循环系统功能失调对中暑休克的影响及阿司匹林预防保护作用的研究
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摘要
中暑休克(heatstroke，HS)，又称热射病或重症中暑，是一种由于持续环境高温导致惊厥、昏迷、谵妄、严重低血压等一系列症状的临床急症，虽然经过积极的降温、补液等处理其死亡率仍可达到12～21％。在我国南方地区，夏季持续时间长，高温高湿的气候特点明显，尤其易发生中暑。随着全球气候变暖、炎热期的频度及强度不断增加，HS的发病率及死亡率还可能上升。
以前认为HS的死亡与中枢神经系统(CNS)的损伤有关，但现在研究认为血液动力学的改变可能是HS发生的关键因素，环境高温(HAT)及内毒素的作用下内皮细胞功能损害可能是导致血管张力丧失、血压下降的罪魁祸首，并且白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)等细胞因子及可诱导性一氧化氮合酶(iNOS)、一氧化氮(NO)等参与了这一过程。有研究发现阿司匹林(ASA)可以抑制IL-1β从而可能具有内皮细胞保护作用。由此可以推测ASA可能通过抑制细胞因子诱导iNOS表达增加，产生对血压的影响，从而具有预防HS的作用。
一、一氧化氮系统在中暑休克中的作用及氨基胍的保护作用：方法：1、将Sprague-Dawley大鼠随机分为对照组及氨基胍(AG)组(均n=10)，给予温度41℃，相对湿度65％环境进行HE诱发HS，连续记录动脉血压、结肠温度(T_(co))、心电图(ECG)；2、取Sprague-Dawley大鼠随机分为对照组及AG组(均n=10)，处理同前，HE后0 min及60 min时各取血1ml，测大鼠血浆NO浓度。结果：(1)两组大鼠血压在HE 0～50 min没有显著差异，在HE 50min时平均动脉压(MAP)升至最高，HE 55～60 min MAP出现下降(HS形成)，对照组MAP下降较AG组差异显著(p＜0.05)。HE后两组K值及重搏切迹相对高度(h_D／H)逐渐下降，尤其在HE 40 min后对照组K值低于AG组(P＜0.05)；(2)HE之后，两组动物心率(HR)及QT间期增加，PR间期缩短；(3)HE之后T_(co)升高，两
组动物未见显著差异(P>0.05);(4) AG组中暑休克形成时间(ToHS)及
生存时间(ST)较对照组显著延长(p<0 .05);(5)两组血浆NO浓度在
HE omin无显著差异(p>.05)，HE 60 min时两组血浆No浓度均升高，
AG组显著高于对照组印<0.05)。
二、工L一lp在中暑休克中的变化及阿司匹林的预防保护作用:方法:
1、将sD大鼠随机分为对照组及ASA组(均n=10)，对照组给予0.5%梭
甲基纤维素钠(CMC)，ASA组给予0.5%cMC+0 .25%ASA混悬液，12
小时后给予温度41℃，相对湿度65%环境进行HE诱发HS，连续记录
动脉血压、Tc。、ECG。2、取对照组及ASA组SD大鼠(均护7)，处理
同前，在HEO、60min时分别取血lml检测大鼠血浆IL一lp浓度;3、
取对照组及AsA组sD大鼠(均n二12)，进行高温疲劳试验，将大鼠置于
直径0.sm、高0.75m水箱中自由游泳，设水高0.5m，水温40.5士0.5℃，
以大鼠沉入水底20秒不上浮为标准，记录大鼠生存时间。结果:(l)两
组大鼠MAP在HEO一50min没有显著性差异(P>0.05)，在50min时
MAP升至最高，在HE 60min后MAP下降，对照组MAP较ASA组下
降显著;(2)两组动物Tc。变化未见显著性差异;(3) TOHs两组无显著
性差异，ASA组ST较对照组显著延长(尸<0.05);(4)HE使大鼠HR、
QT间期增加，pR间期缩短;(5)HE60min后两组IL一lp浓度均较HE Omin
升高(P<0.05)，HE 60min后对照组IL一1日上升水平与ASA组有显著性
差异(P<0.05);(6)在大鼠抗高温疲劳实验中，ASA组大鼠生存时间较
对照组大鼠显著延长(P<0.01)。
以上实验表明，iNOS参与大鼠HS的形成过程，通过AG抑制iNOS
可以改善大鼠HS的过程;预防性给予抗炎剂量ASA可能对HS出现的
血压降低有一定的保护作用，这种作用可能是通过对IL一lp的抑制而
体现的:ASA可以提高清醒大鼠在高温环境下疲劳耐受性。
Heatstroke (HS) is a medical emergency caused by prolonged exposure to high ambient temperature (HAT) and characterized by hypotension, delirium, coma and convulsion. Despite adequate lowering of body temperature and aggressive treatment, HS is always associated with high mortality rates of 12-21%. In the south of China, where the summers always last a long time with a characteristic of high temperature and high humid climate, and HS and deaths associated with HS have attacked more frequently in recent years. The incidence of such deaths may increase with global wanning and the predicted worldwide increase frequency and intensity of heat waves. It was once believed that the main cause of death in HS is related to the damage of central nervous system (CNS) after prolonged exposure to HAT. However, evidence has accumulated indicates that the cause of death is probably not CNS damage, but systemic hemodynamic deterioration .Some people consider that endothelial dysfunction caused by HAT and consequent increased
concentration of endotoxin is the fatal factor of decreased vasoconstrictor tone and profound hypotension, and IL-1β is involved in this complex process. A recent study suggested that pretreatment with aspirin can provide the preventive effects against inflammation-induced endothelial dysfunction which may be through modulation of cytokine (such as IL-1β) cascade. We speculate that pretreatment with aspirin may attenuate the increase of the plasma levels of IL-1β and inhibit IL-1β-stimulated iNOS and NO production in rats with HS, consequently may provide protective effects on rats with HS.
