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PubMed1988

The antihypertensive effects of calcium channel blockade: role of sodium and calcium metabolism.

To study the relation of calcium channel blockade to sodium and calcium metabolism, we measured blood pressure (BP), serum ionized calcium (Ca-io), plasma renin activity (PRA), and 1,25-dihydroxy-vitamin D (1,25D), before and after administration of nitrendipine to essential hypertensive (EH) outpatients on both low and high dietary salt intakes, and on fixed (10 mg b.i.d.) and titrated dose (10-30 mg b.i.d.) schedules. Nitrendipine lowered BP (% delta DBP = -14.9 +/- 3 vs. 1 +/- 3.5, p less than 0.001) and raised Ca-io (0.08 +/- 0.04 vs. -0.04 +/- 0.05 mEq/L, p less than 0.05) in salt-sensitive (SS) but not salt-insensitive (SI) subjects. % delta DBP was related to PRA (r = 0.69, p less than 0.001), to the rise in Ca-io (r = -0.63, p less than 0.01), and to the suppression of circulating 1,25D (r = 0.80, p less than 0.001). Similarly, at doses (10-30 mg b.i.d.) titrated to achieve normotension, nitrendipine uniformly elevated PRA (1.4 +/- 0.3 to 3.5 +/- 0.7 ng/ml/h, p less than 0.05) and Ca-io (2.34 +/- 0.02 to 2.44 +/- 0.02 mEq/L, p less than 0.05). We conclude that the antihypertensive efficacy of nitrendipine appears greatest among SS and lower renin patients, and is related to the drug's ability to alter calcium metabolism. The state of calcium metabolism may thus underlie the sensitivity to calcium blockade and may contribute to its effects.

Blood Pressure↗
PubMed1990

Effects of calcium channel blockers on the coronary circulation.

Calcium channel blockers are among the most effective antiischemic therapies currently available. These agents afford a reduction in vascular smooth muscle tone by interrupting the excitation-contraction coupling process dependent on calcium transport. The efficacy of calcium channel blockers in patients with myocardial ischemia is probably due in large part to their effects on coronary circulation. In experimental models of coronary occlusion, these agents have been demonstrated to increase coronary vasodilation and coronary blood flow. Recruitment of coronary vasodilator reserve by nifedipine has been demonstrated indirectly via enhancement of left ventricular function in a canine model. Additionally, calcium channel blockers have been shown to modify the reactive hyperemic response usually seen after coronary artery occlusion. These changes in coronary resistance vessels, which normally regulate myocardial blood flow in response to metabolic requirements, have important clinical implications. Larger collateral vessels are also affected by calcium channel blockers, although the results observed in experimental models are not as clear cut. Although techniques for measuring coronary blood flow in humans are more limited, considerable data have accumulated on the effects of calcium channel blockers in humans. Assessments of coronary vasodilation using quantitative angiography have produced variable results. However, improved myocardial perfusion, as measured by thallium-201 scintigraphy after administration of nifedipine, and beneficial effects on coronary blood flow and coronary vascular resistance as assessed using the precordial xenon-133 washout technique before and after sublingual administration of nifedipine have been observed. Overall, such studies have not only shown the clinical usefulness of calcium channel blockers, but have broadened our understanding about the complex interplay of their mechanisms of action.

Animals↗
PubMed2001

Kinetics of activation of a PKC-regulated epithelial calcium channel.

The kinetics of calcium entry through regulated calcium channels in cultured renal proximal tubule cells was studied with Fura-2 fluorescence ratio imaging in single cells. The calcium entry was activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and phorbol-12-myristat-13-acetate (PMA), similar to that observed for activation by osmo-mechanical stress. OAG (2.5 microM) or PMA (0.5 microM) activated calcium entry is characterized by a significant latency between agonist application and the response, whereas the effect of osmo-mechanical stress was immediate. This pre-response latency was 260 +/- 70s with OAG stimulation and 79.2 +/- 17.3s with PMA stimulation. Once a cell responds, the intracellular calcium level reaches a peak value within seconds. The cell response to agonist is independent of the response of neighboring cells. The response kinetics resembles those of the calcium sparks in excitable cells, except the response is much slower. In all cases, the response appears to be an all-or-none event, that is characteristics of an elementary binary switch. It is suggested that the binary response and the lack of coordinated response of calcium entry in single cells results from limited availability of the calcium channels and/or PKC that activates the channel. The experimental data could be fit to a single binary response mathematical model assuming each response reflected an elementary event of a single channel opening or a co-ordinated opening of a cluster of several channels.

