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PubMed1988

Monotherapy of hypertension with darodipine: a new calcium-channel blocker.

Calcium-channel blockers are increasingly used as single agents for the treatment of essential hypertension. Following three weeks of single-blind placebo therapy, 43 patients with essential hypertension were randomized into four groups. Group 1 (10 patients) received placebo twice a day, Group 2 (13 patients) received darodipine (PY 108-068) 50 mg twice a day, Group 3 (9 patients) received darodipine 100 mg twice a day, and Group 4 (11 patients) received darodipine 150 mg twice a day. Patients were seen in the clinic weekly for 4 weeks. Clinical and laboratory evaluations were done on each patient. Darodipine caused a sustained decrease in the supine and standing systolic and diastolic blood pressure (p less than .001) and there were no significant pressure differences between the three drug dosages. The effects of the drug on heart rate were not consistent. Placebo had no effect on either blood pressure or heart rate. Side effects were few, mild, and consisted of headaches and peripheral edema, and did not necessitate discontinuation of the drug. No metabolic abnormalities were seen with either low or high doses of the drug. We conclude that: (1) darodipine is effective, safe, and well tolerated; (2) its antihypertensive effectiveness is similar at high and low doses, although the higher doses seemed to have a slightly greater effect on the diastolic arterial pressure; (3) the low dose may be preferable since side effects were dose related.

Calcium Channel Blockers↗

PubMedDate not supplied

Lercanidipine: a novel dihydropyridine calcium-channel blocker.

Calcium-channel blockers (CCBs) have been used for the treatment of hypertension for more than 20 years, and recent clinical trials support the efficacy and safety of long-acting dihydropyridine (DHP) CCBs for a wide spectrum of hypertensive patients, including diabetic hypertensive patients. DHP CCBs are effective agents overall and are particularly effective when used in combination with other agents. Lercanidipine is a novel DHP CCB effective for the treatment of mild-to-moderate hypertension. Compared with other DHP CCBs, lercanidipine has a molecular design that imparts greater solubility within the arterial cellular membrane bilayer, membrane-controlled kinetics, and a high cholesterol tolerance factor. These favorable membrane-controlled kinetics impart a gradual onset of vasodilation and a long duration of action. Further, the unique pharmacokinetic and pharmacodynamic properties of lercanidipine appear to contribute to its efficacy and favorable safety profile. In clinical trials in the treatment of mild-to-moderate hypertension, lercanidipine was administered at a starting dose of 10 mg once daily, and increased to 20 mg once daily for nonresponders. Studies have shown that lercanidipine has a 24-hour antihypertensive effect and causes no significant increase in heart rate. Lercanidipine has been shown to be effective in a wide range of hypertensive patients, including mild-to-moderate hypertension, severe hypertension, the elderly, and those with isolated systolic hypertension. It is associated with a low rate of adverse events. Because of its efficacy and favorable safety profile, lercanidipine has the potential to improve blood pressure control in a wide range of patients, including those who have not responded to, or who have been unable to tolerate, other antihypertensive agents.

Animals↗

PubMed2005

Determining triage guidelines for unintentional overdoses with calcium channel antagonists.

BACKGROUND: Calcium channel antagonists (CCAs) are known to cause significant toxicity in overdose. Determining triage guidelines for CCAs is an important but difficult task. This study was designed to determine if an unintentional overdose of a patient's CCA could result in clinically significant cardiovascular (CV) symptoms (hypotension, bradycardia, conduction disturbances). METHODS: Poison center records over a 3-year period were reviewed for adults ingesting at least double their prescribed dose of CCAs and who were evaluated in an emergency department (ED). Cases were reviewed for: patient age and gender, co-ingestants, CCA involved, dosage form, dose taken, usual dose, symptoms, available vital signs, and medical outcomes. RESULTS: 225 cases were identified; 161 cases met study criteria. There were 51 cases involving co-ingestants and 13 in which the usual dose was unknown. These were excluded. One hundred twenty-two patients (76%) were female and the mean age of all patients was 64 years. One hundred and four (65%) cases involved ingestions equal to double the usual dose (DD), 57 (35%) involved more than a DD. For DD cases, nine (9%) developed clinically significant CV signs or symptoms; while in cases with more than DD, eight (14%) did. CONCLUSIONS: This retrospective review demonstrated that the toxicity of CCAs following a therapeutic overdose can be highly variable and that the dose producing a toxic effect on the cardiovascular system may be within the maximum range of therapeutic doses. This may be the result of a number of factors, including the broad range of therapeutic doses as well as the pre-existing conditions in patients taking these medications. This variability makes home management of these cases difficult and therefore, poison centers should be conservative in their evaluation of these cases.

