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Masahiro Matsubara - One of the best experts on this subject based on the ideXlab platform.

  • Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by Benidipine, a dihydropyridine Ca2+ channel blocker.
    Life sciences, 2011
    Co-Authors: Atsushi Inayoshi, Masahiro Matsubara, Yoshiyuki Sugimoto, Jun Funahashi, Saori Takahashi, Hideaki Kusaka
    Abstract:

    Benidipine, a dihydropyridine Ca(2+) channel blocker, has been reported to block T-type Ca(2+) channels; however, the mechanism underlying this effect was unclear. In this study, we characterized the mechanism responsible for this blocking activity. Furthermore, the blocking activity was compared between two enantiomers of Benidipine, (S, S)- and (R, R)-Benidipine. Human Ca(v)3.2 (hCa(v)3.2) T-type Ca(2+) channels stably expressed in the human embryonic kidney cell line, HEK-293, were studied in whole-cell patch-clamp recordings and Ca(2+) mobilization assay. In whole-cell patch-clamp recordings, Benidipine blocked hCa(v)3.2 T-type Ca(2+) currents elicited by depolarization to a comparable extent as efonidipine. The block was dependent on stimulation frequency and holding potential, but not test potential. Benidipine significantly shifted the steady-state inactivation curve to the hyperpolarizing direction, but had no effect on the activation curve. Benidipine prolonged the recovery from inactivation of hCa(v)3.2 T-type Ca(2+) channels without any effect on the kinetics of activation, inactivation, or deactivation. In the Ca(2+) mobilization assay, Benidipine was more potent than efonidipine in blocking Ca(2+) influx through hCa(v)3.2 T-type Ca(2+) channels. (S, S)-Benidipine was more potent than (R, R)-Benidipine in blocking hCa(v)3.2 T-type Ca(2+) currents, but there was no difference in blocking the Ca(2+) influx. We have characterized the blocking activity of Benidipine against hCa(v)3.2 Ca(2+) channels and revealed the difference between the two enantiomers of Benidipine. The blocking action of Benidipine could be mediated by stabilizing hCa(v)3.2 Ca(2+) channels in an inactivated state. Copyright © 2011 Elsevier Inc. All rights reserved.

  • Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by Benidipine, a dihydropyridine Ca2+ channel blocker.
    Life Sciences, 2011
    Co-Authors: Atsushi Inayoshi, Masahiro Matsubara, Yoshiyuki Sugimoto, Jun Funahashi, Saori Takahashi, Hideaki Kusaka
    Abstract:

    Abstract Aims Benidipine, a dihydropyridine Ca 2+ channel blocker, has been reported to block T-type Ca 2+ channels; however, the mechanism underlying this effect was unclear. In this study, we characterized the mechanism responsible for this blocking activity. Furthermore, the blocking activity was compared between two enantiomers of Benidipine, (S, S)- and (R, R)-Benidipine. Main methods Human Ca v 3.2 (hCa v 3.2) T-type Ca 2+ channels stably expressed in the human embryonic kidney cell line, HEK-293, were studied in whole-cell patch-clamp recordings and Ca 2+ mobilization assay. Key findings In whole-cell patch-clamp recordings, Benidipine blocked hCa v 3.2 T-type Ca 2+ currents elicited by depolarization to a comparable extent as efonidipine. The block was dependent on stimulation frequency and holding potential, but not test potential. Benidipine significantly shifted the steady-state inactivation curve to the hyperpolarizing direction, but had no effect on the activation curve. Benidipine prolonged the recovery from inactivation of hCa v 3.2 T-type Ca 2+ channels without any effect on the kinetics of activation, inactivation, or deactivation. In the Ca 2+ mobilization assay, Benidipine was more potent than efonidipine in blocking Ca 2+ influx through hCa v 3.2 T-type Ca 2+ channels. (S, S)-Benidipine was more potent than (R, R)-Benidipine in blocking hCa v 3.2 T-type Ca 2+ currents, but there was no difference in blocking the Ca 2+ influx. Significance We have characterized the blocking activity of Benidipine against hCa v 3.2 Ca 2+ channels and revealed the difference between the two enantiomers of Benidipine. The blocking action of Benidipine could be mediated by stabilizing hCa v 3.2 Ca 2+ channels in an inactivated state.