Animals↗
PubMed1995

Cloning and expression of a novel truncated calcium channel from non-excitable cells.

Calcium entry, via a dihydropyridine-sensitive pathway, is required for differentiation in murine erythroleukemia cells (MELC). Calcium channel currents have been identified physiologically in some non-excitable cells, but little is known regarding the structure of these channels. We show that a truncated form of the alpha 1 subunit of the cardiac voltage-gated calcium channel (dihydropyridine receptor, DHPR) is expressed in MELC. This MELC calcium channel lacks the first four transmembrane segments of the DHPR (IS1 to IS4). A MELC calcium channel/cardiac DHPR chimera, co-expressed with the alpha 2 and beta subunits of the DHPR, forms a functional calcium channel in Xenopus oocytes.

Acetamides↗
PubMed1991

Calcium channels in PDGF-stimulated A172 cells open after intracellular calcium release and are not voltage-dependent.

Using laser image cytometry and Indo-1 fluorescence, we investigated the intracellular free Ca2+ concentration ([Ca2+]i) of confluent A172 human glioblastoma cells stimulated by the BB homodimer of platelet-derived growth factor (PDGF-BB). The shape of the calcium transients and the delay time between stimulation and the beginning of the transient varied considerably. The percentage of responsive cells, the peak [Ca2+]i and the duration of the response were directly related to PDGF-BB dose, while the delay time was inversely related; the maximal response occurred at a PDGF-BB concentration of 20 ng/ml. Studies with EGTA and inorganic calcium-channel blockers (Ni2+, La3+) showed that the increase of [Ca2+]i resulted from initial release of intracellular stores and subsequent calcium influx across the plasma membrane. Opening of calcium channels in the plasma membrane, monitored directly by studying Mn2+ quenching of Indo-1 fluorescence, was stimulated by PDGF-BB and blocked by La3+; the opening occurred 55 +/- 10 s after the initial increase in [Ca2+]i. Therefore, in these tumor cells, intracellular release always occurs before channel opening in the plasma membrane. Depolarization of cells with high extracellular [K+] did not generally induce calcium transients but did decrease calcium influx. L-type calcium-channel blockers (verapamil, nifedipine, and diltiazem) had little or no effect on the calcium influx induced by PDGF-BB. These results indicate that PDGF-BB induces calcium influx by a mechanism independent of voltage-sensitive calcium channels in A172 human glioblastoma cells.

Calcium↗
PubMed1997

Molecular biology of calcium channels in the cardiovascular system.

Calcium ions are key intracellular messengers in the cardiovascular system. Calcium homeostasis is regulated by an extracellular cycle, which controls the entry and removal of calcium between the cytosol and extracellular space, and an intracellular cycle, which controls calcium fluxes between the cytosol and intracellular stores in the sarcoplasmic reticulum. Several protein families mediate these calcium fluxes including those that (1) regulate the entry of calcium into the cytosol; (2) recognize calcium within the cytosol; and (3) remove calcium from the cytosol. Intracellular calcium binding proteins (the "E-F hand" proteins) recognize the appearance of calcium in the cytosol; in the heart and vascular smooth muscle, these proteins initiate excitation-contraction coupling. Calcium efflux occurs via adenosine triphosphate (ATP)-dependent calcium pumps and sodium-calcium exchangers, while two families of channels--intracellular release calcium channels and plasma membrane calcium channels--regulate calcium entry into the cytosol. The plasma membrane calcium channels, which include the L- and T-type channels, are of the greatest clinical interest because they are targets for pharmacologic therapy. T-type calcium channels, which activate contraction in vascular smooth muscle but have little or no role in cardiac excitation-contraction coupling, appear to be involved in signal transduction pathways that promote cell growth and proliferation. Calcium channel blockers that selectively block T-type calcium channels, therefore, offer a novel approach to cardiovascular drug therapy.