Calcium Channel Blockers↗

PubMed1991

Block of L-type calcium channels by charged dihydropyridines. Sensitivity to side of application and calcium.

We have studied block of L-type calcium channels by intracellular and extracellular application of the ionized dihydropyridine derivatives amlodipine and SDZ 207-180. We find that extracellular application of either drug causes voltage-dependent block of calcium channels. However, neither drug is effective when applied intracellularly. The insensitivity of calcium channels to intracellular drug is not due to the low concentrations of cytosolic calcium, because voltage-dependent block by ionized amlodipine, SDZ 207-180, and the neutral drug nisoldipine persists under conditions in which Ca0 is buffered by EGTA. In fact, the time course of the development of block by the ionized but not neutral drug molecules studied, is slower in the presence than in the absence of calcium. Our results indicate that the DHP binding site of the L-type calcium channel is close to the extracellular surface of the cell membrane and that ionized DHP molecules may interact with the receptor in a manner that is uniquely affected by calcium.

Amlodipine↗

PubMed2003

Drug targets in the voltage-gated calcium channel family: why some are and some are not.

The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.

Animals↗

PubMed2002

Calcium channel antagonists in the treatment of hypertension.

Calcium channel antagonists are widely used antihypertensive agents. Their popularity among primary care physicians is not only due to their blood pressure-lowering effects, but also because they appear to be effective regardless of the age or ethnic background of the patients. The first available calcium channel antagonists utilized immediate-release formulations which, although effective in patients with angina pectoris, were not approved by the US FDA for use in hypertension. When long-acting once-daily formulations were approved in this indication, the short-acting preparations--which had by then become generic and inexpensive--retained some residual unapproved use for hypertension. An observational case-controlled trial, based on such usage, noted that these agents were associated with a greater risk of myocardial infarctions than conventional agents such as diuretics and beta-adrenoceptor antagonists. Further case-controlled trials showed, in fact, that the dangers of calcium channel antagonists were confined to the short-acting agents and that approved long-acting agents were at least as well tolerated and effective as other antihypertensive drugs. Cardiovascular outcomes during treatment with calcium channel antagonists have been examined in randomized, controlled trials. Compared with placebo, the calcium channel antagonists clearly prevented strokes and other cardiovascular events and reduced mortality. The effects of these agents on survival and clinical outcomes were similar to those with other antihypertensive drugs. There is a slight tendency for the calcium channel antagonists to be more effective than other drug types in preventing stroke, but slightly less effective in preventing coronary events. These observations extend to high-risk patients with hypertension including those with diabetes mellitus. Even so, patients with evidence of nephropathy should not receive monotherapy with calcium channel antagonists. Such patients are optimally treated with angiotensin receptor antagonists or ACE inhibitors, although addition of other drugs, including calcium channel antagonists, is often required to achieve the tight blood pressure control necessary to provide adequate renal protection. Calcium channel antagonists have a highly acceptable tolerability profile and careful reviews of available data have shown that their use is not associated with increased bleeding or promotion of tumor formation. It is now recognized that reduction of blood pressure in patients with hypertension to levels often <130/85 mm Hg should be undertaken in presence of other cardiovascular risk factors or evidence of end organ damage. Because of this important concept, calcium channel antagonists, like the other antihypertensive drug classes, are progressively being prescribed less often as monotherapy, but more typically as part of combination regimens.