  • The L-, N-, and T-type triple calcium channel blocker Benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family.
    European Journal of Pharmacology, 2010
    Co-Authors: Hiromichi Kosaka, Hideaki Kusaka, Kazunori Hirayama, Nobuyuki Yoda, Sasaki Katsutoshi, Tetsuya Kitayama, Masahiro Matsubara
    Abstract:

    Aldosterone-induced activation of mineralocorticoid receptor, a member of the nuclear receptor family, results in increased tissue damage such as vascular inflammation and cardiac and perivascular fibrosis. Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for hypertension and angina. Benidipine exhibits pleiotropic pharmacological features such as renoprotective and cardioprotective effects through triple blockade of L-, N-, and T-type calcium channels. However, the mechanism of additional beneficial effects on end-organ damage is poorly understood. Here, we examined the effects of Benidipine and other calcium channel blockers on aldosterone-induced mineralocorticoid receptor activation using luciferase reporter assay system. Benidipine showed more potent activity than efonidipine, amlodipine, or azelnidipine. Benidipine depressed the response to higher concentrations of aldosterone, whereas pretreatment of eplerenone, a steroidal mineralocorticoid receptor antagonist, did not. Binding studies using [3H] aldosterone indicated that Benidipine and other calcium channel blockers competed for binding to mineralocorticoid receptor. Benidipine and other calcium channel blockers showed antagonistic activity on Ser810 to Leu mutant mineralocorticoid receptor, which is identified in patients with early-onset hypertension. On the other hand, eplerenone partially activated the mutant. Results of analysis using optical isomers of Benidipine indicated that inhibitory effect of aldosterone-induced mineralocorticoid receptor activation was independent of its primary blockade of calcium channels. These results suggested that Benidipine directly inhibits aldosterone-induced mineralocorticoid receptor activation, and the antagonistic activity might contribute to the drug's pleiotropic pharmacological features.

  • blockade of t type voltage dependent ca2 channels by Benidipine a dihydropyridine calcium channel blocker inhibits aldosterone production in human adrenocortical cell line nci h295r
    European Journal of Pharmacology, 2008
    Co-Authors: Osamu Akizuki, Kozo Yao, Atsushi Inayoshi, Hideaki Kusaka, Shiro Shirakura, Tetsuya Kitayama, Katsutoshi Sasaki, Masahiro Matsubara
    Abstract:

    Abstract Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca 2+ channels. More recently, it has been demonstrated that Benidipine inhibits T-type Ca 2+ channels in addition to L-type Ca 2+ channels. Therefore, effect of calcium channel blockers, including Benidipine, on aldosterone production and T-type Ca 2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that Benidipine concentration-dependently inhibited T-type Ca 2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca 2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca 2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-β-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca 2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca 2+ influx inhibitory activities of Benidipine for aldosterone production. T-type Ca 2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca 2+ channels.

  • Benidipine an anti hypertensive drug inhibits reactive oxygen species production in polymorphonuclear leukocytes and oxidative stress in salt loaded stroke prone spontaneously hypertensive rats
    European Journal of Pharmacology, 2008
    Co-Authors: Masahiro Matsubara, Jun-ichi Ikeda, Kozo Yao, Osamu Akizuki, Koji Saeki, Katsutoshi Sasaki
    Abstract:

    Abstract Oxidative stress is associated with exacerbation of renal injuries in hypertension. In clinical studies Benidipine hydrochloride (Benidipine), a dihydropyridine calcium channel blocker with antioxidant activity, reduced oxidative stress. However, the mechanism of suppression of oxidative stress remains to be fully characterized. Reactive oxygen species production by polymorphonuclear leukocyte plays important pathological roles in hypertension. Therefore, we examined the effects of Benidipine both on reactive oxygen species production of human polymorphonuclear leukocytes and oxidative stress of an animal model. Human peripheral polymorphonuclear leukocytes or polymorphonuclear leukocyte-like differentiated HL-60 cells were used to examine effects of Benidipine (0.1–30 μM) on formyl-Met-Leu-Phe-induced reactive oxygen species production, calcium mobilization, NADPH oxidase activation and phosphorylation of protein kinase C substrates. High-salt (8% NaCl) loaded stroke-prone spontaneously hypertensive rats were treated with or without Benidipine (1, 3, 10 mg/kg/day) for 2 weeks, and thiobarbituric acid reactive substances, a plasma oxidative stress marker, and renal expression of oxidative stress-induced genes were measured. Benidipine concentration-dependently suppressed formyl-Met-Leu-Phe-induced reactive oxygen species production in polymorphonuclear leukocytes more potently than other calcium channel blockers such as amlodipine, azelnidipine, nitrendipine and nifedipine. Benidipine partially inhibited all of intracellular Ca 2+ elevation, protein kinase C activation and NADPH oxidase activation. Salt loading in stroke-prone spontaneously hypertensive rats augmented plasma thiobarbituric acid reactive substances levels; renal dysfunction; and renal expression of transforming growth factor-β, collagen I and collagen III mRNAs; which were attenuated by Benidipine treatment. These results indicate that Benidipine prevents the polymorphonuclear leukocyte-derived reactive oxygen species production, which is due at least in part to its antioxidant action and inhibition of Ca 2+ /protein kinase C/NADPH oxidase signaling. The attenuation of reactive oxygen species production might contribute to the drug's reduction of oxidative stress and renal injuries in hypertension.

Kozo Yao - One of the best experts on this subject based on the ideXlab platform.

