title: Vasodilator effects of bis-dihydropyridines structurally related to nifedipine.
abstract: 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.
authors.affiliation: 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.
authors.forename: Raquel Gómez
authors.initials: RG
authors.lastname: Pliego
authors.forename: Eduardo Ramírez-San
authors.initials: ER
authors.lastname: Juan
authors.forename: René
authors.initials: R
authors.lastname: Miranda
authors.forename: Rafael
authors.initials: R
authors.lastname: Villalobos-Molina
authors.forename: Francisco
authors.initials: F
authors.lastname: Delgado
authors.forename: Roberto
authors.initials: R
authors.lastname: Osnaya
authors.forename: José Trujillo
authors.initials: JT
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009543:Nifedipine / Q000737:chemistry* / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004095:Dihydropyridines; D014665:Vasodilator Agents; D009543:Nifedipine; D011188:Potassium; D002118:Calcium