Calcium Channel Blockers↗

PubMed1992

Receptor-operated calcium-channels in isolated rabbit jejunum.

Calcium channels were studied in isolated spontaneously rhythmic rabbit jejunum using the muscarinic agonist carbachol as stimulant. Carbachol failed to produce the characteristic phasic and tonic components of smooth muscle contractions. A variety of chemically distinct calcium antagonists, viz. bepridil, diltiazem, isradipine (PN 200-110), nifedipine, and verapamil, non-competitively inhibited the contractions. Diltiazem was most potent (-logIC50 = 8.30) and bepridil least potent (-logIC50 = 6.19) in inhibiting the contractions. The findings conclude with the presence of pharmacologically distinct receptor-operated calcium-channels, besides the potential-dependent calcium-channels, in the rabbit jejunum.

Animals↗

PubMed1993

Functional properties of a neuronal class C L-type calcium channel.

The rat brain class C calcium channel alpha 1 subunit cDNA, rbC-II, was subcloned into a vertebrate expression vector and transient expression was assayed following nuclear injection into Xenopus oocytes. Whole cell recordings showed that rbC-II currents (recorded with 40 mM Ba2+ as the charge carrier) had variable activation rates and minimal inactivation over an approximately 700 msec depolarizing step pulse. The pharmacological properties of the rbC-II current were consistent with those of an L-type calcium channel, being sensitive to dihydropyridines (10 microM nifedipine blocked approximately 85% of the current, 10 microM Bay K 8644 enhanced the current between 2- and 10-fold) and not affected by the N- and P-type calcium channel antagonists, omega-conotoxin GVIA and omega-agatoxin IVA, respectively. Coexpression of rbC-II with cloned rat neuronal calcium channel alpha 2 and beta subunits resulted in several changes to the electrophysiological properties of the rbC-II current including, an increased whole cell peak current, an increased rate of activation and a hyperpolarizing shift in the voltage dependence of activation. Taken together with results showing that the neuronal class D alpha 1 subunit also encodes an L-type calcium channel [Williams M. E., Feldman D. H., McCue A. F., Brenner R., Velicelebi G., Ellis S. B. and Harpold M. M. (1992a) Neuron 8: 71-84], these results indicate that the mammalian nervous system expresses two distinct genes encoding L-type calcium channels.

Animals↗

PubMed2003

Pharmacological modulators of voltage-gated calcium channels and their therapeutical application.

Calcium channels (CCs) play an important role in the transduction of action potential to the cytosol. An influx of Ca(2+) is essential for muscle contraction, neurotransmitter, and hormonal release. Level of cytosolic Ca(2+) controls activities of many enzymes and regulatory proteins. Voltage-gated calcium channels (VGCCs) serve as sensors for membrane depolarization. Blood pressure reduction is due to relaxation of actomyosine filaments in vascular smooth muscles. Calcium channel blockers (CCBs) are traditionally used for treatment of cardiovascular diseases. Neurotransmitter release from presynaptic neurons is triggered by Ca(2+) influx. Blockers of neuronal CCs may be applied for pain treatment. Overload of neurons by Ca(2+) is toxic. CCBs may be applied for prevention of some neurodegenerative disorders.

Animals↗

PubMed1982

Calcium channel blockers.

Calcium (Ca(++)) plays an essential role in many cardiovascular physiologic processes. Electrophysiologic properties of the sinus and atrioventricular nodes greatly depend on Ca(++) ion influx. Also, Ca(++) is the main link for excitation-contraction coupling of the myocardium. Ca(++) channel blockers are a group of heterogeneous compounds that block the ionic influx of Ca(++) into the myocardial and vascular smooth muscle cells. Because Ca(++) plays a central role, it is not surprising that Ca(++) channel blockers can produce profound alterations in cardiovascular functions. Recently several studies have shown these agents to be useful in the treatment of supraventricular tachyarrhythmia, variant angina, chronic stable angina and hypertrophic cardiomyopathy. In the future they may be found useful in preserving myocardium during cardiopulmonary bypass, in limiting infarct size and in the treatment of hypertension and congestive heart failure.

