dibudipine and mebudipine

Calcium channel blockers are clinically useful vasodilators, used widely in the treatment of hypertension. These agents are reported to preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease. Among the classes of calcium channel blockers, dihydropyridine derivatives are widely used because of their potent vasodilating activity and weak cardiodepressant action. Mebudipine and dibudipine are two new 1,4-dihydropyridine calcium channel blockers that recently have been synthesized. In previous research mebudipine and dibudipine showed considerable relaxant effects on vascular and ileal smooth muscle cells. In this study we investigated the effects of these new drugs on vascular flow of isolated kidney of diabetic rat and compare their potencies to amlodipine. It is concluded that mebudipine and dibudipine (1-10 μM) are at least as potent as amlodipine in inhibiting PE-induced perfusion pressure in isolated kidney of diabetic rats. These new dihydropyridines improve kidney perfusion of diabetic rat in the setting of PE infusion. Similarly, amlodipine.

Topics: Amlodipine; Animals; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney; Male; Nifedipine; Rats; Rats, Wistar; Renal Circulation

In the present study, we investigated the effects of mebudipine and dibudipine, two new Ca(2+) channel blockers, on primary murine cortical neurons exposed to oxygen-glucose deprivation/reperfusion. The experiments were performed on cells after 11-16 days of culture. To initiate oxygen-glucose deprivation /reperfusion, the culture medium was replaced by glucose-free medium, and the cells were transferred to a humidified incubation chamber in a mixture of 95% N(2) and 5% CO(2) at 37 degrees C for 30 min. The cultures were pretreated with mebudipine and dibudipine 3 h prior to oxygen-glucose deprivation/reperfusion, in order to explore their effects on neurons under oxygen-glucose deprivation conditions. Cell viability and nitric oxide (NO) production were assessed by MTT assay and the modified Griess method, respectively. Exposure of murine cortical neuronal cells to 30 min oxygen-glucose deprivation significantly decreased cell viability and increased NO production. Pretreatment of the cultures with mebudipine and dibudipine significantly increased cell viability and decreased NO generation in a dose-dependent manner. However, the drugs had no protective effect in cells subjected to oxygen-glucose deprivation for 60 min. Pretreatment of cultures with MK-801 (10 microM), a non-competitive NMDA antagonist, decreased neuronal death after 30-min oxygen-glucose deprivation, while application of NBQX (30 microM), a selective AMPA-kainate receptor antagonist, partially attenuated the cell injury. oxygen-glucose deprivation -induced cytotoxicity and NO production were also inhibited by N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor and MK-801. We conclude that mebudipine and dibudipine could protect cortical neurons against oxygen-glucose deprivation /reperfusion-induced cell injury in a dose-dependent manner, and that this could be mediated partially by decreased NO production.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cell Death; Cell Survival; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Formazans; Glucose; Hypoxia; Mice; N-Methylaspartate; Neurons; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Quinoxalines; Receptors, Kainic Acid; Reperfusion Injury; Tetrazolium Salts; Time Factors

Mebudipine and dibudipine are two newly synthesized dihydropyridine (DHP) calcium channel blockers that have been shown to have considerable relaxant effects on vascular and atrial smooth muscle. The in vitro half-lives of mebudipine and dibudipine are reported to be significantly longer than that of nifedipine. In this study, we investigated the effects of mebudipine and dibudipine on voltage-activated Ca2+ channels on differentiated PC12 cells and compared their potencies to amlodipine. Our results point to absence of voltage-activated Ca2+ currents in undifferentiated PC12 cells. It is also concluded that mebudipine and dibudipine, like amlodipine are L-type calcium channel blockers. When tested in a range of 10-100 microM, mebudipine is at least as potent as amlodipine in inhibition of peak Ba2+ currents in differentiated PC12 cells while dibudipine is significantly less potent compared to amlodipine and mebudipine.

Topics: Amlodipine; Animals; Barium Compounds; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Differentiation; Chlorides; Dose-Response Relationship, Drug; Membrane Potentials; Nerve Growth Factor; Neurons; Nifedipine; PC12 Cells; Rats

The inhibitory effects of calcium channel blockers; nifedipine and two new compounds, mebudipine and dibudipine, on contractions of isolated guinea-pig common bile duct were investigated. All the compounds tested induced a concentration-dependent reduction of the amplitude of contractile response to electrical stimulation and all the compounds displaced concentration-response curve of calcium chloride to the right in a concentration-dependent manner. The pIC50 values for these compounds acting on electrically stimulated common bile duct were calculated as: dibudipine: 8.50 +/- 0.17; mebudipine: 8.27 +/- 0.20; nifedipine: 7.96 +/- 0.07. The compounds also antagonized the contractile response of K+-depolarized guinea-pig common bile duct to cumulative concentration of calcium. However the inhibitory effect of these compounds were not significantly different.

