Vasodilator Effects of Bis-Dihydropyridines Structurally Related to Nifedipine

Author(s): Raquel Gomez Pliego, Eduardo Ramirez-San Juan, Rene Miranda, Rafael Villalobos-Molina, Francisco Delgado, Roberto Osnaya, Jose Trujillo Ferrara

Journal Name: Medicinal Chemistry

Volume 2 , Issue 5 , 2006

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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.

Keywords: Vascular smooth muscle, dihydropyridines, vasodilator, nifedipine, calcium channel blockers, spontaneously hypertensive rats

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Article Details

Year: 2006
Page: [527 - 534]
Pages: 8
DOI: 10.2174/157340606778250243
Price: $65

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