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PubMed1985

Effects of a calcium channel agonist on the electrical, ionic and secretory events in mouse pancreatic B-cells.

The changes in pancreatic B-cell function produced by a Ca channel agonist, the dihydropyridine derivative CGP 28392, have been studied with mouse islets. CGP 28392 (5 microM) modified the electrical activity induced in B-cells by 10 mM glucose: the duration and the amplitude of the slow waves of membrane potential increased, but the overall spike activity decreased. Simultaneously, CGP 28392 markedly increased insulin release and 45Ca2+ efflux, and slightly accelerated 86Rb+ efflux from islet cells. These latter effects were abolished by omission of extracellular Ca2+. Qualitatively similar changes were observed at 15 mM glucose, whereas CGP 28392 was ineffective at 3 mM glucose. These results strongly suggest that an influx of Ca2+ contributes to the slow waves of membrane potential triggered by glucose, and underline the importance of this influx of Ca2+ for the control of insulin release by the sugar.

Action Potentials↗
PubMed1987

Enhancement of long-term potentiation by the calcium channel agonist Bayer K8644 in CA1 of the rat hippocampus in vitro.

The effect of the Ca agonist BAY K8644 was studied on long-term potentiation (LTP) of extracellular excitatory postsynaptic potentials in the stratum radiatum of CA1 of the hippocampus in vitro. LTP was evoked by brief trains of high-frequency stimulation applied to the stratum radiatum of CA1. 0.5% Ethanol, the vehicle used to dissolve BAY K8644, reduced LTP from 43% to 15%. An amount of 15 microM BAY K8644, in 0.5% ethanol, enhanced LTP from 13% in the ethanol control to 57%. The Ca channel antagonist verapamil did not alter control LTP, but did inhibit the potentiating action of BAY K8644 on LTP. It is postulated that the enhancement of LTP by BAY K8644 may occur through enhancement of Ca influx through voltage-dependent Ca channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

The effects of the calcium channel agonist, Bay K-8644, on guinea-pig ileum and rat uterine horn.

Bay K-8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2- trifluoromethylphenyl)pyridine-5-carboxylate) concentration-dependently caused contractions of the partly depolarized ileum, but at higher concentrations (10(-6) to 10(-5) M) produced relaxation. 10(-8) to 4 X 10(-7) M nifedipine antagonized while 10(-9) and 4 X 10(-9) M potentiated Bay K-8644. On the partly depolarized uterus, Bay K-8644 (10(-9) to 10(-6) M) had only a spasmogenic effect whereas nifedipine (4 X 10(-9) to 10(-7) M) was spasmolytic. Verapamil and diltiazem (each at 10(-4) M) both reduced the maximal response to Bay K-8644, while other spasmolytics were ineffective. Thus, Bay K-8644 activates ileum and uterus by opening voltage-operated Ca2+ channels, but its relaxant action at high concentration and its potentiation by nifedipine is not seen in both organs. Such differences probably depend on the concentration of the compounds used and the polarization state of the cell membranes.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Calcium channel agonist and antagonist binding in a highly enriched sarcolemma preparation obtained from canine ventricle.

The purpose of the present study was to characterize the binding of the Ca2+ channel agonist (+/-)[3H]Bay K 8644 in a highly enriched cardiac membrane preparation and to examine its interactions with other Ca2+ channel ligands. Scatchard analysis showed that (+/-)[3H]Bay K 8644 displayed some 265-fold less affinity for its receptor than did the Ca2+ channel antagonist (+)[3H]PN200-110. Furthermore, (+/-)[3H]Bay K 8644 binding site density was significantly less than that seen for (+)[3H]PN200-110. Kinetic analysis of (+/-)[3H]Bay K 8644 binding revealed biphasic association and dissociation rates. The Ca2+ channel antagonist MDL 12,330A stimulated both (+)[3H]PN200-110 and (+/-)[3H]Bay K 8644 binding by effects on Kd. In contrast, diltiazem inhibited (+)[3H]PN200-110 binding but had no effect on (+/-)[3H]Bay K 8644 binding. Both MDL 12,330A and diltiazem inhibited Ca2+-dependent contraction in rat aortic rings but the combination of these two drugs was less than additive in this regard. We conclude that the binding profile of (+/-)[3H]Bay K 8644 results from the racemic nature of this ligand and that MDL 12,330A and diltiazem interact at sites distinct from one another on or around the slow voltage-dependent Ca2+ channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Responses of arterial smooth muscle from normotensive and pre-eclamptic subjects to the calcium channel agonist, Bay K 8644.

