A little goes a long way: Clinical management of calcium channel blocker overdose.
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Additive beneficial effects of the combination of a calcium channel blocker and an angiotensin blocker on a hypertensive rat-heart failure model.
The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.
Albuminuria↗
[The anxiolytic activity of calcium-channel blockers in tests of anxious behavior in mice and rats].
The evidence obtained from the studies of the anxiolytic activity of calcium channel blockers in the tests for anxiety: dark-light chamber, elevated plus-maze, social interaction, incomplete sensory deprivation, and change in the excitability of the CNS is analyzed. Methodological aspects of studying the anxiolytic activity of drugs in these tests are discussed. The problems are considered related with simulation of the normal situational anxiety and pathological anxiety as well as the prospects of using the calcium channels blockers as anxiolytics. In view of these aspects, the problem of search for an "ideal" anxiolytic and possible results of revealing its activity in the tests for the normal and pathological anxiety are discussed.
Animals↗
Evaluation of a novel calcium channel blocker, (S)-emopamil, on regional cerebral edema and neurobehavioral function after experimental brain injury.
The authors investigated the effects of a novel calcium channel blocker, (S)-emopamil, on cerebral edema and neurobehavioral and memory function following experimental fluid-percussion brain injury in the rat. Two independent experiments were performed to evaluate the effects of this compound on cardiovascular variables and postinjury cerebral edema (increases in tissue water content), and on cognitive deficits and neurological motor function following brain injury. Treatment with (S)-emopamil significantly reduced focal brain edema at 48 hours after brain injury. Profound memory dysfunction induced by brain injury was significantly attenuated following (S)-emopamil treatment. In addition, (S)-emopamil also attenuated the deficits in motor function that were observed over a 2-week period following brain injury. These results suggest that changes in calcium homeostasis may play an important role in the pathogenesis of trauma to the central nervous system and that the calcium channel blocker (S)-emopamil might be a useful compound for the treatment of traumatic brain injury.
Animals↗
Efficacy and safety of felodipine, a new dihydropyridine calcium channel blocker, in elderly hypertensive patients.
Felodipine is a new dihydropyridine calcium channel blocker with a number of properties that enhance its suitability as a first-line antihypertensive drug for the elderly. Felodipine has a 100-fold selectivity for inhibiting the contribution of vascular smooth muscle compared with cardiac muscle. Negative inotropic action appears minimal while selectivity appears to increase with age. Felodipine has a minimal effect on smooth muscle of venous capacitance vessels, thereby greatly reducing the likelihood of orthostatic hypotension. Renal effects are favorable; the glomerular filtration rate is increased in some patients. The extended-release formulation of felodipine produces a smooth 24-hour plasma concentration curve and is effective when prescribed once daily. Felodipine appears to lower blood pressure effectively in the elderly patient with few, generally mild, adverse effects.
Aging↗
The effect of calcium channel blockers in experimental spinal cord injury.
The therapeutic effect of calcium channel blockers (nifedipine) was studied in 40 rabbits with acute experimental spinal cord injury. In 30 animals, doses of 2.50 mg/day were orally administered for 10 days (after injury) whereas 10 animals received the same treatment 5 days before and 10 days after injury. The clinical evolution was assessed on a 5-graded scale (clinical marker of the motor deficit) and compared with the clinical evolution of a control group (20 rabbits with untreated spinal cord injury). The animals were sacrificed after 14 days of post-traumatic evolution (death occurring in some of them during this time interval). The mean of motor score was identical in both treated animal groups but significantly higher than in controls. Histopathological findings revealed various degrees of damage at injury site (hemorrhagic necrosis in the central gray matter, ischemic-type neuronal alterations, mesenchyme-glial reaction, demyelination) correlated with the degree of functional loss.
Animals↗
A calcium channel blocker, benidipine, inhibits intimal thickening in the carotid artery of mice by increasing nitric oxide production.
