Antihypertensive effects of new dihydropyridine derivatives on phenylephrine-raised blood pressure in rats

Sara Rowghani Haghighi Fard, Ramin Miri, Ali Akbar Nekooeian


Changes in the substitutions at C-3 and C-5 positions of 4-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine have led to changes in potency of the compounds. The objective of the present study was to examine the hypotensive effects of 5 newly synthesized dihydropyridine derivatives of nifedipine in rats with phenylephrine-raised blood pressure. Anesthetized Sprague-Dawley rats were randomly assigned to 19 groups of 7 animals each. Control group received the vehicle dimethylsulfoxide (0.05 mL), 3 groups were given nifedipine at 100, 300, or 1000 mg/kg, and 5 other groups each composed of 3 subgroups administered one of the 5 new dihydropyridine compound at 100, 300, or 1000 mg/kg. All animals were initially infused with 20 µg/kg/min phenylephrine for 45 min, and were then given a bolus of either dimethylsulfoxide, nifedipine, or new dihydropyridine compounds 20 min after the commencement of phenylephrine infusion. Blood pressure and heart rate (HR) of the animals were measured before and at the end of phenylephrine infusion, or 25 min after injection of vehicle or compounds. Compared to dimethylsulfoxide, nifedipine, and new 1, 4-dihydropyridine derivatives caused significant reductions in MBP. Moreover, cyclohexyl propyl, phenyl butyl, and cyclohexyl methyl analogs of 1, 4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazoyl)-3,5-pyridinedicarboxylase at 100 mg/kg, phenyl butyl, and cyclohexyl methyl analogs at 300 mg/kg, and cyclohexyl methyl analogs at 1000 mg/kg reduced MBP similar to nifedipine. There was no significant difference between HR of all groups before and after administration of the compounds. The findings indicated that changes in substitution at C-3 and C-5 positions of 2-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine were associated with changes in hypotensive activity of the compounds.


1, 4-dihydropyridine; Nifedipine; Phenylephrine; Arterial pressure

Full Text:



Richard S. Vascular effects of calcium channel antagonists: new evidence. Drugs. 2005;65:1-10.

Haria M, Wagstaff AJ. Amlodipine. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs. 1995;50(3):560-586.

The 2007 canadian hypertension education program recommendations: the scientific summary - an annual update. Can J Cardiol. 2007;23(7):521-527.

Safak C, Simsek R. Fused 1,4-dihydropyridines as potential calcium modulatory compounds. Mini Rev Med Chem. 2006;6(7):747-755.

Triggle DJ. The 1,4-dihydropyridine nucleus: a pharmacophoric template part 1. Actions at ion channels. Mini Rev Med Chem. 2003;3(3):215-223.

Weiner DA. Calcium channel blockers. Med Clin North Am. 1988;72(1):83-115.

Takahashi D, Oyunzul L, Onoue S, Ito Y, Uchida S, Simsek R, et al. Structure-activity relationships of receptor binding of 1,4-dihydropyridine derivatives. Biol Pharm Bull. 2008;31(3):473-479.

Mirkhani H, Omrani GR, Ghiaee S, Mahmoudian M. Effects of mebudipine and dibudipine, two new calcium-channel blockers, on rat left atrium, rat blood pressure and human internal mammary artery. J Pharm Pharmacol. 1999;51(5):617-622.

Langs DA, Strong PD, Triggle DJ. Receptor model for the molecular basis of tissue selectivity of 1, 4-dihydropyridine calcium channel drugs. J Comput Aided Mol Des. 1990;4(3):215-230.

Hosseini M, Miri R, Amini M, Mirkhani H, Hemmateenejad B, Ghodsi S, et al. Synthesis, QSAR and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing 1-methyl-4,5-dichloroimidazolyl substituents. Arch Pharm (Weinheim). 2007;340(10):549-556.

Mager PP, Coburn RA, Solo AJ, Triggle DJ, Rothe H. QSAR, diagnostic statistics and molecular modelling of 1,4-dihydropyridine calcium antagonists: a difficult road ahead. Drug Des Discov. 1992;8(4):273-289.

Hemmateenejad B, Miri R, Akhond M, Shamsipur M. Quantitative structure-activity relationship study of recently synthesized 1,4-dihydropyridine calcium channel antagonists. Application of the Hansch analysis method. Arch Pharm (Weinheim). 2002;335(10):472-480.

Janis RA, Triggle DJ. New developments in Ca2+ channel antagonists. J Med Chem. 1983;26(6):775-785.

Spedding M, Fraser S, Clarke B, Patmore L. Factors modifying the tissue selectivity of calcium-antagonists. J Neural Transm Suppl. 1990;31:5-16.

Vo D, Matowe WC, Ramesh M, Iqbal N, Wolowyk MW, Howlett SE, et al. Syntheses, calcium channel agonist-antagonist modulation activities, and voltage-clamp studies of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate racemates and enantiomers. J Med Chem. 1995;38(15):2851-2859.

Nekooeian AA, Khalili A, Javidnia K, Mehdipour AR, Miri R. Antihypertensive effects of some new nitroxyalkyl 1,4-dihydropyridine derivatives in rat model of two-kidney, one-clip hypertension. Iran J Pharm Res. 2010;8:193-199.

Shafiee A, Miri R, Dehpour AR, Soleymani F. Synthesis and calcium-channel antagonist activity of nifedipine analogues containing nitroimidazolyl substituent in Guinea-pig ileal smooth muscle. PharmPharmacolCommun. 1996;2(11):541-543.

Katzung BG. Introduction to autonomic pharmacology. In: Katzung BG, editor. Basic and clinical pharmacology. 13th ed. Norwalk CN: Appleton and Lange. 2015. pp. 87-109.

McGrattan PA, Brown JH, Brown OM. Parasympathetic effects on in vivo rat heart can be regulated through an alpha 1-adrenergic receptor. Circ Res. 1987;60(4):465-471.

Shafiee A, Rastkary N, Jorjani M. Synthesis and calcium channel antagonist activity of 1,4-dihydropyridine derivatives containing 4-nitroimidazolyl substituents. Arzneimittelforschung. 2002;52(7):537-542.

Prisant LM. Calcium antagonists--pharmacologic considerations. Ethn Dis. 1998;8(1):98-102.

Katzung BG. Introduction: The Nature of Drugs. In: Katzung BG, editor. Basic and Clinical Pharmacology. 13th ed. Norwalk CN: Appleton and lange. 2015. pp. 1-19.

Miller S. Noninferiority Trials. In: Wang D, Bakhai A, editors. Clinical trials: 1st ed. London, UK: Remedica. 2006. pp. 131-140.


  • There are currently no refbacks.