The effect of Bay K 8644, a dihydropyridine Ca2+ agonist, on in vitro contractile responses of inferior epigastric arteries from normotensive (N) and pre-eclamptic (P) subjects has been investigated, with a view to further defining the mechanism of the increased vascular sensitivity associated with pregnancy-induced hypertension. Bay K 8644 (10(-10)-10(-7) M) caused dose-dependent contractions of N as well as P arteries under resting conditions in the order: P greater than N and caused development of rhythmic contractions in both N and P arteries. Bay K 8644 effects were prevented by 3 X 10(-8) M Nifedipine (a Ca+2 antagonist). Bay K 8644 also significantly (P less than 0.05) enhanced the sensitivity as well as maximal contractile responses to CaCl2 in 40 mM K+-depolarized Ca-depleted N and P arteries in the order: P greater than N. The results suggest that the increased peripheral vascular sensitivity associated with pregnancy-induced hypertension may be due, at least in part, to enhanced activity of the potential-sensitive Ca2+ channels in arterial smooth muscle plasmalemma.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Immediate and delayed effects of a brief period of calcium loading, induced by the calcium channel agonist Bayer K 8644, on the ultrastructure and sarcolemmal integrity of murine diaphragm in vitro.

Exposure of in vitro mouse diaphragm to the dihydropyridine Ca2+ channel agonist Bayer K 8644 (Bay) and partial depolarisation for 120 min induced severe structural damage within 30-60 min and membrane permeabilisation (60-120 min). Exposure to Bay and depolarisation for 30 min (brief Ca2+ loading) followed by washout for 90 min produced similar effects, even though significant membrane damage does not occur until the second hour of incubation. Development/expression of necrosis during the washout period was not inhibited by manoeuvres designed to combat the effects of any remaining Bay, or by use of a Ca(2+)-free, 1 mM EGTA medium for washout. Exposure to Bay for 15 min followed by washout did not induce damage. Electron microscopic examination revealed that the mitochondria of cells fixed after 30 or 120 min exposure to Bay and depolarisation were in the orthodox (swollen) configuration, but that mitochondria in muscles that had undergone washout with Ca(2+)-free-EGTA saline were electron dense. Further incubation of these muscles in Ca(2+)-containing medium caused readoption of the swollen configuration. We conclude that membrane permeabilisation can occur after removal of the Ca2+ load, and that mitochondrial Ca2+ overload is not necessary for Ca(2+)-induced damage/death to occur.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Effects of the calcium-channel agonist CGP 28392 on insulin secretion from isolated rat islets of Langerhans.

The rate of insulin secretion from isolated rat islets of Langerhans was affected by a number of dihydropyridine derivatives known to interact with voltage-sensitive Ca2+ channels in excitable cells. The channel antagonists nifedipine and nitrendipine were potent inhibitors of glucose-induced insulin secretion in response to both 8 mM- and 20 mM-glucose, although they did not lower the basal secretion rate observed in the presence of 4 mM-glucose. The Ca2+-channel agonist, CGP 28392, also failed to alter the basal rate of insulin secretion. In the presence of 8 mM-glucose, however, 1 microM-CGP 28392 enhanced the insulin-secretion rate to a value approximately double that with 8 mM-glucose alone. This effect was dose-dependent, with half the maximal response elicited by 0.1 microM-CGP 28392, and full enhancement at 10 microM. The response was rapid in onset, with an increase in insulin secretion evident within 2 min of CGP 28392 infusion in perifused islets. Stimulation of insulin secretion by CGP 28392 was correlated with a rapid enhancement of glucose-stimulated 45Ca2+ uptake into islets cells, and with a transiently increased rate of 45Ca2+ efflux from pre-loaded islets. Stimulation of insulin secretion by CGP 28392 was abolished in the presence of noradrenaline, although under these conditions the rapid stimulation of 45Ca2+ influx induced by CGP 28392 was only partially inhibited. In contrast with these results, when islets were incubated in the presence of 20 mM-glucose, CGP 28392 caused a dose-dependent inhibition of insulin secretion. Half-maximal inhibition required approx. 0.2 microM-CGP 28392, with maximal effects observed at 10 microM. Under these conditions, however, the extent of insulin secretion was still only decreased by about 50%, to a value which was similar to that seen in the presence of 8 mM-glucose and CGP 28392. These results suggest that dihydropyridine derivatives can alter the activity of voltage-dependent Ca2+ channels in islet cells, and are consistent with the possibility that gating of these channels plays an important role in regulating the rate of insulin secretion after glucose stimulation.