Angina Pectoris↗

PubMed2003

Several structural domains contribute to the regulation of N-type calcium channel inactivation by the beta 3 subunit.

Calcium channel beta subunits are essential regulatory elements of the gating properties of high voltage-activated calcium channels. Co-expression with beta(3) subunits typically accelerates inactivation, whereas co-expression with beta(4) subunits results in a slowly inactivating phenotype. Here, we have examined the molecular basis of the differential effect of these two subunits on the inactivation characteristics of Ca(v)2.2 + alpha(2)-delta(1) N-type calcium channels by creating a series of 22 chimeric beta subunits that are based on various combinations of variable and conserved regions of the parent beta subunit isoforms. Our data show that replacement of the N terminus region of beta(4) with a corresponding 14-amino acid stretch of beta(3) sequence accelerates the inactivation kinetics to levels seen with wild type beta(3). A similar kinetic speeding is observed by a concomitant substitution of the second conserved and variable regions, but not when these regions are substituted individually, suggesting that 1) the second variable and conserved regions cooperatively regulate N-type calcium channel inactivation and 2) that there are two redundant mechanisms that allow the beta(3) subunit to accelerate N-type channel inactivation. In contrast with previous reports in Ca(v)2.1 calcium channels, deletion of the C-terminal region of Ca(v)2.2 did not alter the regulation of the channel by wild type and chimeric beta subunits. Hence, the molecular underpinnings of beta subunit regulation of voltage-gated calcium channels appear to vary with calcium channel subtype.

Amino Acid Sequence↗

PubMed1995

1,4-Dihydropyridine binding sites in moss plasma membranes. Properties of receptors for a calcium channel antagonist.

An increase in cytoplasmic calcium is an early event in hormone (cytokinin)-induced vegetative bud formation in the moss Physcomitrella patens. Whole cell and calcium transport studies have implicated 1,4-dihydropyridine-sensitive calcium channels in this increase in cellular calcium. To understand the molecular nature of the dihydropyridine-sensitive calcium channel, we have established conditions for the binding of the arylazide 1,4-dihydropyridine, [3H]azidopine, to its receptor in moss plasma membranes. [3H]Azidopine bound specifically in a saturable and reversible manner. The KD for [3H]azidopine binding was 5.2 nM and the Bmax was 35.6 pmol/mg of protein. Association and dissociation of the receptor and [3H]azidopine were temperature-dependent, and association varied as a function of pH. Binding was inhibited by dihydropyridine, phenylalkylamine, and benzothiazepine calcium channel blockers, bepridil, lanthanum, and N-ethylmaleimide. [3H]Azidopine binding was stimulated by cations including calcium, strontium, manganese, and barium. [3H]Azidopine binding was also stimulated by cytokinin with a Km value for kinetin of 0.13 nM. These studies utilize a simple plant system to provide a biochemical framework for understanding calcium regulation during development and have implications for understanding mechanisms of signal transduction in plants.

Azides↗

PubMed1988

Saturation of calcium channels in single isolated smooth muscle cells of guinea-pig taenia caeci.

