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Calcium-channel blocking drugs were introduced to the United States in 1982. The three approved calcium-channel blockers--nifedipine, verapamil and diltiazem--have offered new treatments for angina. This article presents an overview of these drugs with emphasis on their mechanisms of action, clinical use and guidelines for the nurse practitioner in assessing the need for calcium-channel blockers in the management of angina.
Calcium ions are known to be important to the process of signal transduction across the apical and basal sides of the inner hair cells. Calcium channel antagonists have been demonstrated by light microscopy to provide protection against acoustic trauma. To evaluate the protective effect of calcium channel blocker on the inner ear cells to noise exposure, the amount of the histochemical reaction products formed in the cytoplasm of the inner hair cells of the guinea pig after application of pyroantimonate was measured by an image processing system connected to an energy-filtering transmission electron microscope (EFTEM). Compared to untreated control specimens (experimental animal group I) the amount of precipitable calcium had clearly increased in the inner hair cells of noise-exposed cochleae 60 h after an acute noise trauma (group III). In addition, small electron- lucent areas could be identified in the cytoplasm of the hair cells probably representing damage to the cellular fine structure. When the calcium channel blocker diltiazem was administered without any additional noise exposure the calcium content was drastically reduced in the inner hair cells (group II), but when the antagonist was given before and after acute noise trauma (group IV), the calcium content in the inner hair cells was nearly compared to the amount determined in the untreated group of animals. The role of diltiazem is discussed in respect of tissue protection and to the maintenance of the calcium-dependent physiological processes in the inner hair cells during signal transduction.
The action of two antiarrhytmic drugs, moracizine (MOR, CAS 31883-05-3) and ethacizine (ETHA, CAS 33414-33-4) on receptors of potential-operated CA-channels has been investigated. ETHA binding to verapamil receptors was more effective than that of MOR (IC50 = 0.53 +/- 0.08 mumol/l, respectively). The Hill coefficient for ETHA binding was similar to that of verapamil (0.64 +/- 0.09 and 0.60 +/- 0.10, respectively). Interaction of ETHA and MOR with dihydropyridine receptors in concentrations up to 10 mumol/l was similar that of verapamil, however, MOR was less potent. MOR and ETHA did not interact with calmodulin and troponin C at concentrations up to 100 mumol/l. The influence of MOR and ETHA on enzymes dependent on Ca-binding proteins (phosphodiesterase and actomyosin ATPase) was not observed up to 100 mumol/l. Comparison of clinical and electrophysiological data with these results allows the conclusion that ETHA exerts Ca-blocking effects by the interaction with verapamil receptors on potential-operated Ca-channels.
Calcium has been identified as having an important role as a transmembrane messenger in the activation signal for lymphocytes. To additionally examine this model, we evaluated the effect of calcium channel blocking drugs (verapamil, nifedipine, and diltiazem) on lymphocyte activation. In these studies we found that the drugs inhibit, in a dose-dependent fashion, the proliferation of T cells and the appearance of certain activation antigens after mitogen stimulation. This appears to result from the marked decrease in mitogen-induced 45calcium (45Ca+2) influx secondary to the addition of these agents. In addition, T cell proliferation resulting from IL 2 binding to its receptor is also suppressed by the calcium channel blocking drugs. These data suggest that the passive calcium channel plays a pivotal role in both the initial activation of T cells after ligand-receptor interaction and the ongoing signal for proliferation provided by IL 2 binding to its receptor.
Calcium channel entry blockers representing different structural classes were studied for their effects on human erythrocyte basal and calmodulin-stimulated (Ca2+ + Mg2+)-ATPase. Effects on the activity of (Mg2+)-ATPase and (Na+ + K+)-ATPase were also assessed. Of the four Ca2+ entry blockers tested, only verapamil and diltiazem specifically inhibited the calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity, the basal enzyme activity being unaltered by these drugs. Other membrane-associated ATPases were not affected. Calmodulin concentration effect curves showed the inhibition by verapamil (10(-3) M) and diltiazem (10(-3) M) to be non-competitive. This concentration inhibited the calmodulin-dependent increment (5.1 nM calmodulin) of the ATPase activity by 35 and 36% respectively. Similarly, both drugs inhibited the Ca2+-activation process of calmodulin-stimulated activity in a non-competitive manner, decreasing Vmax by 23 and 17% respectively. Basal (Ca2+ + Mg2+)-ATPase activity was not affected by verapamil or diltiazem at any calcium concentration. In contrast, cinnarizine non-specifically inhibited all four membrane ATPases including calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity at concentrations above 3 X 10(-6) M. Nifedipine was without effect on any of the four membrane ATPases. From this we conclude that certain calcium channel entry blockers can inhibit calmodulin-regulated plasma membrane Ca2+-pump ATPase. Therefore, this identifies an additional functional low affinity receptor in the plasma membrane for some of the calcium channel entry blockers.
