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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.

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Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide.

Jörg Hoffmann, Judith Haendeler, Alexandra Aicher … (2001)

Advanced aging leads to impaired endothelial NO synthesis and enhanced endothelial cell apoptosis; therefore, we investigated the sensitivity of aged endothelial cells toward apoptotic stimuli and determined the role of NO. Human umbilical vein endothelial cells (HUVECs) were cultured until 14th passage. In aged cells, oxLDL and tumor necrosis factor-alpha-induced apoptosis and caspase-3-like activity were significantly enhanced more than 3-fold compared with young cells (passage 3). Because NO contributes to protection against endothelial cell death via S-nitrosylation of caspases, we determined endothelial NO synthase (eNOS) protein expression and the content of S-nitrosylated proteins. Aged HUVECs showed significantly reduced eNOS expression (35+/-10%) and a decrease in the overall S-NO content (33+/-3%), suggesting that eNOS downregulation may be involved in age-dependent increase of apoptosis sensitivity. Indeed, eNOS knockout endothelial cells showed a significantly enhanced apoptosis induction. Exogenous NO donors abolished increased apoptosis and caspase-3-like activity. In contrast, the application of shear stress, which exerts a profound apoptosis inhibitory effect via upregulation of NO synthesis in young cells, failed to inhibit apoptosis in aged cells. Moreover, no upregulation of eNOS protein expression and S-NO content in response to shear stress was detected in aged cells. Overexpression of wild-type eNOS completely restored the antiapoptotic effect of shear stress, whereas only a partial inhibitory effect was detected under steady conditions. Strikingly, transfection of constitutively active phosphomimetic eNOS (S1177D) further abrogated apoptosis in aged HUVECs. Thus, aging of endothelial cells is associated with decreased NO synthesis and concomitantly increased sensitivity of apoptosis, which may contribute to functional impairment of the endothelial monolayer.

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Receptor sites for Ca2+ channel antagonists.

William Catterall, Jörg Striessnig (1992)

Ca2+ channel antagonist drugs inhibit voltage-gated Ca2+ channels in many different cell types. Inhibition of Ca2+ channels in smooth muscle and cardiac muscle cells by these drugs is valuable in the therapy of a wide range of cardiovascular disorders including hypertension, atrial arrhythmia and angina pectoris. Additional uses under evaluation are protection against ischemic damage during myocardial infarction and stroke and in a wide range of other conditions. Further understanding of the sites and mechanisms of action of Ca2+ channel antagonists, as described in this review by Bill Catterall and Jörg Striessnig, will provide new insight into the design of novel therapeutic agents acting on Ca2+ channels and provide further understanding of Ca2+ channel structure and function.

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Ion channels and regulation of intracellular calcium in vascular endothelial cells.

J. Adams, Marcory van Dijk, R Laskey … (1989)

Endothelial cells in vivo form an interface between flowing blood and vascular tissue, responding to humoral and physical stimuli to secrete relaxing and contracting factors that contribute to vascular homeostasis and tone. The activation of endothelial cell-surface receptors by vasoactive agents is coupled to an elevation in cytosolic Ca2+, which is caused by Ca2+ entry via ion channels in the plasma membrane and by Ca2+ release from intracellular stores. Ca2+ entry may occur via four different mechanisms: 1) a receptor-mediated channel coupled to second messengers; 2) a Ca2+ leak channel dependent on the electrochemical gradient for Ca2+; 3) a stretch-activated nonselective cation channel; and 4) internal Na+-dependent Ca2+ entry (Na+-Ca2+ exchange). The rate of Ca2+ entry through these ion pathways can be modulated by the resting membrane potential. Membrane potential may be regulated by at least two types of K channels: inwardly rectifying K channels activated upon hyperpolarization or shear stress; and a Ca2+-activated K channel activated upon depolarization, which may function to repolarize the agonist-stimulated endothelial cell. After agonist stimulation, cytosolic Ca2+ increases in a biphasic manner, with an initial peak due to inositol 1,4,5-trisphosphate-mediated Ca2+ release from intracellular stores, followed by a sustained plateau that is dependent on the presence of [Ca2+]o and on membrane potential. The delay in agonist-activated Ca2+ influx is consistent with the coupling of receptor activation to Ca2+ entry via a second messenger. Oscillations in [Ca2+]i, which may involve both Ca2+ entry and release, have been observed in isolated and confluent endothelial cell monolayers stimulated by histamine and bradykinin. Receptor-mediated Ca2+ entry, release, and refilling of intracellular stores follows a cycle that involves the plasma membrane.

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PubMed ID:: 16565579

DOI:: 10.1254/jphs.DTJ05001X

ScienceOpen disciplines: Chemistry

Keywords: Angina Pectoris,drug therapy,Animals,Blood Pressure,drug effects,Calcium Channel Blockers,pharmacokinetics,pharmacology,therapeutic use,Calcium Channels, L-Type,Calcium Channels, N-Type,Calcium Channels, T-Type,Clinical Trials as Topic,Diabetic Nephropathies,Dihydropyridines,Drug Evaluation, Preclinical,Endothelial Cells,Heart,Humans,Hypertension,Kidney,blood supply,Renal Circulation,Vasodilator Agents

Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker.

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Most cited references 64

Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide.

Receptor sites for Ca2+ channel antagonists.

Ion channels and regulation of intracellular calcium in vascular endothelial cells.

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