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Special Issue "Calcium Antagonists"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (28 February 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Toni Schneider

Institute of Neurophysiology, Medical Faculty, University of Cologne, 39 50931 Köln, Germany
Website | E-Mail
Interests: channelopathies; “pharmacoresistant” (R-type) calcium channel
Guest Editor
Prof. Dr. Gary J. Stephens

School of Pharmacy, University of Reading, Whiteknights, PO Box 228, Reading RG6 6AJ, UK
Website | E-Mail
Interests: electrophysiology; voltage-gated calcium channels; cannabinoids; ion channels; GPCRs; pain; ataxia

Special Issue Information

Dear Colleagues,

"Calcium antagonism“ was initially developed as a novel pharmacodynamic concept, which prevented cytosolic Ca2+ increase in cardiac tissue. It was initially developed by the A. Fleckenstein group in Freiburg [1]. The therapeutic consequences are widespread and are initiated by the inhibition of the transmembrane Ca2+ flux. Such an antagonism normalizes hyperkinetic cardiac disorders, suppresses arterial and arteriolar spasms, relieves systemic arterial hypertension and may stop cardiac arrhythmia.

Initially, the targets of classical Ca2+ channel antagonists were only named as “receptors” as Ca2+ channels proteins underlying these responses remained unidentified. Subsequently, ten different genes were successfully cloned for the voltage-gated ion conducting pore, and an increasing number of auxiliary or interacting subunits were identified.
Ca2+ channel antagonists were instrumental in the determination of function for each of the voltage-gated Ca2+ channels. In the genomic age, the development of mouse models with gene inactivated subunits has significantly aid the deduction of their function. The molecular interaction of Ca2+ channel subunits was and will be specified by high resolution crystallography. We now also have some information about the Ca2+ channel proteome. Knowing the molecular minimal structure for interactions will also accelerate the development of more selective Ca2+ channel antagonists. Novel powerful compounds are needed, because some Ca2+ channels are still lacking selective antagonism including the “resistant” (R-) type, and the T-type voltage-gated Ca2+ channels.

Reference List:
1. Fleckenstein A. Historical overview. The calcium channel of the heart. Ann. N.Y. Acad. Sci. 1988, 522, 1-15.

Prof. Dr. Toni Schneider
Dr. Gary J. Stephens
Guest Editors

Submission

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Keywords

  • voltage-gated calcium channels
  • dihydropyridines
  • phenylalkylamines
  • benzothiazepines
  • peptide toxins
  • cloning
  • crystallization

Published Papers (5 papers)

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Research

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Open AccessArticle In Vitro Assessment of Clevidipine Using the Profilin1 Hypertensive Mouse Model
Pharmaceuticals 2013, 6(5), 623-633; doi:10.3390/ph6050623
Received: 21 December 2012 / Accepted: 19 April 2013 / Published: 29 April 2013
Cited by 2 | PDF Full-text (367 KB) | HTML Full-text | XML Full-text
Abstract
Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic
[...] Read more.
Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic arterial resistance. The aim was to assess the effect of clevidipine on the hypertrophic vessels of profilin1 hypertensive transgenic mice compared to sodium nitroprusside (SNP) and labetalol using wire myograph techniques. The effects of clevidipine, SNP and labetalol on the hypertrophic vessels were studied on mesenteric arterial function from 8 profilin1 hypertrophic mice and eight non-transgenic controls. Our results showed a significant difference between the effects of the three drugs on the hypertrophic mesenteric arteries of transgenic profilin1 mice compared to the non-transgenic controls. The half maximal effective concentration (EC50) of clevidipine, SNP and labetalol in profilin1 mice (1.90 ± 0.05, 0.97 ± 0.07, 2.80 ± 0.05 nM, respectively) were significantly higher than the EC50 in non-transgenic controls (0.91 ± 0.06, 0.32 ± 0.06, 0.80 ± 0.09 nM, respectively). Moreover, the increase in the EC50 for clevidipine (2-fold) to produce the same effect on both normal and hypertrophic arteries was less than that of SNP (3-fold) and labetalol (3.5-fold). Therefore, we concluded clevidipine exhibited the lowest dose shift to relax the hypertrophic vessels compared to SNP and labetalol in the profilin1 hypertrophic animal mouse model. Full article
(This article belongs to the Special Issue Calcium Antagonists)