The influences of aging on the response of urinary bladder detrusor smooth muscle in response to neurogenic stimulation (electric field stimulation) were investigated in rats aged 3-4 months (young) and 18-20 months (old). In addition, age-associated changes in calcium homeostasis were evaluated by comparing the basal intracellular free calcium concentration ([Ca2+]i), the change of [Ca2+]i in response to field stimulation, the contractile response at different extracellular calcium concentrations (Ca2+ = 1.8, 0.6, and 0 mM), and the sensitivity to the L-type calcium channel blocker. In both groups, the frequency-response curve in response to field stimulation (1-32 Hz) was similar. The contractile response to field stimulation was biphasic (phasic and tonic). The phasic/tonic ratio at different frequencies was similar between the two groups. The contractile responses were equally inhibited by atropine (1 microM) and preincubation with alpha, beta-methylene ATP (50 microM). Tetrodotoxin (1 microM) virtually abolished the responses to field stimulation in both groups. The biphasic components showed different sensitivities to diltiazem and low calcium. The tonic component was more readily inhibited by diltiazem, whereas the phasic component was more sensitive to low calcium medium. In general, the response to lower frequency stimulations was more sensitive to both diltiazem and low calcium. The aged group was more sensitive to the inhibitory effects of both low calcium and diltiazem. In Ca2(+)-free medium, the contractile response to higher frequency (e.g., 32 Hz) was temporarily preserved in most of the preparations. This response disappeared after repeated stimulation. The magnitude of this Ca2(+)-free response to 32 Hz stimulation was significantly lower in the aged group than in the young group (18.1 +/- 1.4 vs.29.1 +/- 3.2% of the control response in normal Tyrode medium, P < 0.05). The basal [Ca2+]i levels were similar in the two groups (young: 131 +/- 12 nM, n = 5; old: 118 +/- 10 nM, n = 4, P > 0.05). The magnitude and time course of the [Ca2+]i response to field stimulation were also similar in the two groups. It is concluded that aging seems to have little effect on the neuromuscular activities of rat urinary bladder. However, the calcium homeostasis may be altered as evidenced by the increased sensitivity to diltiazem and low extracellular calcium.
The pharmacology of Ca2+ channels and intracellular Ca2+ release from the sarcoplasmic reticulum (s.r.) were compared by injecting Ca2+ channel blockers into the cytoplasm and observing contraction under voltage clamp of frog skeletal muscle fibres, a preparation that contracts only in response to Ca2+ release from the s.r. A method for quantifying intracellular injections by co-injecting a fluorescent dye is described. Nifedipine injected into cells blocks Ca2+ current through the cell membrane showing that nifedipine is active when applied to the cytoplasmic side of the membrane in which Ca2+ channels are located. Neither the presence of Ca2+ channel blockers in the extracellular medium nor 24 h incubation in nifedipine and D-600 affect contraction. Nifedipine and D-600 injected to intracellular concentrations much greater than necessary to block Ca2+ channels do not affect contraction. The presence of 30 microM-D-600 during K+ contractures caused paralysis but 20 microM-nifedipine did not. Thus, contracture-dependent D-600 paralysis is not due to blockade of the transverse tubule Ca2+ channel. It is concluded that: (a) a functioning Ca2+ channel on the cell membrane is not necessary to trigger Ca2+ release from the s.r.; (b) s.r. Ca2+ release and Ca2+ channels are pharmacologically different.
