罗氟司特和齐留通对哮喘大鼠气道平滑肌收缩功能的影响
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摘要
目的通过观察磷酸二酯酶4抑制剂罗氟司特和5-脂氧酶抑制剂齐留通对哮喘气道平滑肌收缩功能的影响,探讨罗氟司特和齐留通对气道平滑肌的药理作用。方法取正常及哮喘大鼠的气道平滑肌条,采用乙酰胆碱(acetylcholine,Ach)梯度累积给药进行肌条收缩功能研究,并进行罗氟司特或齐留通梯度累积给药的肌条舒张功能研究,同时设置药物预孵处理,利用张力换能器和计算机生物信号采集系统观察和记录各种方式处理下其收缩功能的变化。结果采用累积剂量给药法加入收缩剂Ach(10~(-8)～10~(-3)mol?L~(-1))后,正常大鼠和哮喘模型大鼠气道平滑肌收缩无显著性差异。由Ach诱发平滑肌条收缩达到最大程度,采用累积剂量给药法加入罗氟司特或齐留通(10~(-8)～10~(-3)mol?L~(-1))后,哮喘大鼠气道平滑肌对罗氟司特的敏感性高于正常大鼠,而对齐留通的敏感性低于正常大鼠。使用罗氟司特预孵,并采用累积给药法加入收缩剂Ach(10~(-8)～10~(-3)mol?L~(-1)),哮喘大鼠气道平滑肌和正常大鼠对Ach的反应性无明显差异,而齐留通预孵后,累积给药法加入Ach(10~(-8)～10~(-3) mol?L~(-1)),哮喘大鼠平滑肌对Ach的反应性明显高于正常健康大鼠。结论罗氟司特能抑制哮喘气道平滑肌的收缩功能,同时不诱导气道的高反应性,而齐留通对哮喘气道平滑肌的收缩抑制作用不明显,且可能诱导气道高反应性。
OBJECTIVE To observe the effect of PDE4 inhibitor(roflumilast) and 5-lipoxygenase inhibitor(zileuton) on the contraction of airway smooth muscle of asthma rat, and try to discuss their pharmacologic action on airway smooth muscle. METHODS Asthmatic and normal rats were executed for the airway smooth muscle strips. Gradual cumulative dose of acetylcholine(Ach) was used to study the contraction of muscle strips. Roflumilast or zileuton gradient cumulative administration or pre-incubation were used to study their diastolic and contractile function of muscle strips. Tension transducer, biological signal collecting system were used to record changes under various treatments. RESULTS Ach(10~(-8)-10~(-3) mol?L~(-1)) could induce the contraction of airway smooth muscle of asthma rat and normal rat, there were no significant difference. The maximal contraction of smooth muscle was induced by Ach, and the sensitivity of airway smooth muscle to roflumilast in asthmatic rats after cumulative dose administration was higher than normal rats, while the sensitivity of airway smooth muscle to zileuton in asthmatic rats was less sensitive than that of normal rats. Using roflumilast pre-incubation and cumulative administration of the constrictor Ach(10~(-8)-10~(-3) mol?L~(-1)), there was no significant difference in the reactivity of airway smooth muscle for Ach between normal rats and asthmatic rats. But pre-incubated with zileuton, after the cumulative administration of Ach(10~(-8)-10~(-3) mol?L~(-1)), the reactivity of airway smooth muscle of asthmatic rats for Ach was more significant than that of normal rats. CONCLUSION Roflumilast can inhibit the contraction of airway smooth muscle of asthma rats. However, zileuton has no obvious inhibitory effect on the contraction of asthmatic airway smooth muscle and may induce airway hyperresponsiveness.
OBJECTIVE To observe the effect of PDE4 inhibitor(roflumilast) and 5-lipoxygenase inhibitor(zileuton) on the contraction of airway smooth muscle of asthma rat, and try to discuss their pharmacologic action on airway smooth muscle. METHODS Asthmatic and normal rats were executed for the airway smooth muscle strips. Gradual cumulative dose of acetylcholine(Ach) was used to study the contraction of muscle strips. Roflumilast or zileuton gradient cumulative administration or pre-incubation were used to study their diastolic and contractile function of muscle strips. Tension transducer, biological signal collecting system were used to record changes under various treatments. RESULTS Ach(10~(-8)-10~(-3) mol?L~(-1)) could induce the contraction of airway smooth muscle of asthma rat and normal rat, there were no significant difference. The maximal contraction of smooth muscle was induced by Ach, and the sensitivity of airway smooth muscle to roflumilast in asthmatic rats after cumulative dose administration was higher than normal rats, while the sensitivity of airway smooth muscle to zileuton in asthmatic rats was less sensitive than that of normal rats. Using roflumilast pre-incubation and cumulative administration of the constrictor Ach(10~(-8)-10~(-3) mol?L~(-1)), there was no significant difference in the reactivity of airway smooth muscle for Ach between normal rats and asthmatic rats. But pre-incubated with zileuton, after the cumulative administration of Ach(10~(-8)-10~(-3) mol?L~(-1)), the reactivity of airway smooth muscle of asthmatic rats for Ach was more significant than that of normal rats. CONCLUSION Roflumilast can inhibit the contraction of airway smooth muscle of asthma rats. However, zileuton has no obvious inhibitory effect on the contraction of asthmatic airway smooth muscle and may induce airway hyperresponsiveness.
引文
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[2]DAVID M,ESSAYAN M D.Molecular mechanisms in allergy and clinical immunology cyclie nucleotide phosphodiesterases[J].J Allerg Clin Immunol,2001(108):671-680.
[3]ZHOU J,IWASAKI S,YAMAKAGE M.Time-and dose-dependent effects of desflurane in sensitized airways[J].Anesth Analg,2017,124(2):465-471.
[4]LI Z,ZENG B H,WANG H Y,et al.Microbiota modulates behavior and protein kinase C mediated cAMP response element-binding protein signaling[J].Sci Rep,2016(6):29998.
[5]MORALES S,CAMELLO P J,MAWE G M,et al.Cyclic AMP-mediated inhibition of gallbladder contractility:role of K+channel activation and Ca2+signaling[J].Br J Pharmacol,2004,143(8):994-1005.
[6]CINGI C,MULUK N B,IPCI K,et al.Antileukotrienes in upper airway inflammatory diseases[J].Curr Allergy Asthma Rep,2015,15(11):64.
[7]VERCELLI D.Gene-environment interactions in asthma and allergy:the end of the beginning?[J].Curr Opin Allergy Clin Immunol,2010,10(2):145-148.
[8]MAKINDE T,MURPHY R F,AGRAWAL D K.The regulatory role of TGF-beta in airway remodeling in asthma[J].Immunol Cell Biol,2007,85(5):348-356.
[9]BROWN R H,GEORGAKOPOULOS J,MITZNER W.Individual canine airways responsiveness to aerosol histamine and methacholine in vivo[J].Am J Respir Crit Care Med,1998,157(2):491-497.
[10]KINGHAM P J,MCLEAN W G,SAWATZKY D A,et al.Adhesion-dependent interactions between eosinophils and cholinergic nerves[J].Am J Physiol Lung Cell Mol Physiol,2002,282(6):L1229-L1238.
[11]GALE D D,HOFER P,SPINA D,et al.Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor,V11294[J].Pulm Pharmacol Ther,2003,16(2):97-104.