1. Effects of selective iNOS prohibitor aminoguanidine on rat HS: Methods The rats were randomly assigned into 1 of the following 2 groups: control group or aminoguanidine (AG) group. The rats of control group
(n=10) and AG group (n=10) were exposed to a HAT ( Ta 41C, relative humidity 65%) to induce HS, arterial blood pressures, colonic temperature (Tco), electrocardiograph (ECG) were monitored. The other rats of both groups (both n=10) were exposed to a HAT (41C, relative humidity 65%), and the blood samples were taken at 0, 60min after heat exposure (HE) for determination of the plasma NO concentrations. Results (1) From 0 min to 50min after HE, MAPs of two groups were not significantly different, but at about 55min-60min after HE, MAPs of control group were decreased significantly differently from that of AG group, K value and dicrotic pulse relative height (hD/H) were gradually decreased after HE, especially at 40 min after HE, K value of control group decreased significantly comparison with that of AG group;(2) Heart rate (HR) and QT interval of both groups were increased after HE ,while PR interval were decreased;(3) Tco of both groups were increased after HE until Tco increased to 42 C (the onset of HS), b
ut there was not significantly difference between the two groups; (4) The time of the onset of heatstroke (TOHS) and survival time(ST) of AG group were significantly longer than that of control group; (5) the plasma NO concentrations of the two groups were significantly higher at 60min after HE than at 0min after HE, and the plasma NO concentrations of control group were significantly higher than that of AG group at 60 min after HE.
2. Pretreatment with aspirin reduces IL-1β concentration and provides protective effects against rat heatstroke: Methods The rats were randomly assigned into control group and ASA group, the rats of control group were treated with 0.5%CMC, and the rats of ASA group were treated with 0.5%CMC+ 0.25% ASA at 12h before the HE. (l)The rats of the two groups (both n=10) were exposed to a HAT (Ta 41C,relative humidity 65%) to induce HS, arterial blood pressures, Tco, ECG were monitored;(2)The other rats of both groups (n=7) were exposed to a HAT (Ta 41 C,relative humidity 65%),and the blood samples were taken at 0, 60min after HE for determining the plasma IL-1β concentrations of the two groups;(3)To evaluate the effect
of pretreatment with aspirin on the anti-fatigue an
以前认为HS的死亡与中枢神经系统(CNS)的损伤有关，但现在研究认为血液动力学的改变可能是HS发生的关键因素，环境高温(HAT)及内毒素的作用下内皮细胞功能损害可能是导致血管张力丧失、血压下降的罪魁祸首，并且白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)等细胞因子及可诱导性一氧化氮合酶(iNOS)、一氧化氮(NO)等参与了这一过程。有研究发现阿司匹林(ASA)可以抑制IL-1β从而可能具有内皮细胞保护作用。由此可以推测ASA可能通过抑制细胞因子诱导iNOS表达增加，产生对血压的影响，从而具有预防HS的作用。
一、一氧化氮系统在中暑休克中的作用及氨基胍的保护作用：方法：1、将Sprague-Dawley大鼠随机分为对照组及氨基胍(AG)组(均n=10)，给予温度41℃，相对湿度65％环境进行HE诱发HS，连续记录动脉血压、结肠温度(T_(co))、心电图(ECG)；2、取Sprague-Dawley大鼠随机分为对照组及AG组(均n=10)，处理同前，HE后0 min及60 min时各取血1ml，测大鼠血浆NO浓度。结果：(1)两组大鼠血压在HE 0～50 min没有显著差异，在HE 50min时平均动脉压(MAP)升至最高，HE 55～60 min MAP出现下降(HS形成)，对照组MAP下降较AG组差异显著(p＜0.05)。HE后两组K值及重搏切迹相对高度(h_D／H)逐渐下降，尤其在HE 40 min后对照组K值低于AG组(P＜0.05)；(2)HE之后，两组动物心率(HR)及QT间期增加，PR间期缩短；(3)HE之后T_(co)升高，两
组动物未见显著差异(P>0.05);(4) AG组中暑休克形成时间(ToHS)及
生存时间(ST)较对照组显著延长(p<0 .05);(5)两组血浆NO浓度在
HE omin无显著差异(p>.05)，HE 60 min时两组血浆No浓度均升高，
AG组显著高于对照组印<0.05)。
二、工L一lp在中暑休克中的变化及阿司匹林的预防保护作用:方法:
1、将sD大鼠随机分为对照组及ASA组(均n=10)，对照组给予0.5%梭
甲基纤维素钠(CMC)，ASA组给予0.5%cMC+0 .25%ASA混悬液，12
小时后给予温度41℃，相对湿度65%环境进行HE诱发HS，连续记录
动脉血压、Tc。、ECG。2、取对照组及ASA组SD大鼠(均护7)，处理
同前，在HEO、60min时分别取血lml检测大鼠血浆IL一lp浓度;3、
取对照组及AsA组sD大鼠(均n二12)，进行高温疲劳试验，将大鼠置于
直径0.sm、高0.75m水箱中自由游泳，设水高0.5m，水温40.5士0.5℃，
以大鼠沉入水底20秒不上浮为标准，记录大鼠生存时间。结果:(l)两
组大鼠MAP在HEO一50min没有显著性差异(P>0.05)，在50min时