Intracellular calcium is an important determinant for cell death in organ hypothermic preservation for transplantation. In this study, we show that prevention of calcium entry improves the result of liver cold storage in UW solution. The isolated perfused rabbit liver was used. After 48 hr of cold storage in UW solution, bile production was reduced by 70% (P less than 0.005). However, by adding the calcium channel blockers verapamil or nifedipine (40 microM) to the UW solution, this reduction was abolished, and the livers produced the same amount of bile as unpreserved livers. Furthermore, addition of the calcium channel activator, BAY K8644 (40 microM), to the UW solution, reduced bile production by 50% (P less than 0.01) already after preservation for 24 hr. We conclude that calcium entry is of importance for liver function after preservation and cold storage, and that including a calcium channel blocker to the preservation solution makes long-term liver preservation safer.
The calcium-channel blockers represent a group of organic chemical structures that share the ability to inhibit Ca2+ entry into excitable cells. In coronary and peripheral arterial smooth muscle and the heart, inhibition of Ca2+ entry blunts the ability of Ca2+ to serve as an intracellular messenger. Thus, calcium-channel blockers are smooth-muscle dilators and have a negative inotropic effect on the working myocardial cells of the atria and ventricles. Calcium-channel blockers also have effects on impulse formation and conduction in some regions of the heart. A fast, Na+-dependent ionic current is responsible for the upstroke of the action potential in the working cells of the atria and ventricles and in the rapidly conducting cells of the His-Purkinje system, so that the calcium-channel blockers do not inhibit conduction in these cells. In the sinoatrial and atrioventricular nodes, where depolarization is due primarily to a Ca2+-dependent slow inward current, the calcium-channel blockers slow the sinus pacemaker and inhibit atrioventricular conduction. The actions of different calcium-channel blockers are not always similar; for example, nifedipine is much more potent as an inhibitor of calcium channels in smooth muscle than in the heart, whereas verapamil and diltiazem are approximately equipotent in heart and vascular smooth muscle. It is likely that the calcium-channel blockers reach their specific binding sites in membranes by first dissolving in the phospholipid bilayer, after which they may interact with hydrophobic regions of proteins that make up, or regulate, these channels. Further knowledge of these molecular properties should facilitate the development of new calcium-channel blockers with improved specificity.
Voltage-dependent calcium channels control various physiological functions such as the excitation-contraction coupling, the secretion of hormones or the release of neurotransmitters in the nervous system. Molecular genetics has allowed to provide a structural basis to the functional diversity of calcium channels and to initiate studies to understand the relations between the structure and the function of these excitable proteins. The aim of our research is to compare both the functional and structural properties of calcium channels from various tissues. The studies on dissociated or cultured cells allow to describe their properties, regulation, pharmacology and pathophysiology in native tissues. Structure-functions studies using reconstitution models such as Xenopus oocytes aim to understand the molecular basis underlying their diversity. Calcium channels are composed of several subunits (alpha 1, alpha 2-delta, beta, gamma). Six genes have been identified as coding for the pore subunit (alpha 1) which determines the general profile and in particular the pharmacology of a given calcium channel. However, the auxilliary subunits and mainly beta subunits for which 4 genes and several variants have been isolated, are able to modify the level of expression and the properties of a calcium current directed by an alpha 1 subunit in a reconstitution model. The structure-function studies are now mainly designed to investigate the functional consequences of the interaction alpha 1-beta on the electrophysiological and pharmacological properties. These studies should lead to a better understanding of the molecular basis underlying the diversity between cardiac and vascular calcium channels and also of their respective implication in pathophysiology. The co-expression of several families of calcium channels in a single neuron do not allow properly to investigate the properties and the regulation (by phosphorylation or G proteins) of the neuronal calcium channels which are involved in neurosecretion. The use of reconstitution models will provide a better characterization of neuronal calcium channels and should help to the development of new drugs of therapeutical interest.