Calcium↗
PubMed2005

Effect of age, vitamin D, and calcium on the regulation of rat intestinal epithelial calcium channels.

Transepithelial transport of calcium involves uptake at the apical membrane, movement across the cell, and extrusion at the basolateral membrane. Active vitamin D metabolites regulate the latter two processes by induction of calbindin D and the plasma membrane ATPase (calcium pump), respectively. The expression of calbindin D and the calcium pump declines with age in parallel with transepithelial calcium transport. The apical uptake of calcium is thought to be mediated by the recently cloned calcium channels-CaT1 (or ECaC2, TRPV6) and CaT2 (or ECaC1, TRPV5). The purpose of these studies was to determine whether there were age-related changes in intestinal calcium channel regulation and to identify the dietary factors responsible for their regulation. Young (2 months) and adult (12 months) rats were fed either a high calcium or low calcium diet for 4 weeks. The low calcium diet significantly increased duodenal CaT1 and CaT2 mRNA levels in both age groups, but the levels in the adult were less than half that of the young. The changes in calcium channel expression with age and diet were significantly correlated with duodenal calcium transport and with calbindin D levels. To elucidate the relative roles of serum 1,25(OH)2D3 and calcium in the regulation of calcium channel expression, young rats were fed diets containing varying amounts of calcium and vitamin D. Dietary vitamin D or exogenous 1,25(OH)2D3 more than doubled CaT1 mRNA levels, and this regulation was independent of dietary or serum calcium. These findings suggest that the apical calcium channels, along with calbindin and the calcium pump, may play a role in intestinal calcium transport and its modulation by age, dietary calcium, and 1,25(OH)2D3.

Aging↗
PubMed2006

Type of electrical stimulation influences diaphragm response to adrenoceptor and calcium channel modulators: the role of extracellular and intracellular calcium events.

The influence of direct single pulse and subtetanic electrical stimulation (ES) on isolated rat hemidiaphragm response to adrenoceptor antagonists and calcium channel blockers was investigated. Muscle contractility was stimulated by cumulative micromolar noradrenaline. Noradrenaline effects on developed tension (Td) in the presence of various alpha- and beta-adrenoceptor antagonists (e.g., prazosin and ICI 118551) were qualitatively different during different types of ES. Also, intact L-voltage calcium channels were necessary for noradrenaline-induced potentiation of Td during both types of ES, while the balance between ryanodine receptors- and inositol triphosphate (IP3)-related calcium events in the muscle was influenced by the pattern of the ES.

Adrenergic Agents↗
PubMedDate not supplied

[The modification of potential-dependent calcium channels in the membrane of secretory cells in a calcium-free medium].

Effect of modification of potential-dependent calcium channels in cells of the upper lobe of the salivary gland in Chironomus larva has been ascertained in the Ca-free medium containing Ca-binding substances (EGTA or EDTA). It is shown that the inward current depends on the sodium transmembrane gradient. The amplitude of the inward sodium current decreases under the influence of verapamil as well as with an increase of external concentration of Ca2+ ions. The metabolic dependence of modified calcium channels as well as the pharmacological sensitivity are unchanged. Tau n of the sodium current through modified calcium channels increases insignificantly comparing with that of the calcium current. Maximum of the current-voltage relationship of the sodium current through modified calcium channels is shifted to a negative side by 10-15 mV as compared with the calcium current through native channels.

Animals↗
PubMed1993

Protein kinase A modulates an endogenous calcium channel, but not the calcium-activated chloride channel, in Xenopus oocytes.