Animals↗
PubMed1985

Effects of the calcium channel agonist, BAY K 8644, on electrical activity in mouse pancreatic B-cells.

We studied the effects of the dihydropyridine derivative BAY K 8644 on the membrane potential of B-cells in mouse pancreatic islets. BAY K 8644, in a dose-dependent manner, decreased the spike frequency but increased the duration of the spikes elicited by glucose with or without quinine or tetraethylammonium (TEA). These effects were antagonized by cobalt and nifedipine but not by tetrodotoxin. The interval between spikes was proportionate to the duration of the spikes and the ratio of the interval to the spike duration was constant at all concentrations of BAY K 8644 tested. Peak inward current, estimated from the derivative of the action potential recorded in the presence of TEA, was increased by BAY K 8644 and decreased by nifedipine. BAY K 8644 elicited spike activity when the membrane was moderately depolarized by either 5.6 mM glucose or 15 mM K+, but did not change the membrane potential of the resting hyperpolarized B-cell. These results suggest that BAY K 8644 acts on the open Ca2+-channels. The threshold occurs at a membrane potential of -50 mV. Also, the modifications of the shape of the spikes appear to reflect specific changes in Ca2+ entry. We propose the existence of a Ca2+-induced Ca2+-channel inactivation process in the pancreatic B-cell.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Interactions of calcium antagonists and the calcium channel agonist Bay K 8644 on neurotransmission of the mouse isolated vas deferens.

1. The present study compares the effects of verapamil and Bay K 8644 on twitches of the mouse vas deferens induced by field stimulation at 0.1 Hz. The influence of interactions between these drugs and nifedipine on neurotransmission was also investigated. 2. Bay K 8644 (0.1 nM-3 microM) and verapamil (1-100 microM) potentiated twitches maximally by about 1000% (EC50 17.3 nM) and 300% (EC50 17.5 microM), respectively. Nifedipine (0.1 nM-1 microM) only reduced twitch magnitude (IC50 7.7 nM). All effects were reversed following washout. 3. Yohimbine (1-100 microM) reversed twitch potentiation caused by verapamil but not by Bay K 8644. Prazosin (1 microM) did not reduce basal twitch tension nor antagonize twitch potentiation by verapamil. 4. Twitch inhibition by nifedipine was unaltered by previous incubation with verapamil (30 microM), but Bay K 8644 (1 microM) shifted the curve to nifedipine 120 fold to the right. Previous incubation with nifedipine (1 microM) blocked potentiation induced by verapamil but did not modify responsiveness to Bay K 8644. 5. Previous addition of verapamil (30 microM) markedly enhanced twitch potentiation caused by Bay K 8644 in a supra-additive fashion. In experiments conducted in the reversed condition, Bay K 8644 (1 nM but not 10 nM) potentiated the effect of verapamil in a similar manner but to a lesser extent. 6. It is concluded that verapamil, in contrast to nifedipine, markedly enhances neurally-evoked twitches of the mouse vas deferens. Bay K 8644 produces essentially the same effect as verapamil, but its potency is 1000 fold and its maximal effect about 3 fold greater than that observed for verapamil. It is suggested that the mechanism of twitch potentiation by verapamil is different from that of Bay K 8644 and may involve an increased release of non-adrenergic co-transmitter(s).

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

The calcium channel agonist, Bay K-8644, antagonizes effects of diacetyl monoxime on cardiac tissues.

Effects of a novel slow channel activator, Bay K-8644 (Bay K), were studied on slow action potential (APs) in young and old embryonic chick hearts, and on its antagonism of the effects of diacetyl monoxime (DAM). The slow APs of young hearts are mediated by slow Na+ channels, whereas those of old hearts are mediated by slow Ca2+ channels. In slow APs of old (13-18 days old) embryonic chick hearts superfused with a high (22 mM) K+ solution, Bay K (10-6 M) gradually increased the amplitude, maximum rate of rise (Vmax), and duration of the slow APs. The actions of Bay K persisted for a long time (greater than 30 min) after washout of the drug. DAM (10 mM) depressed the Vmax, duration and amplitude of the slow APs. Some of the changes in slow AP parameters produced by DAM, e.g., Vmax decrease, were antagonized by the addition of Bay K (10(-6) M). In 3-day-old embryonic chick hearts. Bay K potentiated the slow APs and DAM depressed them; Bay K antagonized these effects of DAM. Thus, the actions of Bay K and DAM are likely to be produced, respectively, via the activation and depression of slow Ca2+ channels in old embryonic chick hearts. In addition, the drugs seem to influence slow Na+ channels found in young embryonic chick hearts.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Analysis of the effects of (-) and (+) isomers of the 1,4-dihydropyridine calcium channel agonist BAY k 8644 on postrest potentiation in the canine ventricular muscle.