Calcium influx via L-type calcium channels in osteoblast cells causes a rapid (in seconds) elevation in intracellular calcium initiated by plasma membrane receptors for 1alpha, 25-dihydroxyvitamin D3 (1alpha,25-D3). 24R,25-Dihydroxyvitamin D3 (24,25-D3) alone, in concentrations up to 200 nM, does not cause potentiation of calcium currents in osteoblasts, but it does inhibit the current potentiation by 1alpha,25-D3. To determine how various steroids interact in their potentiation of calcium channels, the action of vitamin D3 analogues and testosterone with calcium channels in the rat osteoblast-like cell line ROS 17/2.8 was investigated. Bath additions of both 1alpha,25-D3 and testosterone at doses below K1/2 (the dose causing 50% left shift in the current-voltage relationship) are additive in their ability to potentiate calcium channels. When 1alpha,25-D3 and testosterone are added together at concentrations that would cause a maximal shift in the current-voltage relationship by each agent alone (Vmax), the effect of these steroids is not additive. Taken together these data suggest one population of calcium channels is activated by 1alpha, 25-D3 or testosterone. The shift in the current-voltage relationship caused by 1alpha,25-D3 is reduced by 1beta,25-dihydroxyvitamin D3 (1beta,25-D3), an agent which is thought to act specifically on the plasma membrane receptor for 1alpha,25-D3, but the potentiation caused by testosterone is not blocked by 1beta,25-D3. However, 24, 25-D3 inhibits the left shift in the peak current-voltage relationship mediated by either 1alpha,25-D3 and testosterone. This result implies that 1) 1beta,25-D3 directly displaces 1alpha,25-D3 but not testosterone from its plasma membrane receptor, and 2) the rapid (in seconds) stimulatory effects of 1alpha,25-D3 and testosterone on calcium channels are mediated by separate plasma membrane receptors for testosterone and 1alpha,25-D3, which are blocked by another receptor for 24,25-D3. The interaction of these three receptors with L-type calcium channels is pertussis toxin-sensitive.
The calcium channel blockers, nifedipine, verapamil, and diltiazem, are widely used for the treatment of cardiovascular disease. In spite of their widespread use, little data about the frequency and spectrum of cutaneous reactions associated with these agents have been published. Based on reports provided to the FDA's Division of Epidemiology and Drug Surveillance, and the American Academy of Dermatology's Adverse Drug Reaction Reporting System, it appears that the frequency of adverse cutaneous events associated with these drugs is low, but that occasionally severe reactions are associated with the use of these drugs. Among the more serious reactions associated with the calcium channel blockers are toxic epidermal necrolysis with diltiazem, Stevens-Johnson syndrome and erythema multiforme, which have been associated with all three drugs in this class, and exfoliative dermatitis, which has also been reported with all three agents. Most serious reactions associated with these agents occur within two weeks of initiating drug therapy. These findings suggest that calcium channel blockers are occasional causes of a wide spectrum of cutaneous reactions and should be considered as possible causative factors in patients who develop adverse cutaneous reactions while using these drugs.
The mechanisms of Ca2+ entry and their effects on cell function were investigated in cultured chicken osteoclasts and putative osteoclasts produced by fusion of mononuclear cell precursors. Voltage-gated Ca2+ channels (VGCC) were detected by the effects of membrane depolarization with K+, BAY K 8644, and dihydropyridine antagonists. K+ produced dose-dependent increases of cytosolic calcium ([Ca2+]i) in osteoclasts on glass coverslips. Half-maximal effects were achieved at 70 mM K+. The effects of K+ were completely inhibited by dihydropyridine derivative Ca2+ channel blocking agents. BAY K 8644 (5 X 10(-6) M), a VGCC agonist, stimulated Ca2+ entry which was inhibited by nicardipine. VGCCs were inactivated by the attachment of osteoclasts to bone, indicating a rapid phenotypic change in Ca2+ entry mechanisms associated with adhesion of osteoclasts to their resorption substrate. Increasing extracellular Ca2+ ([Ca2+]e) induced Ca2+ release from intracellular stores and Ca2+ influx. The Ca2+ release was blocked by dantrolene (10(-5) M), and the influx by La3+. The effects of [Ca2+]e on [Ca2+]i suggests the presence of a Ca2+ receptor on the osteoclast cell membrane that could be coupled to mechanisms regulating cell function. Expression of the [Ca2+]e effect on [Ca2+]i was similar in the presence or absence of bone matrix substrate. Each of the mechanisms producing increases in [Ca2+]i, (membrane depolarization, BAY K 8644, and [Ca2+]e) reduced expression of the osteoclast-specific adhesion structure, the podosome. The decrease in podosome expression was mirrored by a 50% decrease in bone resorptive activity. Thus, stimulated increases of osteoclast [Ca2+]i lead to cytoskeletal changes affecting cell adhesion and decreasing bone resorptive activity.