MAP升至最高，在HE 60min后MAP下降，对照组MAP较ASA组下
降显著;(2)两组动物Tc。变化未见显著性差异;(3) TOHs两组无显著
性差异，ASA组ST较对照组显著延长(尸<0.05);(4)HE使大鼠HR、
QT间期增加，pR间期缩短;(5)HE60min后两组IL一lp浓度均较HE Omin
升高(P<0.05)，HE 60min后对照组IL一1日上升水平与ASA组有显著性
差异(P<0.05);(6)在大鼠抗高温疲劳实验中，ASA组大鼠生存时间较
对照组大鼠显著延长(P<0.01)。
以上实验表明，iNOS参与大鼠HS的形成过程，通过AG抑制iNOS
可以改善大鼠HS的过程;预防性给予抗炎剂量ASA可能对HS出现的
血压降低有一定的保护作用，这种作用可能是通过对IL一lp的抑制而
体现的:ASA可以提高清醒大鼠在高温环境下疲劳耐受性。
Heatstroke (HS) is a medical emergency caused by prolonged exposure to high ambient temperature (HAT) and characterized by hypotension, delirium, coma and convulsion. Despite adequate lowering of body temperature and aggressive treatment, HS is always associated with high mortality rates of 12-21%. In the south of China, where the summers always last a long time with a characteristic of high temperature and high humid climate, and HS and deaths associated with HS have attacked more frequently in recent years. The incidence of such deaths may increase with global wanning and the predicted worldwide increase frequency and intensity of heat waves. It was once believed that the main cause of death in HS is related to the damage of central nervous system (CNS) after prolonged exposure to HAT. However, evidence has accumulated indicates that the cause of death is probably not CNS damage, but systemic hemodynamic deterioration .Some people consider that endothelial dysfunction caused by HAT and consequent increased
concentration of endotoxin is the fatal factor of decreased vasoconstrictor tone and profound hypotension, and IL-1β is involved in this complex process. A recent study suggested that pretreatment with aspirin can provide the preventive effects against inflammation-induced endothelial dysfunction which may be through modulation of cytokine (such as IL-1β) cascade. We speculate that pretreatment with aspirin may attenuate the increase of the plasma levels of IL-1β and inhibit IL-1β-stimulated iNOS and NO production in rats with HS, consequently may provide protective effects on rats with HS.
1. Effects of selective iNOS prohibitor aminoguanidine on rat HS: Methods The rats were randomly assigned into 1 of the following 2 groups: control group or aminoguanidine (AG) group. The rats of control group
(n=10) and AG group (n=10) were exposed to a HAT ( Ta 41C, relative humidity 65%) to induce HS, arterial blood pressures, colonic temperature (Tco), electrocardiograph (ECG) were monitored. The other rats of both groups (both n=10) were exposed to a HAT (41C, relative humidity 65%), and the blood samples were taken at 0, 60min after heat exposure (HE) for determination of the plasma NO concentrations. Results (1) From 0 min to 50min after HE, MAPs of two groups were not significantly different, but at about 55min-60min after HE, MAPs of control group were decreased significantly differently from that of AG group, K value and dicrotic pulse relative height (hD/H) were gradually decreased after HE, especially at 40 min after HE, K value of control group decreased significantly comparison with that of AG group;(2) Heart rate (HR) and QT interval of both groups were increased after HE ,while PR interval were decreased;(3) Tco of both groups were increased after HE until Tco increased to 42 C (the onset of HS), b
ut there was not significantly difference between the two groups; (4) The time of the onset of heatstroke (TOHS) and survival time(ST) of AG group were significantly longer than that of control group; (5) the plasma NO concentrations of the two groups were significantly higher at 60min after HE than at 0min after HE, and the plasma NO concentrations of control group were significantly higher than that of AG group at 60 min after HE.