  • The dihydropyridine calcium channel blocker Benidipine prevents lysophosphatidylcholine-induced endothelial dysfunction in rat aorta
    Journal of biomedical science, 2009
    Co-Authors: Makoto Takayama, Kozo Yao, Michihito Wada
    Abstract:

    Background Lysophosphatidylcholine (LPC), an atherogenic component of oxidized low-density lipoprotein, has been shown to induce the attenuation of endothelium-dependent vascular relaxation. Although Benidipine, a dihydropyridine-calcium channel blocker, is known to have endothelial protective effects, the effects of Benidipine on LPC-induced endothelial dysfunction remain unknown. We examined the effects of Benidipine on the impairment of endothelium-dependent relaxation induced by LPC.

  • blockade of t type voltage dependent ca2 channels by Benidipine a dihydropyridine calcium channel blocker inhibits aldosterone production in human adrenocortical cell line nci h295r
    European Journal of Pharmacology, 2008
    Co-Authors: Osamu Akizuki, Kozo Yao, Atsushi Inayoshi, Hideaki Kusaka, Shiro Shirakura, Tetsuya Kitayama, Katsutoshi Sasaki, Masahiro Matsubara
    Abstract:

    Abstract Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca 2+ channels. More recently, it has been demonstrated that Benidipine inhibits T-type Ca 2+ channels in addition to L-type Ca 2+ channels. Therefore, effect of calcium channel blockers, including Benidipine, on aldosterone production and T-type Ca 2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that Benidipine concentration-dependently inhibited T-type Ca 2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca 2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca 2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-β-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca 2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca 2+ influx inhibitory activities of Benidipine for aldosterone production. T-type Ca 2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca 2+ channels.

  • Benidipine an anti hypertensive drug inhibits reactive oxygen species production in polymorphonuclear leukocytes and oxidative stress in salt loaded stroke prone spontaneously hypertensive rats
    European Journal of Pharmacology, 2008
    Co-Authors: Masahiro Matsubara, Jun-ichi Ikeda, Kozo Yao, Osamu Akizuki, Koji Saeki, Katsutoshi Sasaki
    Abstract:

    Abstract Oxidative stress is associated with exacerbation of renal injuries in hypertension. In clinical studies Benidipine hydrochloride (Benidipine), a dihydropyridine calcium channel blocker with antioxidant activity, reduced oxidative stress. However, the mechanism of suppression of oxidative stress remains to be fully characterized. Reactive oxygen species production by polymorphonuclear leukocyte plays important pathological roles in hypertension. Therefore, we examined the effects of Benidipine both on reactive oxygen species production of human polymorphonuclear leukocytes and oxidative stress of an animal model. Human peripheral polymorphonuclear leukocytes or polymorphonuclear leukocyte-like differentiated HL-60 cells were used to examine effects of Benidipine (0.1–30 μM) on formyl-Met-Leu-Phe-induced reactive oxygen species production, calcium mobilization, NADPH oxidase activation and phosphorylation of protein kinase C substrates. High-salt (8% NaCl) loaded stroke-prone spontaneously hypertensive rats were treated with or without Benidipine (1, 3, 10 mg/kg/day) for 2 weeks, and thiobarbituric acid reactive substances, a plasma oxidative stress marker, and renal expression of oxidative stress-induced genes were measured. Benidipine concentration-dependently suppressed formyl-Met-Leu-Phe-induced reactive oxygen species production in polymorphonuclear leukocytes more potently than other calcium channel blockers such as amlodipine, azelnidipine, nitrendipine and nifedipine. Benidipine partially inhibited all of intracellular Ca 2+ elevation, protein kinase C activation and NADPH oxidase activation. Salt loading in stroke-prone spontaneously hypertensive rats augmented plasma thiobarbituric acid reactive substances levels; renal dysfunction; and renal expression of transforming growth factor-β, collagen I and collagen III mRNAs; which were attenuated by Benidipine treatment. These results indicate that Benidipine prevents the polymorphonuclear leukocyte-derived reactive oxygen species production, which is due at least in part to its antioxidant action and inhibition of Ca 2+ /protein kinase C/NADPH oxidase signaling. The attenuation of reactive oxygen species production might contribute to the drug's reduction of oxidative stress and renal injuries in hypertension.

  • Pharmacological, pharmacokinetic, and clinical properties of Benidipine hydrochloride, a novel, long-acting calcium channel blocker.
    Journal of pharmacological sciences, 2006
    Co-Authors: Kozo Yao, Ken Nagashima, Hiroyuki Miki
    Abstract:

    Benidipine is a dihydropyridine-derived calcium channel blocker developed in Japan, with several unique mechanisms of action, that is, triple calcium channels (L, N, and T) blocking action with a membrane approach. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of Benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, Benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, Benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate anti-hypertensive effects are not achieved by ARBs alone, indicating that Benidipine is an useful calcium channel blocker in combination therapy for hypertension. Benidipine was launched on the Japanese market 14 years ago, but few severe side effects have been reported, suggesting that this is a drug with established safety and long-acting pharmacological effects.

