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Ca2+ Channel Antagonists (ca2+ + channel_antagonist)
Selected AbstractsEnhanced Calcium Influx in Hippocampal CA3 Neurons of Spontaneously Epileptic RatsEPILEPSIA, Issue 3 2001Hiroko Amano Summary: ,Purpose: The spontaneously epileptic rat (SER: tm/tm, zi/zi) shows both absence-like seizures and tonic convulsions. Our previous electrophysiologic studies have demonstrated that SER has abnormal excitability of hippocampal CA3 neurons, which shows a long-lasting depolarization shift by a single stimulation of mossy fibers, probably resulting from the Ca2+ channel abnormalities. The present study was performed to determine whether Ca2+ influx is actually enhanced in the CA3 area of SER. Methods: Hippocampal slices were prepared from normal Wistar rats and SER aged 11,16 weeks old, when the epileptic seizures had been observed, and loaded with fura-2AM. Intracellular Ca2+ concentration ([Ca2+]i) was monitored as the ratio of fluorescence intensities excited at wavelengths of 340 and 380 nm (RF340/F380) with photometric devices. Results: High K+ (10,60 mM) applied to the bath for 2 min increased [Ca2+]i in hippocampal CA1, CA3, and dentate gyrus (DG) areas of both the normal rats and SER in a concentration-dependent manner. However, the high K+,induced increase in [Ca2+]i was significantly more pronounced in the CA3 area of the SER than in that of the normal animals, whereas there were no significant differences in high K+,induced increases of [Ca2+]i in CA1 or DG between the SER and controls. The high K+,induced increases in [Ca2+]i of CA1, CA3, and DG were inhibited by nifedipine (1,10 nM), a Ca2+ channel antagonist in both SER and controls. However, the inhibition of the high K+,induced increase in [Ca2+]i by nifedipine (1 nM) was significantly greater in the CA3 area of SER than that of controls. Conclusions: These findings suggest that Ca2+ influx through the L-type Ca2+ channels is much greater in the CA3 area of SER than in that of normal animals and is involved in the epileptic seizures of the SER. [source] Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidineFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2003William C. Stanley Abstract The primary result of myocardial ischaemia is reduced oxygen consumption and adenosine triphosphate (ATP) formation in the mitochondria, and accelerated anaerobic glycolysis, lactate accumulation and cell acidosis. Classic pharmacotherapy for demand-induced ischaemia is aimed at restoring the balance between ATP synthesis and breakdown by increasing the oxygen delivery (i.e. with long acting nitrates or Ca2+ channel antagonist) or by decreasing cardiac power by reducing blood pressure and heart rate (i.e. with , -blocker or Ca2+ channel antagonist). Animal studies show that fatty acids are the primary mitochondrial substrate during moderate severity myocardial ischaemia, and that they inhibit the oxidation of carbohydrate and drive the conversion of pyruvate to lactate. Drugs that partially inhibit myocardial fatty acid oxidation increase carbohydrate oxidation, which results in reduced lactate production and a higher cell pH during ischaemia. Trimetazidine (1-[2,3,4-trimethoxibenzyl]-piperazine) is the first and only registered drug in this class, and is available in over 90 countries world-wide. Trimetazidine selectively inhibits the fatty acid , -oxidation enzyme 3-keto-acyl-CoA dehydrogenase (3-KAT), and is devoid of any direct haemodynamic effects. In double-blind placebo-controlled trials trimetazidine significantly improved symptom-limited exercise performance in stable angina patients when used either as monotherapy or in combination with , -blockers or Ca2+ channel antagonists. Given available evidence, trimetazidine is an excellent alternative to classic haemodynamic agents, and is unique in its ability to reduce symptoms of angina when used in patients resistant to a haemodynamic treatment as vasodilators, , -blockers or Ca2+ channel antagonists. [source] Relaxant responses to calcium channel antagonists and potassium channel opener in human saphenous veinAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2006C. Ford Summary 1 As shown in a parallel study the magnitude of depolarization induced in human saphenous vein by raising external potassium ([K+]e) falls markedly below the theoretical values predicted by the Goldman,Hodgkin,Katz equations. This anomaly prompted us to re-examine the relaxant actions of L-type (nifedipine) and T-type (mibefradil) Ca2+ channel antagonists, and relaxant and electrophysiological effects of the K+ channel opener, pinacidil, on saphenous veins contracted by the elevation of [K+]e. 2 Nifedipine produced concentration,dependent relaxations in tissues contracted at various high [K+]e. In tissues contracted with 20 mm [K+]e, the pIC50 for nifedipine was significantly (8.20 ± 0.05; n = 6; mean ± SEM; P < 0.05) greater than in tissues contracted with ,40 mm [K+]e. 3 Tissues contracted with 20 mm [K+]e also relaxed in response to mibefradil (pIC50 = 6.1 ± 0.14) and pinacidil (pIC50 = 6.45 ± 0.08), the latter being almost completely reversed (93.4 ± 9.9%) by addition of glibenclamide (10 ,m). 4 The resting Em of smooth muscle cells of saphenous vein was ,77.0 ± 0.7 mV (n = 52), and 20 mm [K+]e produced a modest but significant depolarization to ,73.0 ± 0.7 mV (n = 52). Incubation with pinacidil plus 20 mm [K+]e resulted in a significant hyperpolarization of the Em to ,82 ± 0.6 mV (n = 52). 5 N, -nitro- l -arginine methyl ester did not impede the relaxant responses of nifedipine, mibefradil or pinacidil. 6 In conclusion, the relaxant effects of nifedipine and pinacidil (i) occurred at an Em distinctly below the presumed threshold for the opening of the classic (CaV1.3,1) L-type Ca2+ channels, and (ii) did not depend on generation of nitric oxide. [source] A comparison of Ca2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slicesBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Michiko Oka The mode of Ca2+ channel blocking by gabapentin [1-(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca2+ channel blockers, and the potential role of Ca2+ channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices. mRNA for the ,2, subunits of Ca2+ channels was found in rat cerebral cortex. Nitric oxide (NO) synthesis estimated from cGMP formation was enhanced by KCl stimulation, which was mediated primarily by the activation of N- and P/Q-type Ca2+ channels. Gabapentin blocked both types of Ca2+ channels, and preferentially reversed the response to 30 mM K+ stimulation compared with 50 mM K+ stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K+. Gabapentin inhibited KCl-induced elevation of intracellular Ca2+ in primary neuronal culture. Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM glucose (mild injury). Gabapentin preferentially inhibited mild injury, while verapamil suppressed only severe injury. , -Conotoxin GVIA (, -CTX) and , -agatoxin IVA (, -Aga) were effective in both models. NO synthesis was enhanced in a manner dependent on the severity of hypoxic insults. Gabapentin reversed the NO synthesis induced by mild insults, while verapamil inhibited that elicited by severe insults. , -CTX and , -Aga were effective in both the cases. Therefore, the data suggest that gabapentin and verapamil cause activity-dependent Ca2+ channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults. British Journal of Pharmacology (2003) 139, 435,443. doi:10.1038/sj.bjp.0705246 [source] Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic ratsCELL BIOCHEMISTRY AND FUNCTION, Issue 4 2004na Briede Abstract Analysis of the effect of several 1,4-DHP Ca2+ channel antagonists on experimental and clinical diabetes shows that structurally similar Ca2+ channel antagonists can exert opposite effects on Ca2+ influx, glucose homeostasis and insulin secretion. The influence of the Ca2+ channel antagonists on pancreatic , cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure,function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF2 group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5,mg,kg,1, p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats. Copyright © 2004 John Wiley & Sons, Ltd. [source] | ||||||||||