Hirota K, Hashiba E, Yoshioka H, Kabara S, Matsuki A
Department of Anesthesiology, University of Hirosaki, School of Medicine, Japan.
Br J Anaesth. 2003 May;90(5):671-5. doi: 10.1093/bja/aeg118.
The crucial role of L-type Ca(2+) channels in airway smooth muscle contraction suggests that these channels could be an important therapeutic target. There are three separate drug binding sites on this channel: those for dihydropyridines, benzothiazepines and phenyl alkylamines. In this study, we examined the effects of the dihydropyridines nifedipine and nicardipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil on airway constriction.
Tension of guinea-pig tracheal strips was measured isometrically in vitro with a force displacement transducer. Strips were precontracted with carbachol 10(-7) M with or without 4-aminopyridine 10(-3) M, a voltage-sensitive K(+ )channel blocker. Then, nifedipine 10(-8)-10(-4) M, diltiazem 10(-8)-3 x 10(-4) M or verapamil 10(-8)-3 x 10(-4) M was added cumulatively to the organ bath (n=6 each). The bronchial cross-sectional area of pentobarbital-anaesthetized dogs was assessed using a bronchoscopy method. Bronchoconstriction was elicited with methacholine 0.5 micro g kg(-1) plus 5 micro g kg(-1) min(-1), and then nicardipine 0-1000 micro g kg(-1), diltiazem 0-3000 micro g kg(-1) or verapamil 0-3000 micro g kg(-1) were given i.v. (n=7 each).
In the in vitro experiments, nifedipine and diltiazem fully reversed carbachol-mediated tracheal contraction with logIC(50) values of 4.76 (SEM 0.22) (mean 17.5 micro M) and 4.60 (0.33) (mean 24.8 micro M), respectively. Although verapamil 10(-6)-10(-4) M reversed the contraction by 87.2%, strip tension re-increased by 18.1% following maximal relaxation with verapamil 3 x 10(-4 )M. This re-increase was almost fully abolished by pretreatment with 4-aminopyridine. In the in vivo experiments, nicardipine and diltiazem dose-dependently reversed methacholine-induced bronchoconstriction, with logID(50) values of 3.22 (0.05) (mean 0.60 mg kg(-1)) and 1.85 (0.32) (mean 14.0 mg kg(-1)), respectively. Verapamil worsened methacholine-induced bronchoconstriction.
Although supraclinical doses of dihydropyridines and benzothiazepines can produce airway relaxant effects, these agents are unlikely to be used in the treatment of bronchoconstriction. In addition, verapamil may aggravate airway constriction.
L型钙通道在气道平滑肌收缩中起关键作用，提示这些通道可能是重要的治疗靶点。该通道有三个独立的药物结合位点：二氢吡啶类、苯并噻氮䓬类和苯烷基胺类的结合位点。在本研究中，我们检测了二氢吡啶类药物硝苯地平与尼卡地平、苯并噻氮䓬类药物地尔硫䓬以及苯烷基胺类药物维拉帕米对气道收缩的影响。
在体外，使用力位移换能器等长测量豚鼠气管条的张力。气管条用10⁻⁷M卡巴胆碱预收缩，同时或不加入10⁻³M 4-氨基吡啶（一种电压敏感性钾通道阻滞剂）。然后，将10⁻⁸～10⁻⁴M硝苯地平、10⁻⁸～3×10⁻⁴M地尔硫䓬或10⁻⁸～3×10⁻⁴M维拉帕米累积加入器官浴槽（每组n = 6）。采用支气管镜检查法评估戊巴比妥麻醉犬的支气管横截面积。用0.5μg kg⁻¹加5μg kg⁻¹ min⁻¹的乙酰甲胆碱诱发支气管收缩，然后静脉注射0～1000μg kg⁻¹尼卡地平、0～3000μg kg⁻¹地尔硫䓬或0～3000μg kg⁻¹维拉帕米（每组n = 7）。
在体外实验中，硝苯地平和地尔硫䓬完全逆转了卡巴胆碱介导的气管收缩，logIC₅₀值分别为4.76（标准误0.22）（平均17.5μM）和4.60（0.33）（平均24.8μM）。虽然10⁻⁶～10⁻⁴M维拉帕米使收缩逆转了87.2%，但在用3×10⁻⁴M维拉帕米最大程度舒张后，气管条张力又增加了18.1%。用4-氨基吡啶预处理几乎完全消除了这种再次增加。在体内实验中，尼卡地平和地尔硫䓬剂量依赖性地逆转了乙酰甲胆碱诱导的支气管收缩，logID₅₀值分别为3.22（0.05）（平均0.60mg kg⁻¹）和1.85（0.32）（平均14.0mg kg⁻¹）。维拉帕米使乙酰甲胆碱诱导的支气管收缩加重。
虽然超临床剂量的二氢吡啶类和苯并噻氮䓬类药物可产生气道舒张作用，但这些药物不太可能用于治疗支气管收缩。此外，维拉帕米可能会加重气道收缩。