1. Calcium channel currents were recorded in Cs+-dialysed voltage-clamped single smooth muscle cells isolated from the guinea-pig taenia caeci to evaluate the current-carrying ability of Ca2+, Ba2+, Sr2+ and Mg2+ ions. 2. Ba2+ and Sr2+ ions, as well as Ca2+ ions, were able to carry an inward current through calcium channels. Calcium channel current was not observed when Mg2+ was the only divalent cation in the external solution. 3. Concentration dependences of calcium (ICa), barium (IBa) and strontium (ISr) currents were studied. It was found that currents through calcium channels saturated with increasing the extracellular concentration of a current carrier. Saturation of each current can be fitted with a Langmuir curve with apparent dissociation constants of 1.2 mM for Ca2+, 1.8 mM for Sr2+ and 9.6 mM for Ba2+ ions. 4. External Mg2+ ions reduced both ICa and IBa.IBa was depressed to a greater extent than ICa by Mg2+ ions. Reduction of ICa by Mg2+ ions seems to agree with competitive antagonism between Ca2+ and Mg2+ ions (Hagiwara & Takahashi, 1967). 5. When the external divalent cation concentration [( C2+]o) was changed, the current-voltage relationship of currents through calcium channels was shifted along the potential axis suggesting that activation gating of calcium channels was affected by [C2+]o. These voltage shifts can be fitted with the Gouy-Chapman theory supposing the density of surface charges near calcium channels to be 0.5 e nm-2 and including more potent binding of Ca2+ ions to surface charges than of Ba2+, Sr2+ and Mg2+ ions. 6. The changes in the Ca2+, Ba2+ and Sr2+ concentrations at the surface of the membrane were calculated. It was found that saturation of IBa can be explained by saturation of Ba2+ surface concentration while saturation of ICa and ISr cannot. 7. It was suggested that barium ions were able to carry the larger current through calcium channels in smooth muscle cells due to their much weaker binding within the calcium channel.

Animals↗

PubMed1999

Cytoplasmic determinants of piperidine blocking affinity for N-type calcium channels.

Piperidines are a relatively novel class of calcium channel blockers which act at a unique receptor site associated with the calcium channel alpha1 subunit. Calcium channel blocking affinities ranging from subnanomolar to several hundred micromolar have been reported in the literature, suggesting that piperidine block is highly sensitive to the cellular environment experienced by the channel. Here, I have investigated some of the cytoplasmic determinants of haloperidol block of N-type calcium channels expressed in human embryonic kidney cells. In perforated patch clamp recordings, haloperidol blocks N-type calcium channels with an inhibition constant of 120 microM. Upon internal dialysis with chloride containing pipette solution, the blocking affinity increases by 40-fold. This effect could be attributed in part to the presence of internal chloride ions, as replacement of intracellular chloride with methanesulfonate reduced haloperidol blocking affinity by almost one order of magnitude. Tonic inhibition of N-type channels by Gbetagamma subunits further enhanced the blocking effects of haloperidol, suggesting the possibility of direct effects of Gbetagamma binding on the local environment of the piperidine receptor site. Overall, depending on the cytoplasmic environment experienced by the channel, the blocking affinity of N-type calcium channels for haloperidol may vary by more than two orders of magnitude. Thus, absolute blocking affinities at the piperidine receptor site must be interpreted cautiously and in the context of the particular experimental setting.

Binding Sites↗

PubMed1994

Selective potentiation of a novel calcium channel in rat hippocampal neurones.

1. Calcium channel activity in cultured embryonic hippocampal neurones was studied with the cell-attached configuration of the patch clamp technique. Single-channel recordings revealed the presence of a novel kind of calcium channel activity characterized by marked bursts of re-openings following voltage pulses to +20 mV from a holding potential of -40 mV. 2. The re-openings were greatly prolonged by the dihydropyridine (DHP) agonist (+)-(S)-202-791, thus ruling out the possibility that they arose from T-, N- or P-type channels. Furthermore, the novel gating pattern could be readily distinguished from that of the L-type channel which showed only conventional tail currents. 3. Since the novel gating pattern was stable over many minutes, we provisionally referred to it as a novel kind of calcium channel that showed voltage-dependent potentiation (Lp channel) to distinguish it from the 'standard' L-type channel (Ls channel). 4. Lp channels could also be distinguished from Ls channels on the basis of slope conductance (24.3 vs. 26.9 pS for Lp and Ls, respectively) and mean DHP-induced long open time (2.7 vs 11 ms at +20 mV for Lp and Ls, respectively). 5. Voltage-dependent potentiation of Lp channel activity was studied using a dual-pulse protocol. When preceded by conditioning prepulses, Lp responses to test pulses were greatly increased. Ls- and N-type calcium channels showed no such enhancement of their activity. 6. Long-duration recordings revealed no clear evidence for transitions from Ls to Lp gating (or vice versa), suggesting that Ls and Lp activities arose from different kinds of calcium channels or that Lp gating is an unusually long-lived mode of Ls channel gating.