  • Combined effects of Benidipine and diltiazem on cardiohemodynamics in anesthetized dogs.
    Biological & pharmaceutical bulletin, 2006
    Co-Authors: Kozo Yao, Hiroshi Maeda, Yasuhiro Ina, Miwa Sato, Kazuhiro Fujita, Takashi Kuwabara, Hiroyuki Kobayashi, Shiro Shirakura
    Abstract:

    We examined the combined effects of the calcium channel blockers 1,4-dihydropyridine (Benidipine) and benzothiazepine (diltiazem) on cardiohemodynamics in anesthetized dogs. Benidipine (3 μg/kg) lowered blood pressure (BP) slightly and continuously increased coronary flow (CF). Diltiazem (300, 1000 μg/kg) decreased BP, heart rate (HR), and the maximum rate of rise of left ventricular pressure (LV dP/dt max) with the increase of doses. Diltiazem increased CF, though it was transient when compared to Benidipine. A combination of Benidipine (3 μg/kg) and diltiazem (300 μg/kg) showed continuous decreases in BP, HR, and LV dP/dt max, and an increase in CF that was similar to that recorded for the Benidipine group. The level of double product (DP: systolic BP×HR, an index of myocardium energy consumption) in the combination group was significantly lower than that of the Benidipine group. The plasma concentrations of Benidipine and diltiazem in the combination group were similar to those of the groups receiving either drug. These results demonstrate that the combination of Benidipine and diltiazem increases CF more continuously than diltiazem alone, and decreases DP more potently than Benidipine alone, indicating that the combination therapy possesses favorable properties as a treatment for angina pectoris. Therefore, the combination of Benidipine and diltiazem is suggested as a useful treatment for improving the clinical benefits of monotherapy for angina, compared with the use of diltiazem alone at higher doses.

Hideaki Kusaka - One of the best experts on this subject based on the ideXlab platform.

  • Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by Benidipine, a dihydropyridine Ca2+ channel blocker.
    Life sciences, 2011
    Co-Authors: Atsushi Inayoshi, Masahiro Matsubara, Yoshiyuki Sugimoto, Jun Funahashi, Saori Takahashi, Hideaki Kusaka
    Abstract:

    Benidipine, a dihydropyridine Ca(2+) channel blocker, has been reported to block T-type Ca(2+) channels; however, the mechanism underlying this effect was unclear. In this study, we characterized the mechanism responsible for this blocking activity. Furthermore, the blocking activity was compared between two enantiomers of Benidipine, (S, S)- and (R, R)-Benidipine. Human Ca(v)3.2 (hCa(v)3.2) T-type Ca(2+) channels stably expressed in the human embryonic kidney cell line, HEK-293, were studied in whole-cell patch-clamp recordings and Ca(2+) mobilization assay. In whole-cell patch-clamp recordings, Benidipine blocked hCa(v)3.2 T-type Ca(2+) currents elicited by depolarization to a comparable extent as efonidipine. The block was dependent on stimulation frequency and holding potential, but not test potential. Benidipine significantly shifted the steady-state inactivation curve to the hyperpolarizing direction, but had no effect on the activation curve. Benidipine prolonged the recovery from inactivation of hCa(v)3.2 T-type Ca(2+) channels without any effect on the kinetics of activation, inactivation, or deactivation. In the Ca(2+) mobilization assay, Benidipine was more potent than efonidipine in blocking Ca(2+) influx through hCa(v)3.2 T-type Ca(2+) channels. (S, S)-Benidipine was more potent than (R, R)-Benidipine in blocking hCa(v)3.2 T-type Ca(2+) currents, but there was no difference in blocking the Ca(2+) influx. We have characterized the blocking activity of Benidipine against hCa(v)3.2 Ca(2+) channels and revealed the difference between the two enantiomers of Benidipine. The blocking action of Benidipine could be mediated by stabilizing hCa(v)3.2 Ca(2+) channels in an inactivated state. Copyright © 2011 Elsevier Inc. All rights reserved.

  • Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by Benidipine, a dihydropyridine Ca2+ channel blocker.
    Life Sciences, 2011
    Co-Authors: Atsushi Inayoshi, Masahiro Matsubara, Yoshiyuki Sugimoto, Jun Funahashi, Saori Takahashi, Hideaki Kusaka
    Abstract:

    Abstract Aims Benidipine, a dihydropyridine Ca 2+ channel blocker, has been reported to block T-type Ca 2+ channels; however, the mechanism underlying this effect was unclear. In this study, we characterized the mechanism responsible for this blocking activity. Furthermore, the blocking activity was compared between two enantiomers of Benidipine, (S, S)- and (R, R)-Benidipine. Main methods Human Ca v 3.2 (hCa v 3.2) T-type Ca 2+ channels stably expressed in the human embryonic kidney cell line, HEK-293, were studied in whole-cell patch-clamp recordings and Ca 2+ mobilization assay. Key findings In whole-cell patch-clamp recordings, Benidipine blocked hCa v 3.2 T-type Ca 2+ currents elicited by depolarization to a comparable extent as efonidipine. The block was dependent on stimulation frequency and holding potential, but not test potential. Benidipine significantly shifted the steady-state inactivation curve to the hyperpolarizing direction, but had no effect on the activation curve. Benidipine prolonged the recovery from inactivation of hCa v 3.2 T-type Ca 2+ channels without any effect on the kinetics of activation, inactivation, or deactivation. In the Ca 2+ mobilization assay, Benidipine was more potent than efonidipine in blocking Ca 2+ influx through hCa v 3.2 T-type Ca 2+ channels. (S, S)-Benidipine was more potent than (R, R)-Benidipine in blocking hCa v 3.2 T-type Ca 2+ currents, but there was no difference in blocking the Ca 2+ influx. Significance We have characterized the blocking activity of Benidipine against hCa v 3.2 Ca 2+ channels and revealed the difference between the two enantiomers of Benidipine. The blocking action of Benidipine could be mediated by stabilizing hCa v 3.2 Ca 2+ channels in an inactivated state.

  • The L-, N-, and T-type triple calcium channel blocker Benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family.
    European Journal of Pharmacology, 2010
    Co-Authors: Hiromichi Kosaka, Hideaki Kusaka, Kazunori Hirayama, Nobuyuki Yoda, Sasaki Katsutoshi, Tetsuya Kitayama, Masahiro Matsubara
    Abstract:

    Aldosterone-induced activation of mineralocorticoid receptor, a member of the nuclear receptor family, results in increased tissue damage such as vascular inflammation and cardiac and perivascular fibrosis. Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for hypertension and angina. Benidipine exhibits pleiotropic pharmacological features such as renoprotective and cardioprotective effects through triple blockade of L-, N-, and T-type calcium channels. However, the mechanism of additional beneficial effects on end-organ damage is poorly understood. Here, we examined the effects of Benidipine and other calcium channel blockers on aldosterone-induced mineralocorticoid receptor activation using luciferase reporter assay system. Benidipine showed more potent activity than efonidipine, amlodipine, or azelnidipine. Benidipine depressed the response to higher concentrations of aldosterone, whereas pretreatment of eplerenone, a steroidal mineralocorticoid receptor antagonist, did not. Binding studies using [3H] aldosterone indicated that Benidipine and other calcium channel blockers competed for binding to mineralocorticoid receptor. Benidipine and other calcium channel blockers showed antagonistic activity on Ser810 to Leu mutant mineralocorticoid receptor, which is identified in patients with early-onset hypertension. On the other hand, eplerenone partially activated the mutant. Results of analysis using optical isomers of Benidipine indicated that inhibitory effect of aldosterone-induced mineralocorticoid receptor activation was independent of its primary blockade of calcium channels. These results suggested that Benidipine directly inhibits aldosterone-induced mineralocorticoid receptor activation, and the antagonistic activity might contribute to the drug's pleiotropic pharmacological features.

  • blockade of t type voltage dependent ca2 channels by Benidipine a dihydropyridine calcium channel blocker inhibits aldosterone production in human adrenocortical cell line nci h295r
    European Journal of Pharmacology, 2008
    Co-Authors: Osamu Akizuki, Kozo Yao, Atsushi Inayoshi, Hideaki Kusaka, Shiro Shirakura, Tetsuya Kitayama, Katsutoshi Sasaki, Masahiro Matsubara
    Abstract:

    Abstract Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca 2+ channels. More recently, it has been demonstrated that Benidipine inhibits T-type Ca 2+ channels in addition to L-type Ca 2+ channels. Therefore, effect of calcium channel blockers, including Benidipine, on aldosterone production and T-type Ca 2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that Benidipine concentration-dependently inhibited T-type Ca 2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca 2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca 2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-β-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca 2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca 2+ influx inhibitory activities of Benidipine for aldosterone production. T-type Ca 2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca 2+ channels.

  • Effects of Benidipine on Renal Function in Anesthetized Spontaneously Hypertensive Rats
    Japanese journal of pharmacology, 1994
    Co-Authors: Hideaki Kusaka, Hiroko Nomura, Akira Karasawa
    Abstract:

    Effects of Benidipine on urine volume, excretion of electrolytes and renal hemodynamics were investigated in anesthetized spontaneously hypertensive rats (SHR). Benidipine at 3 and 10 μg/kg (i.v.) significantly increased urine volume, sodium (Na) and potassium (K) excretion with no change of creatinine clearance (CCRE). The increase in K excretion was relatively slight when compared with that in Na excretion. In another series of experiments, the tubular sites of action of Benidipine were determined by the lithium clearance (CLi) technique and the stop-flow method. Benidipine at 3 μg/kg (i.v.) increased CLi, decreased creatinine concentration and increased Na concentration in the stop-flow urine from the distal nephron. These results suggest that Benidipine produces diuresis and natriuresis by the inhibition of water and Na reabsorption at both the proximal tubule and the distal nephron. Benidipine increased p-aminohippuric acid clearance, but not CCRE, at doses of 3 and 10 μg/kg (i.v.), suggesting that Benidipine dilates the glomerular efferent arteriole as well as the afferent arteriole. It is, therefore, expected that Benidipine does not cause intraglomerular hypertension and has a beneficial effect in progressive renal disease.