Contraction of canine ventricular trabeculae were recorded stimulation at a frequency of 0.5 Hz and after rest periods of 2 and 8 min to analyze the effect of the Ca channel agonist BAY k 8644, on sarcoplasmic reticular function. Short periods of rest interposed between steady trains of stimuli caused a potentiation of the postrest beat. This is believed to be due to the mobilization of activator Ca from the sarcoplasmic reticulum (SR). Racemic BAY k 8644 and its Ca channel agonist enantiomer, (-) BAY k 8644, both produced an increase in contraction in response to a steady train of stimuli but converted rest potentiation into rest depression. This has been interpreted as increased loss of Ca from the SR during diastole. Addition of Ca channel antagonists, (+) BAY k 8644, nitrendipine, or nifedipine, to reverse the agonistic effect of (-) and racemic BAY k 8644 on the Ca channel did not convert the rest depression into rest potentiation. In the presence of stimuli but converted rest potentiation into rest depression. This has been interpreted as increased loss of Ca from the SR during diastole.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Dihydropyridine antagonists and agonists of calcium channels inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages.

Here we investigate the effects of the dihydropyridine-type antagonists of calcium channels nitrendipine, nimodipine, nisoldipine and the calcium channel agonist BAY K 8644 on the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in J774.2 macrophages cultured in vitro. Pretreatment of J774.2 cells with these dihydropyridines (10(-8) -3 x 10(-6) M for 30 min) dose-dependently inhibited the LPS-stimulated (1 microgram/ml, 24 h) nitrite formation. For instance, at 10(-6) M, the inhibition was 59 +/- 3% for nitrendipine; 47 +/- 5% for nimodipine and 42 +/- 3% for nisoldipine (n = 9; p < 0.05). BAY K 8644 caused a moderate, but significant inhibition of nitrite accumulation (by 16 +/- 3% at 10(-7) M, n = 9; p < 0.05). The inhibition of LPS-stimulated nitrite accumulation produced by nitrendipine, nimodipine, and BAY K 8644 was significantly smaller when they were applied 2 or 4 h after LPS, indicating that these agents inhibit the induction, but not the activity of the induced NOS. At concentrations which caused a significant inhibition of the LPS-stimulated nitrite accumulation, the dihydropyridine calcium channel modulators did not inhibit mitochondrial respiration. Thus, dihydropyridine calcium channel modulators (antagonists and an agonist) inhibit the induction of the calcium-independent isoform of NOS produced by LPS in J774.2 macrophages. This effect is not related to the modulation of intracellular calcium levels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Distribution of L-type calcium channels in rat thalamic neurones.

One major pathway for calcium entry into neurones is through voltage-activated calcium channels. The distribution of calcium channels over the membrane surface is important for their contribution to neuronal function. Electrophysiological recordings from thalamic cells in situ and after acute isolation demonstrated the presence of high-voltage activated calcium currents. The use of specific L-type calcium channel agonists and antagonists of the dihydropyridine type revealed an about 40% contribution of L-type channels to the total high-voltage-activated calcium current. In order to localize L-type calcium channels in thalamic neurones, fluorescent dihydropyridines were used. They were combined with the fluorescent dye RH414, which allowed the use of a ratio technique and thereby the determination of channel density. The distribution of L-type channels was analysed in the three main thalamic cell types: thalamocortical relay cells, local interneurones and reticular thalamic neurones. While channel density was highest in the soma and decreased significantly in the dendritic region, channels appeared to be clustered differentially in the three types of cells. In thalamocortical cells, L-type channels were clustered in high density around the base of dendrites, while they were more evenly distributed on the soma of interneurones. Reticular thalamic neurones exhibited high density of L-type channels in more central somatic regions. The differential localization of L-type calcium channels found in this study implies their predominate involvement in the regulation of somatic and proximal dendritic calcium-dependent processes, which may be of importance for specific thalamic functions, such as those mediating the transition from rhythmic burst activity during sleep to single spike activity during wakefulness or regulating the relay of visual information.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Repeated stimulation of L-type calcium channels in the rat ventral tegmental area mimics the initiation of behavioral sensitization to cocaine.

