二氢吡啶类钙激动剂Bay k 8644对硝苯地平、维拉帕米、地尔硫䓬和锰离子在犬心室肌中负性肌力作用的差异性拮抗作用。
Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.
作者信息
Ishii K, Taira N, Yanagisawa T
出版信息
Br J Pharmacol. 1985 Feb;84(2):577-84. doi: 10.1111/j.1476-5381.1985.tb12943.x.
Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_
在犬离体心室肌小梁中研究了二氢吡啶类钙激动剂Bay k 8644、高浓度细胞外Ca2+与钙拮抗剂硝苯地平、维拉帕米和地尔硫䓬以及Mn2+之间的拮抗作用。Bay k 8644（10−7 - 10−5M）使舒张期张力缓慢升高，在10−6M时达到最大值。10−5M的Bay k 8644正性肌力作用略有降低，可能是由于溶剂0.5%乙醇的负性肌力作用所致。Bay k 8644（10−7 - 10−5M）使硝苯地平（10−8 - 10−5M）和维拉帕米（10−7 - 3×10−5M）负性肌力作用的浓度-反应曲线向右平行移动。硝苯地平的Schild图斜率为-0.92（pA2值 = 6.58），维拉帕米为-0.48。Bay k 8644（10−6和10−5M）仅使地尔硫䓬（10−7 - 3×10−5M）负性肌力作用的浓度-反应曲线略有右移，且不影响Mn2+（10−4 - 10−2M）的负性肌力作用。向培养基中添加2.5×10−３M Ca2+（5.05×10−３M Ca2+）产生的最大正性肌力作用比Bay k 8644更大。在这些条件下获得的硝苯地平、维拉帕米和地尔硫䓬负性肌力作用的浓度-反应曲线与对照条件（2.55×10−３M Ca2+）下的曲线基本无差异。这些结果表明，Bay k 8644在产生正性肌力作用的同时，通过与硝苯地平竞争与钙通道紧密相关的同一位点来拮抗其负性肌力作用。相反，Bay k 8644通过变构干扰这些钙拮抗剂与其作用位点的结合来拮抗维拉帕米和地尔硫䓬的负性肌力作用。Bay k 8644不拮抗Mn2+的负性肌力作用。未观察到三种有机钙拮抗剂与高浓度细胞外Ca2+之间的药理学拮抗作用。
Zotero 插件