2. Pretreatment with aspirin reduces IL-1β concentration and provides protective effects against rat heatstroke: Methods The rats were randomly assigned into control group and ASA group, the rats of control group were treated with 0.5%CMC, and the rats of ASA group were treated with 0.5%CMC+ 0.25% ASA at 12h before the HE. (l)The rats of the two groups (both n=10) were exposed to a HAT (Ta 41C,relative humidity 65%) to induce HS, arterial blood pressures, Tco, ECG were monitored;(2)The other rats of both groups (n=7) were exposed to a HAT (Ta 41 C,relative humidity 65%),and the blood samples were taken at 0, 60min after HE for determining the plasma IL-1β concentrations of the two groups;(3)To evaluate the effect
of pretreatment with aspirin on the anti-fatigue an
引文
1．罗志昌，张松，杨文鸣等。脉搏波波形特征信息的研究。北京工业大学学报，1996，22(1)：71-79。
2. Eshel GM and Safer P. The role of the central nervous system in heatstroke: reversible profound depression of cerebral activity in a
primate model. Aviat Space Environ Med, 2002, 73(4): 327-332.
3. Murray PT, Wylam ME and Umans JG. Nitric oxide and septic vascular dysfunction. Anesth Analg, 2000, 90(1): 89-101.
4. Szabo C and Billiar TR. Novel roles of nitric oxide in hemorrhagic shock. Shock, 1999, 12(1): 1-9.
5. Titheradge MA. Nitric oxide in septic shock. Biochim Biophys Acta, 1999, 1411(2-3): 437-455.
6. Alzeer AH, Al-Arifi A, Warsy AS, et al. Nitric oxide production is enhanced in patients with heat stroke. Intensive Care Med, 1999, 25(1): 58-62.
7. Hall DM, Buettner GR, Oberley LW, et al. Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia. Am J Physiol Heart Circ Physiol , 2001, 280(2): H509-21.
8. Ryan KL, Tehrany MR and Jauchem JR. Nitric oxide does not contribute to the hypotension of heatstroke. J Appl Physiol, 2001, 90(3): 961-70.
9. Price S, Mitchell JA, Anning PB, et al. Type Ⅱ nitric oxide synthase activity is cardio-protective in experimental sepsis. Eur J Pharmacol, 2003, 472(1-2): 111-8.
10. Canini F, Buguet A and Bourdon L. Inhibition of different types of nitric oxide synthase: effect on thermoregulation in the rat exposed to high ambient temperature. Neurosci Lett, 2001, 316(1): 45-9.
2. Eshel GM and Safer P. The role of the central nervous system in heatstroke: reversible profound depression of cerebral activity in a
primate model. Aviat Space Environ Med, 2002, 73(4): 327-332.
3. Murray PT, Wylam ME and Umans JG. Nitric oxide and septic vascular dysfunction. Anesth Analg, 2000, 90(1): 89-101.
4. Szabo C and Billiar TR. Novel roles of nitric oxide in hemorrhagic shock. Shock, 1999, 12(1): 1-9.
5. Titheradge MA. Nitric oxide in septic shock. Biochim Biophys Acta, 1999, 1411(2-3): 437-455.
6. Alzeer AH, Al-Arifi A, Warsy AS, et al. Nitric oxide production is enhanced in patients with heat stroke. Intensive Care Med, 1999, 25(1): 58-62.
7. Hall DM, Buettner GR, Oberley LW, et al. Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia. Am J Physiol Heart Circ Physiol , 2001, 280(2): H509-21.
8. Ryan KL, Tehrany MR and Jauchem JR. Nitric oxide does not contribute to the hypotension of heatstroke. J Appl Physiol, 2001, 90(3): 961-70.
9. Price S, Mitchell JA, Anning PB, et al. Type Ⅱ nitric oxide synthase activity is cardio-protective in experimental sepsis. Eur J Pharmacol, 2003, 472(1-2): 111-8.
10. Canini F, Buguet A and Bourdon L. Inhibition of different types of nitric oxide synthase: effect on thermoregulation in the rat exposed to high ambient temperature. Neurosci Lett, 2001, 316(1): 45-9.