm,亚硫酸氢钠和焦亚硫酸钠水溶液的特征吸收峰均为257nm,亚硫酸钠水溶液在200～800nm之间未表现出特征吸收峰。(2)二氧化硫衍生物亚硫酸氢钠、亚硫酸钠和焦亚硫酸钠对离体大鼠血管环的舒张效应并不相同,其中亚硫酸钠表现为低浓度收缩,高浓度舒张；而亚硫酸氢钠和焦亚硫酸钠则均表现为舒张效应,且焦亚硫酸钠对离体大鼠血管环的舒张效应要大于亚硫‘酸氢钠。(3)亚硫酸氢钠或焦亚硫酸钠在低浓度下的舒张效应是内皮依赖性的,其舒张途径部分地与cGMP途径和BKO。离子通道有关；亚硫酸氢钠或焦亚硫酸钠在高浓度下的舒张效应与内皮无关,可能与KATP和L型Ca2+通道部分地有关。亚硫酸氢钠或焦亚硫酸钠的舒张效应与PKC, PGI2,p-肾上腺素受体途径无关。(4)在加入适当H+情况下,焦亚硫酸钠或亚硫酸氢钠可以用作二氧化硫供体进行毒理学等方面的研究。
As we know, sulfur dioxide (SO2) is a common gaseous pollutant. Our previous studies showed that SO2and its derivatives are systemic toxins, which may cause many kinds of toxicological effects not only in respiratory system but also other system of mammals. Epidemiological studies have shown that SO2was correlative with the cardiovascular diseases such as ischemic heart diseases, myocardial ischemia, spontaneous hypertension, and hypoxic pulmonary hypertension. Compared with epidemiological studies, little research has been made on the mechanism of SO2induced cardiovascular diseases. Our recent studies demonstrated that gaseous SO2had a biological role in regulating cardiovascular functions, and SO2could cause relaxation of rat thoracic aortic rings in a concentration-dependent manner. Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) were considered as gasotransmitters. Recent studies found that SO2was may be the fourth endogenous gaseous transmitter in the cardiovascular system. To the best of our knowledge, few publications tried to show the spectra of SO2and its derivatives. In present study, the absorption spectra of SO2, sodium sulfite (Na2SO3), sodium bisulfite (NaHSO5) and sodium metabisulfite (Na2S2O5, SMB) in aqueous solution were studied. At the same time, the vasodilator effects and its ion channel and signal transduction mechanisms of Na2SO3, Na2S2O5and NaHSO3on isolated rat aortic rings were investigated.
In present paper, we investigated the absorption spectra of SO2, sodium sulfite, sodium bisulfite and sodium metabisulfite in aqueous solution. In the meanwhile, the effects of HCl on spectral properties of SO2and its derivatives were also investigated. The results showed that:(1) Sulfur dioxide in water, ethanol, n-butyl-alcohol and glycerol had a characteristic absorption peak at276,277,276and278nm respectively.(2) The absorption value of SO2in water was much smaller than in ethanol, n-butyl-alcohol and glycerol. We attributed the absorbing power of SO2to SO2molecule, rather than hydrated sulfur dioxide.(3) Na2S2O5and NaHS03exhibited a characteristic absorption peak at257nm. Na2SO3solution did not show a characteristic absorption from200to800nm.(4) The absorption of SO2at276nm was strongly enhanced in the presence of HC1, H2SO4, HNO3, H3PO4and HAc but not KC1, MgCl2, NaCl and CaCl2solution. The absorption of SO2strongly enhanced by HCl at276nm was due to H+, instead of the formation of a complex SO2Cl-.(5) NaHSO3, Na2SO3and Na2S2O5also exhibited an absorption at276nm with the addition of HC1, which was enhanced with the increase of HCl concentration.(6) NaHSO3and Na2S2O5solution in presence of H+may be acted as a donor of SO2in biology and other area.
To study the biological role of bisulfite on vascular contractility and its underlying cellular and molecular mechanisms, and to explore whether bisulfite can be used as a SO2donor in the biological experiments, the vasorelaxant effects of sodium bisulfite and sodium sulfite on isolated rat thoracic aortic rings were compared; and the signal transduction pathways and the ion channels involved in the vascular effects of bisulfite were investigated. The results showed that:(1) Sodium bisulfite relaxed rat thoracic aortic rings in a concentration-dependent manner (from100to4000μM); however, sodium sulfite at500and1000μM caused vasoconstriction, and only at higher concentrations (from2000to4000μM) it caused vasorelaxation in a concentration-dependent manner.(2) The EC50values of vasorelaxation effects induced by NaHSO3solution with and without200μM HCl were2078±88.57μM and2326±78.56μM, respectively. The vasorelaxation of isolated rat thoracic aortic rings induced by NaHSO3solution with HCl added was stronger than that of NaHSO3solution without HC1.(3) The vasorelaxation caused by the bisulfite at low concentrations (<500μM) was endothelium-dependent, but at high concentrations (>1000μM) it was endothelium-independent.(4) The vasorelaxant effects induced by the high concentrations (2000,4000μM) NaHSO3solution were partially inhibited by nifedipine (an L-type Ca2+channel blocker). But the vasorelaxant effects induced by the low concentration (400μM) NaHSO3solution were not affected by nifedipine.(5) The vasorelaxant effects induced by NaHSO3at low concentration were partially inhibited by TEA (many different types of K+channel inhibitor) or iberiotoxin (BKCa channel inhibitor), but not by glibenclamide (KATP channel inhibitor). The vasorelaxant effects induced by NaHSO3at high concentrations were partially inhibited by TEA or glibenclamide, but not by iberiotoxin.(6) The vasorelaxation induced by NaHSO3at low concentrations was virtually abolished by L-NNA or NS-2028. However, the vasorelaxation induced by NaHSO3at high concentrations was not altered by L-NNA or NS-2028.(7) Indomethacin (an inhibitor of cycloxygenase, one of PGl2-synthetases) or staurosporine (an inhibitor of PKC) or propranolol (an antagonist of P-noradrenoceptor) did not change the vasorelaxation effect of NaHSO3on isolated rat aortic rings.