Topics: Animals; Calcium Channel Blockers; Common Bile Duct; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Nifedipine; Parasympatholytics

The prototype 1,4-dihydropyridine (1,4-DHP) nifedipine, indicated for the management of hypertension and angina pectoris, has drawbacks of rapid onset of vasodilating action and a short half-life. Several newer analogues have been designed to offset these problems and these include mebudipine and dibudipine. These analogues contain t-butyl substituents that have been selected to alter the fast metabolism without altering pharmacological activity. In this study, the metabolism of mebudipine and dibudipine by isolated rat hepatocytes has been investigated. These compounds were extensively metabolized in 2 h by oxidative pathways, analogous to those known for nifedipine, and by O-glucuronidation after hydroxylation of the t-butyl substituents. The in-vitro half-lives of mebudipine (22 +/- 7.1 min) and dibudipine (40 +/- 9.8 min) were significantly longer than that of nifedipine (5.5 +/- 1.1 min), which was investigated in parallel in this study. These newer 1,4-DHPs address the problem of the short half-life of nifedipine and have potential for further development in view of their comparable potency to nifedipine.

Topics: Angina Pectoris; Animals; Cell Culture Techniques; Half-Life; Hepatocytes; Hydroxylation; Hypertension; Male; Nifedipine; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

Mebudipine and dibudipine are two new dihydropyridine (DHP) Ca2+ channel blockers that have been synthesized by Mahmoudian et al. (1997). In previous studies, they showed considerable relaxant effect on vascular and ileal smooth muscles. These two compounds also reduced the contraction force of rat left atrium (20, 22). In the present study, we attempted to compare the inhibitory actions of these new DHPs and nifedipine on the high threshold Ca2+ spikes of F1 neuronal soma membrane in the subesophageal ganglia of Helix aspersa, using current-clamp method. At a concentration of 1 microM, two new DHP compounds (mebudipine and dibudipine) were tested for their L-type Ca2+ channel blocker activity. Both compounds reversibly reduced the peak amplitude of action potential and after hyperpolarization potential and markedly decreased the duration of Ca2+ spikes. The most potent of these DHPs was mebudipine. Neither the two new DHPs nor nifedipine changed the resting membrane potential in a statistically significant way.

Topics: 4-Aminopyridine; Analysis of Variance; Animals; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Dose-Response Relationship, Drug; Electrophysiology; Esophagus; Helix, Snails; Membrane Potentials; Neurons; Nifedipine; Patch-Clamp Techniques

Mebudipine and dibudipine are two new dihydropyridine calcium-channel blockers that have been synthesized in our laboratory. In a previous study, they showed considerable relaxant effect on vascular and ileal smooth muscle. Here, the pharmacological effects of mebudipine and dibudipine on isolated rat left atrium, rat blood pressure and isolated human internal mammary artery are described. Results are compared with those obtained for nifedipine. Mebudipine and dibudipine reduced contraction force of rat left atrium (pIC30 values: 5.37+/-0.13 and 5.49+/-0.15, respectively) but their negative inotropic effects were significantly weaker than that of nifedipine (pIC30 value: 6.63+/-0.11). Mebudipine and dibudipine lowered rat blood pressure. The hypotensive effect of mebudipine was similar to that of nifedipine while dibudipine was weaker than nifedipine. It was found that the half-life of the hypotensive action of dibudipine (41.91+/-3.77 min, 31.13+/-2.26 min and 28.20+/-4.37 min at 2, 4 and 8 mg kg(-1) orally administered doses, respectively) was longer than that of nifedipine (11.85+/-2.88 min, 16.65+/-2.42 min and 14.03+/-0.10 min at the same doses, respectively). Also, it appeared that mebudipine had a slower rate of absorption compared with nifedipine (the time to reach peak hypotensive action at 2, 4 and 8 mg kg(-1) orally administered doses were, respectively, 24.00+/-6.96 min, 23.75+/-2.39 min and 15.00+/-2.04 min for mebudipine and 7.80+/-0.86 min, 13.75+/-3.15 min and 833+/-0.88 min for nifedipine). The two new compounds, as well as nifedipine, relaxed KCl-treated isolated human internal mammary artery (pEC50 values; 7.87+/-0.12, 7.22+/-0.24 and 7.67+/-0.12 for mebudipine, dibudipine and nifedipine, respectively). The relaxant effects of mebudipine and dibudipine did not show any significant difference compared with that of nifedipine. It is concluded that these new compounds are weak cardiodepressants and, with due attention to its significant vasorelaxant action, mebudipine is a vasoselective compound. In addition, these two compounds have potent blood pressure lowering effects. Also, their vasorelaxant action can be reproduced in human vascular preparations.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Heart Atria; Humans; Male; Mammary Arteries; Nifedipine; Rats; Rats, Sprague-Dawley

Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mM)-treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.

Topics: Animals; Aorta, Thoracic; Calcium; Calcium Channel Blockers; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Ileum; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Nifedipine; Potassium; Rats