In Xenopus oocytes, Ca2+ influx through an endogenous voltage-gated Ca2+ channel activates a transient outward Cl- current (ICl(Ca)), which is potentiated by cAMP increase. The site of cAMP effect appears to be the Ca2+ channel instead of the Ca(2+)-activated Cl- channel, because cAMP potentiates the Ba2+ current through the Ca2+ channel in a similar way to the ICl(Ca), and cAMP does not potentiate the Ca(2+)-dependent Cl- current in cells treated with Ca2+ ionophore. Using the catalytic subunit of protein kinase A (PKA) and PKA inhibitors, it was shown that PKA is both necessary and sufficient for the cAMP effect on ICl(Ca). Furthermore, the cAMP/PKA-mediated potentiation of ICl(Ca) was inhibited by both type 1 and type 2A protein phosphatases.

Amino Acid Sequence↗
PubMed1991

Identification of the site of interaction of the dihydropyridine channel blockers nitrendipine and azidopine with the calcium-channel alpha 1 subunit.

The dihydropyridine binding site of the rabbit skeletal muscle calcium channel alpha 1 subunit was identified using tritiated azidopine and nitrendipine as ligands. The purified receptor complex was incubated either with azidopine or nitrenidpine at an alpha 1 subunit to ligand ratio of 1:1. The samples were then irradiated by a 200 W UV lamp. The ligands were only incorporated into the alpha 1 subunit, which was isolated by size exclusion chromatography and digested either by trypsin (azidopine) or endoproteinase Asp-N (nitrendipine). Each digest contained two radioactive peptides, which were isolated and sequenced. The azidopine peptides were identical with amino acids 13-18 (minor peak) and 1428-1437 (major peak) of the primary sequence of the skeletal muscle alpha 1 subunit. The nitrendipine peptides were identical with amino acids 1390-1399 (major peak) and 1410-1420 (minor peak). The sequence from amino acids 1390 to 1437 is identical in the alpha 1 subunits of skeletal, cardiac and smooth muscle and follows directly repeat IVS6. These results indicate that dihydropyridines bind to an area that is located at the putative cytosolic domain of the calcium channel.

Amino Acid Sequence↗
PubMed2001

Amyloid-beta promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons.

Exposure of cultured neurons and neuronal cells to aggregated amyloid-beta (Abeta) induces multiple neurodegenerative events including accumulation of cytosolic calcium, generation of reactive oxygen species, abnormal levels of phosphorylation of the microtubule-associated protein tau, and apoptosis. Prevention of accumulation of calcium within the cytosol also prevents all other events, suggesting that calcium accumulation is an early and pivotal event in Abeta neurotoxicity. Calcium influx has been suggested to occur via L voltage-sensitive calcium channels or NMDA channels. Calcium influx into differentiated human neuroblastoma cells has been previously attributed to the L voltage-sensitive calcium channel, but the contribution of the NMDA channel was not examined. In the present study, treatment of these cells with MK-801, an antagonist of NMDA channels, failed to attenuate Abeta-induced calcium influx or neurodegeneration, while nimopridine, an antagonist of the L voltage-sensitive calcium channel, blocked Abeta-induced calcium influx. Our findings suggest that NMDA channels do not contribute significantly to Abeta neurotoxicity in these acute cell culture analyses.

Journal Article↗
PubMed1981

Inhibitory effect on calcium channel blockers on alpha -adrenergic activation of glycogenolysis and calcium efflux in perfused rat liver.