In the present paper, the vasodilator effects of Na2S2O5and roles of Ca2+and K+channels as well as the cGMP pathway on isolated rat aortic rings were studied. The results show that the removal of functional endothelium abolished the relaxation response to Na2S2O5at low concentrations (<400μM), indicating that vasorelaxation was endothelium-dependent. However, Na2S2O5at high concentrations (>500μM) caused vasorelaxation of both endothelium-intact and endothelium-denuded rings, indicating that the vasorelaxation was endothelium-independent. The maximal endothelium-dependent vasorelaxation of Na2S2O5was rather smaller, approximately20%in comparison with those not depending on the presence of the endothelium was more than90%. We also studied the role of L-type calcium channels in Na2S2O5-induced vasorelaxation. The result showed that the vasorelaxant effects of1000μM Na2S2O5on both endothelium-intact and endothelium-denuded rings were partially inhibited by nifedipine. The relaxation effect induced by1000μM Na2S2O5in presence of1μM nifedipine was lower than that in absence of1μM nifedipine, which suggested a possible involvement of L-type Ca2+channels. We investigated the role of indomethacin in the vasorelaxation effect of Na2S2O5. The result showed that the treatment of indomethacin did not affect the vasorelaxation of Na2S2O5at low and high concentrations, which suggested that the vasorelaxant effect of Na2S2O5was not mediated by PGI2. To clarify the potential involvement of K+channels, aortic rings were pre-incubated with10mM TEA,2.5mM4-AP,100nM iberiotoxin,50nM apamin and10μM glibenclamide for20min prior to the application of Na2S2O5, respectively. The results showed that (1) The Na2S2O5-induced vasorelaxation was partially inhibited by TEA that blocked many K+channels in vascular SMCs, including Kca, Kv and KATP channels. Blocker of Kv channel failed to affect the vascular effects of Na2S2O5.(2) Iberiotoxin partially inhibited the50,200μM Na2S2O5-induced vasorelaxation for the endothelium-intact rings, suggesting that BKCa channels might be responsible for the low concentrations Na2S2O5-induced vasorelaxation. The Na2S2O5-induced vasorelaxation was not affected by apamin, suggesting that small-conductance KCa channels might not be responsible for the Na2S2O5-induced vasorelaxation.(3) Glibenclamide partially inhibited the1000μM Na2S2O5-induced vasorelaxation for both endothelium-intact and endothelium-denuded rings, showing that KATP channel might be attributed to the high concentrations Na2S2O5-induced vasorelaxation.(4) The relaxant effect of Na2S2O5was not affected by4-AP. These results suggested that opening of K+channels (BKCa and KATP) might contribute to the vasorelaxant effect of Na2S2O5. To examine whether the Na2S2O5-induced vasorelaxation was mediated by cGMP pathway, we studied the vascular effect of Na2S2O5in the presence of the sGC inhibitors NS-2028and the NO synthase inhibitor L-NNA, respectively. Relaxation induced by low concentrations Na2S2O5was virtually abolished by L-NNA or NS-2028. However, the high concentrations Na2S2O5-induced relaxation was not altered by L-NNA or NS-2028.
In summary, these findings led to the conclusions:(1) Spectral properties of sulfur dioxide and its derivatives dissolved in water were different. Sulfur dioxide in water had a characteristic absorption peak at276rm. And the characteristic aborption peak of Na2S2O5and NaHSO3were257nn. Na2SO3solution did not show a characteristic absorption from200to800nm.(2) The vasodilator effects of Na2SO3, Na2S2O5and NaHSO3on isolated rat aortic rings were different. Na2S2O5or NaHSO3caused relaxation of isolated rat thoracic aortic rings in a concentration-dependent manner. However, Na2SO3could cause constriction in low concentration (<2mM) and relaxation in high concentration.(3) The vasorelaxation of Na2S2O5or NaHSO3at low concentrations was endothelium-dependent and mediated by the cGMP pathway and BKca channel, but that at high concentrations was endothelium-independent and mediated by KATP and L-type Ca2+channels. The vasorelaxant effect of Na2S2O5or NaHSO3was disproved the involvement of PKC, PGI2and β-adrenoceptor pathways.(4) Na2S2O5or NaHSO3in presence of H+can be used as a SO2donor for the study of SO2biology.
引文
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