Review

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Open AccessReview Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury
Pharmaceuticals 2013, 6(7), 788-812; doi:10.3390/ph6070788
Received: 29 March 2013 / Revised: 6 June 2013 / Accepted: 6 June 2013 / Published: 26 June 2013
Cited by 10 | PDF Full-text (260 KB) | HTML Full-text | XML Full-text
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this
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Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC) antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i). These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic. Full article
(This article belongs to the Special Issue Calcium Antagonists)
Open AccessReview Calcium Channel Blockers as Tocolytics: Principles of Their Actions, Adverse Effects and Therapeutic Combinations
Pharmaceuticals 2013, 6(6), 689-699; doi:10.3390/ph6060689
Received: 4 March 2013 / Revised: 15 April 2013 / Accepted: 2 May 2013 / Published: 23 May 2013
Cited by 7 | PDF Full-text (129 KB) | HTML Full-text | XML Full-text
Abstract
Dihydropyridine Ca2+ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca2+ channels, influenced by the Ca2+-activated K+ channels, beta-adrenergic receptors (β-ARs) and sexual
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Dihydropyridine Ca2+ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca2+ channels, influenced by the Ca2+-activated K+ channels, beta-adrenergic receptors (β-ARs) and sexual hormones. In clinical practice, most experience has been gained with the use of nifedipine, whose efficacy is superior or comparable to those of β-agonists and oxytocin antagonists. Additionally, it has a favourable adverse effect profile as compared with the majority of other tocolytics. The most frequent and well-tolerated side-effects of CCBs are tachycardia, headache and hypotension. In tocolytic therapy efforts are currently being made to find combinations of tocolytic agents that yield better therapeutic action. The available human and animal studies suggest that the combination of CCBs with β-AR agonists is beneficial, although such combinations can pose risk of pulmonary oedema in multiple pregnancies and maternal cardiovascular diseases. Preclinical data indicate the potential benefit of combinations of CCBs and oxytocin antagonists. However, the combinations of CCBs with progesterone or cyclooxygenase inhibitors may decrease their efficacy. The CCBs are likely to remain one of the most important groups of drugs for the rapid inhibition of premature uterine contractions. Their significance may be magnified by further clinical studies on their combined use for tocolysis. Full article
(This article belongs to the Special Issue Calcium Antagonists)
Open AccessReview Clevidipine for Perioperative Blood Pressure Control in Infants and Children
Pharmaceuticals 2013, 6(1), 70-84; doi:10.3390/ph6010070
Received: 11 December 2012 / Revised: 28 December 2012 / Accepted: 11 January 2013 / Published: 15 January 2013
Cited by 5 | PDF Full-text (184 KB) | HTML Full-text | XML Full-text
Abstract
Various pharmacologic agents have been used for perioperative BP control in pediatric patients, including sodium nitroprusside, nitroglycerin, β-adrenergic antagonists, fenoldopam, and calcium channel antagonists. Of the calcium antagonists, the majority of the clinical experience remains with the dihydropyridine nicardipine. Clevidipine is a short-acting,
[...] Read more.
Various pharmacologic agents have been used for perioperative BP control in pediatric patients, including sodium nitroprusside, nitroglycerin, β-adrenergic antagonists, fenoldopam, and calcium channel antagonists. Of the calcium antagonists, the majority of the clinical experience remains with the dihydropyridine nicardipine. Clevidipine is a short-acting, intravenous calcium channel antagonist of the dihydropyridine class. It undergoes rapid metabolism by non-specific blood and tissue esterases with a half-life of less than 1 minute. As a dihydropyridine, its cellular and end-organ effects parallel those of nicardipine. The clevidipine trials in the adult population have demonstrated efficacy in rapidly controlling BP in various clinical scenarios with a favorable adverse effect profile similar to nicardipine. Data from large clinical trials regarding the safety and efficacy of clevidipine in children is lacking. This manuscript aims to review the commonly used pharmacologic agents for perioperative BP control in children, discuss the role of calcium channel antagonists such as nicardipine, and outline the preliminary data regarding clevidipine in the pediatric population. Full article
(This article belongs to the Special Issue Calcium Antagonists)

Other

Jump to: Research, Review

Open AccessBrief Report Phorbol Ester Modulation of Ca2+ Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones
Pharmaceuticals 2013, 6(6), 777-787; doi:10.3390/ph6060777
Received: 25 February 2013 / Revised: 13 May 2013 / Accepted: 14 May 2013 / Published: 29 May 2013
PDF Full-text (208 KB) | HTML Full-text | XML Full-text
Abstract
Phorbol esters are analogues of diacylglycerol which activate C1 domain proteins, such as protein kinase C (PKC). Phorbol ester/PKC pathways have been proposed as potential therapeutic targets for chronic pain states, potentially by phosphorylating proteins involved in nociception, such as voltage-dependent Ca2+
[...] Read more.
Phorbol esters are analogues of diacylglycerol which activate C1 domain proteins, such as protein kinase C (PKC). Phorbol ester/PKC pathways have been proposed as potential therapeutic targets for chronic pain states, potentially by phosphorylating proteins involved in nociception, such as voltage-dependent Ca2+ channels (VDCCs). In this brief report, we investigate the potential involvement of CaV2 VDCC subtypes in functional effects of the phorbol ester, phorbol 12-myristate 13-acetate (PMA) on nociceptive transmission in the spinal cord. Effects of PMA and of selective pharmacological blockers of CaV2 VDCC subtypes on nociceptive transmission at laminae II dorsal horn neurones were examined in mouse spinal cord slices. Experiments were extended to CaV2.3(−/−) mice to complement pharmacological studies. PMA increased the mean frequency of spontaneous postsynaptic currents (sPSCs) in dorsal horn neurones, without an effect on event amplitude or half-width. sPSC frequency was reduced by selective VDCC blockers, w-agatoxin-IVA (AgTX; CaV2.1), w-conotoxin-GVIA (CTX; CaV2.2) or SNX-482 (CaV2.3). PMA effects were attenuated in the presence of each VDCC blocker and, also, in CaV2.3(−/−) mice. These initial data demonstrate that PMA increases nociceptive transmission at dorsal horn neurones via actions on different CaV2 subtypes suggesting potential anti-nociceptive targets in this system. Full article
(This article belongs to the Special Issue Calcium Antagonists)

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