In an attempt to verify the importance of calcium ions in mediating alpha -adrenergic stimulation, the effects of a calcium channel blocker, verapamil, on phenylephrine-induced glycogenolysis and calcium efflux in perfused livers prepared from fed rats were determined. The blocker inhibited phenylephrine-induced glycogenolysis in a noncompetitive and dose-dependent manner between 50 micro M and 500 micro M. However, it did not affect 2, 4-dinitrophenol-induced glycogenolysis. It had no significant effect on 45 Ca uptake by the perfused liver, but inhibited basal as well as phenylephrine-induced efflux of 45Ca from 45Ca-loaded liver. The inhibitory effects on basal 45Ca release and phenylephrine-induced glycogenolysis and 45Ca released correlated very well. All the the effects of verapamil were reproduced by another calcium channel blocker, diltiazem, suggesting that these effects are common to a variety of calcium channel blockers. These results indicate that the process of calcium influx and the function of phosphorylase per se are not directly involved in the inhibitory action of the blocker. Although it is possible that verapamil interferes with binding of the alpha -adrenergic agonist to the plasma membrane, the good correlation between the inhibitory effects of verapamil on basal 45Ca released and on phenylephrine-induced release of 45Ca suggests another mechanism, involving calcium ions. The blocker appears to inhibit the glycogen phosphorylase activity induced by phenylephrine via a cell-membrane mechanism in which calcium ion flux changes are intimately involved.

Animals↗
PubMed1996

Role of calcium channel blockers in reducing acute ischaemia and preventing restenosis in PTCA.

Calcium channel blockers (calcium antagonists) are widely used before, during and after percutaneous transluminal coronary angioplasty (PTCA). When administered during PTCA, calcium channel blockers may be beneficial in decreasing regional ischaemia in patients with proven or suspected variant angina, as a result of their cardioprotective effects, their ability to enhance collateral flow, and their antispastic effects at the epicardial level. More recently, the agents have also proven to be effective in patients who have developed "no-reflow' phenomenon during PTCA. Preliminary findings suggest that calcium channel blockers may also have potential benefits when administered after angioplasty. The combined results of 5 studies, evaluating a total of 919 patients, showed a trend towards angiographic reduction in restenosis. These observations are of interest but may be due to reporting bias. In conclusion, calcium channel blockers are effective in reducing ischaemia induced by PTCA. These agents may, thus, be appropriate in high risk patients. Further large studies examining the effects of calcium channel blockers on restenosis are required to confirm the observations available to date.

Angioplasty, Balloon, Coronary↗
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↗
PubMed1986

[Single channels of low and high-threshold calcium channels of the membrane of sensory neurons in the mouse].

Single calcium channels of cultured dorsal root ganglion cells from mouse embryos were studied using patch clamp method in its cell-attached configuration. Two types of activity of unitary calcium channels were found. The first one which arose at membrane potentials near--50-40 mV was characterized by unitary current amplitude of 0.37 +/- 0.04 pA with 40 mmol/l Ca2+ in the pipette solution, mean open time of 0.6 ms and intraburst mean shut time of 1.2 ms. It displayed voltage- and time-dependent inactivation. The corresponding values for the second one which required much more positive depolarization to be activated (approximately 0 mV) and did not express noticeable inactivation were: 0.53 +/- 0.04 pA, 0.8 ms and 0.8 ms. It is concluded that the recorded types of unitary activity are associated respectively with low- and high-threshold calcium currents which have been found earlier while studying whole cell currents.

Animals↗
PubMed1988

Hormonal and metabolic effects of calcium channel antagonists in man.

Calcium is a component of many metabolic reactions. By blocking calcium transport across cell membranes, calcium channel antagonists can therefore theoretically affect numerous metabolic and hormonal processes. In vitro studies have often documented just such an effect. Because of the expanding use and prevalence of calcium antagonists in clinical practice, a review of their in vivo effects on hormones and metabolism is warranted. The effect on glucoregulatory hormones, calcium regulatory hormones, anterior and posterior pituitary secretion, the renin-angiotensin axis, plasma catecholamines, and plasma lipids and lipoproteins is herein reviewed. The various calcium antagonists, by virtue of their distinct chemical structures, influence metabolism in their own unique manner. Despite the widespread involvement of calcium in hormone action, however, calcium channel antagonists have little dramatic impact on hormone regulation. This is, in part, due to the drug dosage used in clinical practice and to the inherent compensatory mechanisms built into normal endocrine function. The development of agents with greater and more potent metabolic specificity, however, coupled with the ability to target drug action, holds promise for expanded therapeutic application in the future.

Adrenal Cortex Hormones↗