Calcium influx through voltage-activated Ca(2+) channels (VACCs) plays a critical role in neurotransmission. Capsaicin application inhibits VACCs and desensitizes nociceptors. In this study, we determined the signaling mechanisms of the inhibitory effect of capsaicin on VACCs in primary sensory neurons. Whole-cell voltage clamp recordings were performed in acutely isolated rat dorsal root ganglion neurons. Capsaicin caused a profound decrease in the Ca(2+) current (I(Ca)) density in capsaicin-sensitive, but not -insensitive, dorsal root ganglion neurons. At 1 mum, capsaicin suppressed about 60% of N-, P/Q-, L-, and R-type I(Ca) density. Pretreatment with iodoresiniferatoxin, a specific transient receptor potential vanilloid type 1 (TRPV1) antagonist, or intracellular application of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid blocked the inhibitory effect of capsaicin on I(ca). However, neither W-7, a calmodulin blocker, nor KN-93, a CaMKII inhibitor, attenuated the inhibitory effect of capsaicin on I(Ca). Furthermore, intracellular dialysis of deltamethrin or cyclosporin A, the specific calcineurin (protein phosphatase 2B) inhibitors, but not okadaic acid (a selective protein phosphatase 1/protein phosphatase 2A inhibitor), abolished the effect of capsaicin on I(Ca). Interestingly, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, deltamethrin, cyclosporin A, and okadaic acid each alone significantly increased the I(Ca) density and caused a depolarizing shift in the voltage dependence of activation. Immunofluorescence labeling revealed that capsaicin induced a rapid internalization of Ca(V)2.2 channels on the membrane. Thus, this study provides novel information that VACCs are tonically modulated by the intracellular Ca(2+) level and endogenous phosphatases in sensory neurons. Stimulation of TRPV1 by capsaicin down-regulates VACCs by dephosphorylation through Ca(2+)-dependent activation of calcineurin.
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Platelet derived growth factor (PDGF) mobilizes multiple calcium pools in the C3H 10T1/2 mouse fibroblast, including a sustained influx of extracellular calcium. We have used the whole cell patch-clamp technique to directly test for a role of plasma membrane calcium channels in this influx. Whole-cell patch-clamp recordings revealed a voltage-gated calcium channel with gating properties consistent with a 'T-type' designation. This phenotype of the C3H 10T1/2 fibroblasts was dependent upon the cell density in culture. The fraction of cells expressing calcium channels was low (< 10%) in subconfluent culture but rose to approximately 50% as the cells established a confluent monolayer. The magnitude of the PDGF-stimulated sustained calcium influx component measured using Fura-2 increased in parallel with the expression of calcium current. We interpret these results to support the hypothesis that T-type voltage-gated calcium channels contribute to the PDGF-stimulated intracellular calcium signals in these cells.
Three calcium channel blockers were studied for efficacy in preventing seizures and death from cocaine intoxication. Rats were first pretreated with a test drug then subjected to high dose intraperitoneal cocaine. In this model, control animals developed seizures within six minutes, followed by death within ten minutes. Animals that were pretreated with diltiazem, nifedipine, or verapamil developed seizures significantly faster than controls, and at specific doses the death rate was higher than in controls for all three drugs. The potentiation of seizures and death by 2 mg/kg nifedipine pretreatment was further shown by challenge with three different doses of cocaine. This study fails to demonstrate a protective effect and suggests augmentation of cocaine toxicity by pretreatment with the three currently available calcium channel blockers. Several mechanisms by which calcium channel blockers may augment cocaine-induced toxicity are discussed.
Vesicular fragments of sarcoplasmic reticulum isolated from rabbit skeletal muscle were actively loaded with Ca2+ in the presence of ATP and an ATP-regenerating system using Arsenazo III as metallochromic indicator to monitor Ca2+ movements across the membrane. Once the Ca2+ release is triggered by the presence of tetraphenylboron in the reaction medium, the addition of verapamil or diltiazem gives rise to a net Ca2+ entry inside the vesicles. Preincubation in the presence of verapamil does not abolish the tetraphenylboron-induced Ca2+ release, the verapamil-induced Ca2+ accumulation being still observed. There appears to be a high-affinity site for verapamil titrated in the micromolar concentration range, whereas diltiazem demonstrates more complex behavior when its concentration is raised. This study suggests the existence of a Ca2+ pathway (putative channels) which is blocked by the drugs tested allowing Ca2+ accumulation inside the vesicles owing to the Ca2+-dependent ATPase activity.