Jae-gook Shin - One of the best experts on this subject based on the ideXlab platform.

  • Effect of rifampin on enantioselective disposition and anti-hypertensive effect of Benidipine.
    British journal of clinical pharmacology, 2019
    Co-Authors: Yu Eun Sunwoo, Phuong Thi Thu Nguyen, Chin May Chien, Ji Young Ryu, Ji-hong Shon, Jae-gook Shin
    Abstract:

    AIMS In vitro study showed that Benidipine is exclusively metabolized by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of Benidipine. METHODS Benidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)-(S)-(+)-α and (R)-(R)-(-)-α isomers of Benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam. RESULTS The exposure of (S)-(S)-(+)-α-Benidipine was greater than that of (R)-(R)-(-)-α-Benidipine by approximately three-fold following single dose of Benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of Cmax and AUC∞ for (S)-(S)-(+)-α-Benidipine were 0.14 (0.10-0.18) and 0.12 (0.08-0.18), respectively. GMRs (95% CI) of Cmax and AUC∞ for (R)-(R)-(-)-α-Benidipine were 0.10 (0.06-0.17) and 0.10 (0.06-0.17), respectively. Oral clearances of both isomers were increased equally by approximately 10-fold. There were no significant differences in cardiovascular effect following Benidipine administration between control and rifampin treatment. CYP3A activity using midazolam did not appear to correlate with oral clearance of Benidipine. CONCLUSIONS After single administration of racemic Benidipine, enantioselective disposition of (S)-(S)-(+)-α- and (R)-(R)-(-)-α-Benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure-lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of Benidipine should be assessed in hypertensive patients.

  • Characterization of Benidipine and its enantiomers' metabolism by human liver cytochrome P450 enzymes.
    Drug metabolism and disposition: the biological fate of chemicals, 2007
    Co-Authors: Yune-jung Yoon, Kwon-bok Kim, Hyun-mi Kim, Kyung-ah Seo, Ho-sook Kim, In-june Cha, Eun Young Kim, Kwang-hyeon Liu, Jae-gook Shin
    Abstract:

    Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (-)-α and (+)-α isomers of Benidipine. This study was performed to elucidate the metabolism of Benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of Benidipine. Human liver microsomal incubation of Benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylBenidipine and dehydroBenidipine. The intrinsic clearance (CLint) of the formation of N-desbenzylBenidipine and dehydroBenidipine metabolites from (-)-α isomer was similar to those from the (+)-α isomer (1.9 ± 0.1 versus 2.3 ± 2.3 μl/min/pmol P450 and 0.5 ± 0.2 versus 0.6 ± 0.6 μl/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of Benidipine metabolites in the 15 HLMs showed that Benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that theN-debenzylation and dehydrogenation of Benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CLint values of CYP3A4-mediated metabolite formation from (-)-α isomer were similar to those from (+)-α isomer (17.7 versus 14.4 μl/min/pmol P450, respectively). The total CLint values of CYP3A5-mediated metabolite formation from (-)-α isomer were also similar to those from (+)-α isomer (8.3 versus 11.0 μl/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of Benidipine, but stereoselective disposition of Benidipine in vivo may be influenced not by stereoselective metabolism but by other factors.

  • Characterization of Benidipine and Its Enantiomers ’ Metabolism by Human Liver Cytochrome P450 Enzymes
    2007
    Co-Authors: Yune-jung Yoon, Kwon-bok Kim, Hyun-mi Kim, Kyung-ah Seo, Ho-sook Kim, In-june Cha, Eun Young Kim, Kwang-hyeon Liu, Jae-gook Shin
    Abstract:

    Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the ()- and ()- iso-mers of Benidipine. This study was performed to elucidate the metabolism of Benidipine and its enantiomers in human liver mi-crosomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of Benidipine. Human liver microsomal incubation of Benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzyl-Benidipine and dehydroBenidipine. The intrinsic clearance (CLint) of the formation of N-desbenzylBenidipine and dehydroBenidipine metabolites from ()- isomer was similar to those from the ()- isomer (1.9 0.1 versus 2.3 2.3 l/min/pmol P450 and 0.5 0.2 versus 0.6 0.6 l/min/pmol P450, respectively). Correlation anal-ysis between the known P450 enzyme activities and the rate of th

  • analysis of Benidipine enantiomers in human plasma by liquid chromatography mass spectrometry using a macrocyclic antibiotic vancomycin chiral stationary phase column
    Journal of Chromatography B, 2005
    Co-Authors: Wonku Kang, Yu Eun Sunwoo, In-june Cha, Kwang-hyeon Liu, Kwang-il Kwon, Dongjun Lee, Jae-gook Shin
    Abstract:

    We used a novel chromatographic method to rapidly and simply characterize the pharmacokinetics of Benidipine enantiomers in human plasma. The stereoisomers of Benidipine were extracted from plasma using diethylether under alkaline conditions. After evaporating the organic layer, the residue was reconstituted in the mobile phase (methanol:acetic acid:triethylamine, 100:0.01:0.0001, v/v/v). The enantiomers in the extract were separated on a macrocyclic antibiotic (Vancomycin) chiral stationary phase column. The mobile phase was eluted at 1 ml/min and was split by an interface. One-fifth of the eluent was used to quantify both isomers in a tandem mass spectrometer in multiple reactionmonitoring mode. The coefficient of variation of the precision of the assay was less than 8%, the assay accuracy was between 93.4 and 113.3%, and the limit of detection was 0.05 ng/ml for 1 ml of plasma. The method described above was used to measure the concentration of both Benidipine enantiomers in plasma from healthy subjects who received a single oral dose of a racemate of 8 mg Benidipine. The Cmax and AUCinf values of (+)-alpha Benidipine were higher than those of (−)-alpha Benidipine by 1.96- and 1.85-fold, respectively ( p < 0.001), whereas, the Tmax and t1/2 for each of the Benidipine stereoisomers were not significantly different. © 2004 Elsevier B.V. All rights reserved.

  • Determination of Benidipine in human plasma using liquid chromatography–tandem mass spectrometry
    Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2004
    Co-Authors: Wonku Kang, Kwang-hyeon Liu, Hwi-yeol Yun, Kwang-il Kwon, Jae-gook Shin
    Abstract:

    Abstract We developed a method for determining Benidipine, a dihydropyridine analogue calcium-channel blocker, in plasma using liquid chromatography–tandem mass spectrometry (LC–MS–MS). Benidipine and Benidipine-d 5 , an internal standard, were extracted from plasma using diethyl ether in the presence of 5 M NaOH. After drying the organic layer, the residue was reconstituted in acetonitrile and injected onto a reversed-phase C 18 column. The isocratic mobile phase (acetonitrile–5 mM ammonium acetate, 90:10, v/v) was eluted at 0.2 ml/min. The ion transitions monitored in multiple reaction-monitoring mode were m / z 506–174 for Benidipine and m / z 511–179 for the internal standard. The coefficient of variation of the assay precision was less than 13%, and the accuracy exceeded 92%, except at the limit of quantification, 0.05 ng/ml with 1 ml of plasma, when it was 85%. This method was used to measure the Benidipine concentration in plasma from healthy subjects after a single 4-mg oral dose of Benidipine. This method is a very simple, sensitive, and accurate way to determine the plasma Benidipine concentration.

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  • Effects of Benidipine hydrochloride (Coniel) on blood pressure, heart rate and plasma norepinephrine concentration in spontaneously hypertensive rats
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 1999
    Co-Authors: Akira Karasawa, Hiroko Nomura, Rie Sonoda, Masaaki Nito, Hideyuki Tanaka, Nobuo Kosaka, Kazuo Yamaguchi, Satoshi Kobayashi
    Abstract:

    We investigated the effects of Benidipine hydrochloride (Benidipine, Coniel) on blood pressure, heart rate and plasma norepinephrine (NE) concentration in spontaneously hypertensive rats and compared them with those of other calcium channel blockers. Benidipine (2 mg/kg, p.o.) was compared with the equihypotensive doses of nifedipine (5 mg/kg), cilnidipine (6 mg/kg) and amlodipine (3 mg/kg). All the 4 calcium channel blockers exhibited significant antihypertensive effects. Nifedipine and cilinidipine significantly increased heart rate, as compared with that in the control group, whereas Benidipine or amlodipine did not significantly affect it. The area under the curves for hypotensive effect and tachycardic effect for 10 hr after the drug administration were compared among the 4 compounds. As a result, the tachycardic effect of Benidipine was significantly lower than those of nifedipine, cilnidipine and amlodipine, while the hypotensive effects were similar among the 4 compounds. Nifedipine and amlodipine, significantly increased plasma NE concentration, cilnidipine tended to increase it. In contrast, Benidipine did not significantly affect plasma NE concentration. These results suggest that the effects of Benidipine on plasma NE concentration and heart rate are less prominent than those of the other calcium channel blockers.