Animals↗

PubMedDate not supplied

Calcium channel modulation: ability to inhibit or promote calcium influx resides in the same dihydropyridine molecule.

BAY K 8644, a dihydropyridine of the nifedipine type, was shown to increase coronary resistance and to enhance myocardial contractility (Schramm et al., Nature 1983;303:535-7), in contrast to the well-known vasodilating and negative inotropic effects of the "classical" calcium channel blockers. In the isolated perfused guinea pig heart at high concentrations (greater than 3 microM), however, the coronary constricting and positive inotropic effects of BAY K 8644 progressively reverse until the drug has a negative inotropic effect and decreases coronary resistance, thus mimicking the effects of the "classical" calcium antagonists. On the other hand, in the same experimental model, calcium antagonists like nifedipine, nitrendipine, and nicardipine are shown to exert a small but definite positive inotropic effect at low concentrations, indicating a calcium agonistic action at those concentrations. To explain the pharmacological effects of BAY K 8644 and the calcium channel blockers of the dihydropyridine type, a model is proposed that suggests the existence of two dihydropyridine binding sites per channel. According to this model, it depends on the chemical structure of the respective dihydropyridine whether, after occupation of the first site, which increases the calcium influx through the channel, the occupation of the second site is unimpaired, turning the channel to one with low calcium permeability; or whether occupation of the second site is hindered, leaving the channel in the high conductance state.

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

PubMedDate not supplied

Delayed presentation of calcium channel antagonist overdose.

The calcium channel antagonists are generally safe in therapeutic dosage, but severe side effects with elevated intake are increasingly described. Typical features include confusion, lethargy, hypotension, sinus node depression, and cardiac conduction defects. Even if patients are stable on presentation, this does not preclude the possible late development of adverse events from the long-acting formulations of calcium channel blockers. A case of toxic overdose with 1440 mg of slow-release diltiazem is presented; this patient was stable on presentation, but rapidly became hemodynamically unstable, requiring treatment with intravenous calcium, temporary pacemaker, inotropic support and mechanical ventilation with a successful outcome. A concise review of the therapeutic considerations is provided.

Bradycardia↗

PubMed1991

The use of PCR to probe calcium channel diversity.

Voltage-dependent calcium channels are a diverse set of proteins that can be classified into at least 3 classes based on their electrophysiological and pharmacological behavior. Our studies have focused on the dihydropyridine-sensitive L-type class, which has two isoforms that have been cloned and expressed. In this report we describe the development of a polymerase chain reaction (PCR, Cetus) to probe for the expression of L-type calcium channel isoforms. We describe the optimization of the PCR reaction in terms of the following: methods for producing the template cDNA, concentration of primers, and magnesium concentration. In addition, we discuss our efforts to understand the factors involved in the design of oligonucleotides for PCR primers. These studies led to the following conclusions: 1) that primers should be less than 30 base pairs in length, 2) that the addition of extraneous polylinker sequences on the 5' end of the primer has no effect, 3) that the primer should not be located in regions where secondary structure may exist, and 4) that non-degenerate primers can be used to amplify homologous gene family members. We also present methods for subcloning PCR fragments, which allow the product of a single reaction to be subcloned and sequenced. We illustrate the use of all these techniques with RNA from mouse ovary, where we have discovered the expression of the cardiac isoform of the dihydropyridine-sensitive L-type calcium channel, and the expression of a novel sequence that we postulate to be an isoform of L-type calcium channels.

Amino Acid Sequence↗