Raquel Gomez Pliego, Eduardo Ramirez-San Juan, Rene Miranda, Rafael Villalobos-Molina, Francisco Delgado, Roberto Osnaya and Jose Trujillo Ferrara Pages 527 - 534 ( 8 )
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 (1x10-7 M) in another and the corresponding IC50 values were obtained (1.5x10-6-2.4x10- 7M). Later, the relaxing action of bis-DHP-03,04 and nifedipine on the contraction evoked by Ca2+ in K+-depolarized rat aorta was analyzed and the corresponding EC50 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 Ca2+ 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.
Vascular smooth muscle, dihydropyridines, vasodilator, nifedipine, calcium channel blockers, spontaneously hypertensive rats
Seccion de Graduados e Investigacion y Departamento de Bioquimica, Escuela Superior de Medicina,Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron, Mexico D. F., 11340 Mexico.