Magnon M, Calderone V, Floch A, Cavero I
Rhône-Poulenc Rorer S.A., Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Oct;358(4):452-63. doi: 10.1007/pl00005278.
We examined the effects of various KCl concentrations on the actions of some vasodilators belonging to different pharmacological classes in rat aortic rings. In some experiments, tissues were precontracted with noradrenaline after blocking voltage-dependent channels to assess the effects of depolarisation unaccompanied by the entry of extracellular Ca2+ into the cytosol. Concentration/response curves for the vasorelaxant effect of calcium entry blockers (e.g. diltiazem), K+ channel openers (e.g. aprikalim), nitrate derivatives (e.g. nitroglycerin), a beta2-adrenergic agonist (salbutamol) and papaverine were obtained by using endothelium-denuded rat aortic rings precontracted with KC1 (20-60 mM) to determine the potencies and efficacies of the drugs. The efficacies and potencies of calcium entry inhibitors were virtually independent of the [KCl]. A reduction in the potency (up to 18-fold) of papaverine occurred without changes in efficacy when the [KCl] was raised from 20 to 60 mM. The decline in potency was even greater for nitrate-like compounds. The potency of K+ channel openers in aortic rings precontracted with 30 mM KCI decreased by three- to sixfold compared with those precontracted with 20 mM KCl. With the exception of pinacidil, the efficacy of these agents already started to decline in preparations precontracted with 25 mM KCI and was virtually zero in preparations precontracted with 60 mM KCI. In contrast to other K+ channel openers, the vasorelaxant action of pinacidil was relatively resistant to glibenclamide. Salbutamol produced only a slight relaxation even in preparations precontracted with 20 mM KCl. In nitrendipine-pretreated, noradrenaline-precontracted aortic rings, the vasorelaxant effects of aprikalim, but not those of linsidomine or papaverine, declined when the [KCl] of the bathing medium was increased. In conclusion, the vasorelaxant potency and efficacy of calcium entry blockers is independent of the [KCI] used to precontract rat aortic rings, and thus, of the degree of membrane depolarisation. In contrast, increasing the [KCl] strongly reduces the potency and the efficacy of K+ channel openers not only in this preparation but also in noradrenaline-precontracted rings in which the entry of extracellular Ca2+ was prevented with nitrendipine. This indicates that, with the exception of pinacidil, the vasorelaxant activity of K+ channel openers depends on the degree of membrane depolarisation. Finally, the vasorelaxant potency and efficacy of nitrate-like compounds and papaverine are independent of depolarisation per se but they are markedly affected by the influx of Ca2+ accompanying elevated [KCI]. Thus, the degree of vessel depolarisation should be taken into consideration when attempting to compare potencies and efficacies among vasorelaxant agents.
我们研究了不同氯化钾（KCl）浓度对大鼠主动脉环中某些属于不同药理类别的血管舒张剂作用的影响。在一些实验中，在阻断电压依赖性通道后用去甲肾上腺素使组织预收缩，以评估去极化的影响，此时细胞外Ca2+不进入细胞质。通过使用用KCl（20 - 60 mM）预收缩的去内皮大鼠主动脉环，获得钙通道阻滞剂（如地尔硫卓）、钾通道开放剂（如阿普卡林）、硝酸盐衍生物（如硝酸甘油）、β2肾上腺素能激动剂（沙丁胺醇）和罂粟碱的血管舒张作用的浓度/反应曲线，以确定药物的效价和效能。钙通道抑制剂的效能和效价实际上与[KCl]无关。当[KCl]从20 mM升高到60 mM时，罂粟碱的效价降低（高达18倍），而效能不变。对于硝酸盐类化合物，效价下降甚至更大。与用20 mM KCl预收缩的主动脉环相比，用30 mM KCl预收缩的主动脉环中钾通道开放剂的效价降低了三到六倍。除吡那地尔外，这些药物在与25 mM KCl预收缩的制剂中效能就已开始下降，在与60 mM KCl预收缩的制剂中几乎为零。与其他钾通道开放剂不同，吡那地尔的血管舒张作用对格列本脲相对耐药。即使在与20 mM KCl预收缩的制剂中，沙丁胺醇也仅产生轻微的舒张作用。在尼群地平预处理、去甲肾上腺素预收缩的主动脉环中，当浴液中的[KCl]增加时，阿普卡林的血管舒张作用下降，但林西多明或罂粟碱的血管舒张作用未下降。总之，钙通道阻滞剂的血管舒张效价和效能与用于预收缩大鼠主动脉环的[KCl]无关，因此也与膜去极化程度无关。相反，增加[KCl]不仅在该制剂中而且在尼群地平阻止细胞外Ca2+进入的去甲肾上腺素预收缩环中都强烈降低钾通道开放剂的效价和效能。这表明，除吡那地尔外，钾通道开放剂的血管舒张活性取决于膜去极化程度。最后，硝酸盐类化合物和罂粟碱的血管舒张效价和效能与去极化本身无关，但它们受到伴随[KCl]升高的Ca2+内流的显著影响。因此，在比较血管舒张剂的效价和效能时，应考虑血管去极化程度。