  • Effects of Benidipine, a long-acting calcium antagonist, on renal functions in anaesthetized spontaneously hypertensive rats.
    Clinical and experimental pharmacology & physiology. Supplement, 1995
    Co-Authors: Hiroko Nomura, H. Kusaka, Akira Karasawa
    Abstract:

    Summary 1. The effects of Benidipine, a long-acting calcium antagonist, on renal functions were determined in anaesthetized spontaneously hypertensive rats (SHR), as compared with those of amlodipine. 2. Benidipine at 3 and 10 μg/kg (i.v.) significantly increased urine volume, sodium (Na) and potassium (K) excretions with no change in creatinine clearance (C-CRE). The increase in K excretion was relatively slight. Benidipine increased p-amino-hippuric acid clearance (C-PAH) without any change in C-CRE and, thus, decreased filtration fraction (FF). 3. On the other hand, amlodipine at 300 μg/kg (i.v.) significantly increased Na and K excretions, but did not change FF. 4. Thus Benidipine, but not amlodipine, can dilate glomerular efferent arteriole as well as afferent arteriole in SHR. It is, therefore, expected that Benidipine would not induce intraglomerular hypertension, which could result in the progression of glomerular injury. 5. Benidipine at 3 μg/kg (i.v.) increased lithium clearance, while it decreased CRE concentration and increased Na concentration in the stop-flow urine from the distal tubule. 6. These results suggest that Benidipine produces diuresis by the inhibition of water and Na reabsorption at both the proximal and the distal tubules.

  • Suppressive effects of Benidipine on the development of hypertension and renal lesions in salt-loaded stroke-prone spontaneously hypertensive rats.
    Clinical and experimental pharmacology & physiology. Supplement, 1995
    Co-Authors: M. Nito, Akira Karasawa, H. Sato, T. Hara, K. Yamada, Yoshio Ohta
    Abstract:

    Summary 1. The effects of Benidipine hydrochloride (Benidipine), a long-acting dihydropyridine calcium antagonist, on the development of hypertension and renal lesions were examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were fed with 8% NaCl diet for 3 weeks from 13 weeks of age, and Benidipine (1 or 3 mg/kg per day) was orally administered during the same period. 3. The high salt diet accelerated an increase in urinary excretions of total protein and albumin, and caused marked arteriole, glomerular and tubular lesions in the kidney. 4. Benidipine significantly inhibited these changes, and also suppressed the elevation of blood pressure in salt-loaded SHRSP. 5. These results reveal that Benidipine has protective effects against the development of hypertension and the progression of renal lesions induced by the high salt diet in SHRSP.

  • Effects of Benidipine on Renal Function in Anesthetized Spontaneously Hypertensive Rats
    Japanese journal of pharmacology, 1994
    Co-Authors: Hideaki Kusaka, Hiroko Nomura, Akira Karasawa
    Abstract:

    Effects of Benidipine on urine volume, excretion of electrolytes and renal hemodynamics were investigated in anesthetized spontaneously hypertensive rats (SHR). Benidipine at 3 and 10 μg/kg (i.v.) significantly increased urine volume, sodium (Na) and potassium (K) excretion with no change of creatinine clearance (CCRE). The increase in K excretion was relatively slight when compared with that in Na excretion. In another series of experiments, the tubular sites of action of Benidipine were determined by the lithium clearance (CLi) technique and the stop-flow method. Benidipine at 3 μg/kg (i.v.) increased CLi, decreased creatinine concentration and increased Na concentration in the stop-flow urine from the distal nephron. These results suggest that Benidipine produces diuresis and natriuresis by the inhibition of water and Na reabsorption at both the proximal tubule and the distal nephron. Benidipine increased p-aminohippuric acid clearance, but not CCRE, at doses of 3 and 10 μg/kg (i.v.), suggesting that Benidipine dilates the glomerular efferent arteriole as well as the afferent arteriole. It is, therefore, expected that Benidipine does not cause intraglomerular hypertension and has a beneficial effect in progressive renal disease.

  • Cardiovascular Effects of Benidipine and Amlodipine in Isolated Tissues and Anesthetized Dogs
    Biological & pharmaceutical bulletin, 1994
    Co-Authors: Takahiro Moriyama, Akira Karasawa
    Abstract:

    Benidipine and amlodipine, 1,4-dihydropyridine calcium channel blocking drugs, are long-acting antihypertensive and antianginal drugs. In the present study, the vascular-selectivity and duration of action of Benidipine were determined in vitro and in vivo, and compared with those of amlodipine. The relaxing effect of Benidipine on the canine coronary artery precontracted by KCl (55 mM) was about 40 times that of amlodipine. The negative inotropic effect of Benidipine in the electrically-stimulated canine right ventricular papillary muscle was about twice that of amlodipine. The potency ratios of the vasorelaxing effect in the coronary artery and the negative inotropic effect in papillary muscle were 1300 for Benidipine and 67 for amlodipine, respectively. In anesthetized dogs, the maximum hypotensive effect and the duration of action of 3 micrograms/kg (i.v.) Benidipine was almost the same as those of 500 micrograms/kg (i.v.) amlodipine. The duration of the hypotensive action of Benidipine at 10 micrograms/kg (i.v.) was almost the same as that of amlodipine at 1500 micrograms/kg (i.v.). Amlodipine at 1500 micrograms/kg (i.v.) reduced mean blood pressure and left ventricular dp/dt max immediately after its administration, whereas such transient falls were not observed after the administration of Benidipine at 10 micrograms/kg (i.v.). These results suggest that Benidipine possesses a stronger vasodilating effect and a higher vascular-selectivity, compared with amlodipine.