RATIONALE: A substantial body of evidence indicates that ion flux through L-type calcium channels and N-methyl-D-aspartate (NMDA) receptors contributes to behavioral sensitization to cocaine. OBJECTIVES: The following experiments were designed to evaluate the role of calcium influx through L-type calcium channels or NMDA receptors in the ventral tegmental area (VTA) in the initiation of behavioral sensitization to cocaine. METHODS: The L-type calcium channel agonist BayK 8644, the glutamate agonist NMDA, or vehicle was microinjected into the VTA on 3 consecutive days. Following a 2-week withdrawal period, all rats received a challenge injection of cocaine (15 mg/kg, i.p.) in order to assess potential cross-sensitization with the NMDA or BayK 8644 pretreatments. RESULTS: Repeated intra-VTA microinjections of BayK 8644, but not NMDA, resulted in an augmentation of the behavioral response to cocaine. CONCLUSIONS: These results indicate that calcium influx through L-type calcium channels produces neurophysiological adaptations that mimic those resulting from intermittent exposure to cocaine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Single-channel properties of L-type calcium channels from failing human ventricle.

OBJECTIVE: The aim of our study was to analyse the single-channel properties of L-type calcium channels from failing human heart and to compare them to the respective animal data. Furthermore, we intended to evaluate the feasibility of future single-channel studies on the role of calcium channels in the pathophysiology of heart failure. METHODS: Single L-type calcium channels were recorded in ventricular myocytes from explanted failing human heart, using the cell-attached configuration of the patch-clamp technique. RESULTS: One or more successful registrations of calcium channels could be obtained in 11 of 19 cell isolations. Determination of single-channel conductance yielded a mean value of 16.6 +/- 1.2 pS (70 mM Ba2+ as the charge carrier) under control conditions and 23.7 +/- 2.8 pS in presence of the calcium-channel agonist FPL 64176. The rapid gating process could be described by a C<-->C<-->O gating scheme. Slow gating analysis revealed a highly significant clustering of active and non-active sweeps. CONCLUSION: Single-channel measurements of L-type calcium channels in human failing ventricle are feasible and reproducible despite the varying patient characteristics. Their channel properties are qualitatively comparable to those found in other mammals. Whether there are quantitative differences due to the underlying heart failure can be elucidated in further studies.

Adult↗
PubMed2001

Calcium entry through L-type calcium channels causes mitochondrial disruption and chromaffin cell death.

Sustained, mild K+ depolarization caused bovine chromaffin cell death through a Ca(2+)-dependent mechanism. During depolarization, Ca(2+) entered preferentially through L-channels to induce necrotic or apoptotic cell death, depending on the duration of the cytosolic Ca(2+) concentration ([Ca(2+)](c)) signal, as proven by the following. (i) The L-type Ca(2+) channel activators Bay K 8644 and FPL64176, more than doubled the cytotoxic effects of 30 mm K+; (ii) the L-type Ca(2+) channel blocker nimodipine suppressed the cytotoxic effects of K+ alone or K+ plus FPL64176; (iii) the potentiation by FPL64176 of the K+ -evoked [Ca(2+)](c) elevation was totally suppressed by nimodipine. Cell exposure to K+ plus the L-type calcium channel agonist FPL64176 caused an initial peak rise followed by a sustained elevation of the [Ca(2+)](c) that, in turn, increased [Ca(2+)](m) and caused mitochondrial membrane depolarization. Cyclosporin A, a blocker of the mitochondrial transition pore, and superoxide dismutase prevented the apoptotic cell death induced by Ca(2+) overload through L-channels. These results suggest that Ca(2+) entry through L-channels causes both calcium overload and mitochondrial disruption that will lead to the release of mediators responsible for the activation of the apoptotic cascade and cell death. This predominant role of L-type Ca(2+) channels is not shared by other subtypes of high threshold voltage-dependent neuronal Ca(2+) channels (i.e. N, P/Q) expressed by bovine chromaffin cells.

Adrenal Medulla↗