Pliego Raquel Gómez, Juan Eduardo Ramírez-San, Miranda René, Villalobos-Molina Rafael, Delgado Francisco, Osnaya Roberto, Ferrara José Trujillo
Sección de Graduados e Investigación y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México D. F., 11340 México.
Med Chem. 2006 Sep;2(5):527-34. doi: 10.2174/157340606778250243.
Calcium channel blockers are widely used in therapy for hypertension and angina pectoris, and among these blockers some 1,4-dihydropyridines (e.g. amlodipine, nitrendipine and nifedipine) have had widespread clinical use. In this work we investigated the vascular effects of four bis-1,4-dihydropyridines (bis-DHPs: 01-04), structurally related to nifedipine, in which a second 1,4-dihydropyridinic moiety was incorporated in the corresponding arylic moiety in para and meta position. Of these four bis-DHPs, the meta regioisomers (bis-DHP-03 and bis-DHP-04; 0.01-3.16 mg kg(-1)) and nifedipine induced a greater decrease on diastolic and systolic blood pressure than the para isomers (bis-DHP-01 and bis-DHP-02), as shown in two experimental models: normotensive and spontaneously hypertensive rats. Complementarily, bis-DHPs action was examined in intact and endothelium-denuded rat aorta, depolarized by KCl [80 mM] in one group and stimulated by noradrenaline (1 x 10(-7) M) in another and the corresponding IC(50) values were obtained (1.5 x 10(-6)-2. 4 x 10(-7)M). Later, the relaxing action of bis-DHP-03,04 and nifedipine on the contraction evoked by Ca(2+) in K(+)-depolarized rat aorta was analyzed and the corresponding EC(50) values for the meta isomers and nifedipine were obtained. The results showed a concentration dependent vasodilating activity in both KCl precontracted and noradrenaline stimulated aorta rings. The apparent order of potency with and without endothelium in both experimental models was nifedipine >bis-DHP-04 >bis-DHP-03. The cumulative concentration-effect curves for Ca(2+) in the presence of the bis-DHPs tested show the same potency order. Unlike nifedipine, the tested compounds are not photosensitive, which makes them more attractive in therapy for hypertension related diseases.
钙通道阻滞剂广泛用于治疗高血压和心绞痛，在这些阻滞剂中，一些1,4 - 二氢吡啶类药物（如氨氯地平、尼群地平和硝苯地平）已得到广泛临床应用。在本研究中，我们研究了四种与硝苯地平结构相关的双 - 1,4 - 二氢吡啶类化合物（双 - DHP：01 - 04）的血管效应，其中第二个1,4 - 二氢吡啶部分连接在对位和间位的相应芳基部分上。在正常血压和自发性高血压大鼠这两种实验模型中，这四种双 - DHP中的间位区域异构体（双 - DHP - 03和双 - DHP - 04；0.01 - 3.16 mg·kg⁻¹）和硝苯地平引起的舒张压和收缩压下降幅度比对位异构体（双 - DHP - 01和双 - DHP - 02）更大。作为补充，在完整和去内皮的大鼠主动脉中检测了双 - DHP的作用，一组用80 mM KCl使其去极化，另一组用去甲肾上腺素（1×10⁻⁷ M）刺激，并获得了相应的半数抑制浓度（IC₅₀）值（1.5×10⁻⁶ - 2.4×10⁻⁷ M）。随后，分析了双 - DHP - 03、04和硝苯地平对K⁺去极化大鼠主动脉中Ca²⁺诱发收缩的舒张作用，并获得了间位异构体和硝苯地平的相应半数有效浓度（EC₅₀）值。结果表明，在KCl预收缩和去甲肾上腺素刺激的主动脉环中均存在浓度依赖性血管舒张活性。在两种实验模型中，无论有无内皮，效力的明显顺序为硝苯地平＞双 - DHP - 04＞双 - DHP - 03。在测试的双 - DHP存在下，Ca²⁺的累积浓度 - 效应曲线显示出相同的效力顺序。与硝苯地平不同，测试的化合物无光敏性，这使得它们在治疗高血压相关疾病方面更具吸引力。