OBJECTIVE: Recent studies suggest that several calcium channel blockers exert their protective effects against vascular disorders by increasing nitric oxide (NO) production from the endothelium. The purpose of this study was to clarify the effects of a long-lasting calcium channel blocker, benidipine, on vascular remodeling. METHODS: The left common carotid arteries of mice were completely ligated just proximal to the carotid bifurcation. Treatment with benidipine (3 mg/kg per day) or vehicle was started 1 week before the carotid ligation, and continued throughout the experiments. Four weeks after the carotid ligation, these mice were killed and vascular remodeling was analyzed. Moreover, NO production and endothelial NO synthase (eNOS) expression were assessed. RESULTS: At 4 weeks after ligation, the neointimal area in the vehicle-treated mice was 39,400 +/- 4,900 microm2 (n = 8), whereas that in the drug-treated mice was reduced to 18,300 +/- 3,800 microm2 (n = 10). Consequently, the luminal area was 35% larger in the drug-treated mice. Benidipine increased the basal as well as agonist-induced NO production from the endothelium, detected by Griess method or NOx analyzer. Endothelial NOS expression in vessels of the drug-treated mice was increased compared with that of the vehicle-treated mice. CONCLUSION: Our data provide evidence that benidipine increases NO production via increment of eNOS protein in vessels and prevents intimal thickening in mice. These results show the possibility of benidipine as a protective tool against vascular remodeling independent of its effect on blood pressure.
Animals↗
Effects of calcium channel blockers on atherosclerosis: new insights.
Atherosclerotic disease is the most frequent cause of death in the western world. The key role of calcium ions in atherogenesis has created interest in the antiatherogenic potential of calcium channel blockers. Nifedipine, administered in a long-acting gastrointestinal transport system (GITS) formulation, was shown to have similar efficacy to the diuretic co-amilozide in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Two side-arm studies of INSIGHT suggest that nifedipine GITS has a greater antiatherosclerotic effect than diuretic therapy, which may signal additional cardiovascular protection in the long term. This paper reviews the evidence for the antiatherogenic properties of calcium channel blockers and discusses their clinical implication.
Arteriosclerosis↗
Comparison of the hemodynamic effects of five calcium channel blockers at rest and during exercise in essential hypertension.
Dihydropyridine and verapamil-like calcium channel blockers reduce blood pressure (BP) in essential hypertension (EH) but have different effects on heart rate (HR) at rest. This study compares the HR and hemodynamic responses to exercise of long-term treatment with nifedipine, nisoldipine, verapamil, tiapamil and diltiazem in five groups of patients with mild and moderate EH (diastolic BP ranging 100-120 mmHg). In a total of 76 patients (mean age 43 years) BP was measured intraarterially, cardiac output by dye dilution (Cardiogreen) and HR by electrocardiogram. Acutely HR and cardiac index (CI) rose (9 and 12%) while BP and total peripheral resistance index (TPRI) were reduced (9 and 19%). After one year calcium channel blockade intraarterial pressure at rest sitting fell from 172/105 to 150/91 mmHg (13%) and at 100 W exercise from 205/109 to 188/97 mmHg (10%). HR remained unchanged in the dihydropyridine groups (range +/- 3%) in all situations while it invariably fell (range 3 to 15%) in the groups treated with verapamil-like calcium blockers. The fall in HR was greater during exercise than at rest (mean 10% vs 6%). With these drugs stroke volume (SV) tended to increase (range 1 to 10%) while it remained unchanged in the dihydropyridine groups. Only minor changes were seen in CO. In all groups the TPRI fell, averaging 15% at rest and during exercise. Thus, the verapamil-like calcium blockers induce a negative chronotropic effect that is enhanced during work, but the cardiac pump function is preserved by a compensatory increase in SI. Independent on the cardiac responses both groups of calcium blockers lower BP by peripheral vasodilatation both at rest and during exercise.
Blood Pressure↗
Effects of mebudipine and dibudipine, two new calcium channel blockers, on guinea-pig isolated common bile duct.
The inhibitory effects of calcium channel blockers; nifedipine and two new compounds, mebudipine and dibudipine, on contractions of isolated guinea-pig common bile duct were investigated. All the compounds tested induced a concentration-dependent reduction of the amplitude of contractile response to electrical stimulation and all the compounds displaced concentration-response curve of calcium chloride to the right in a concentration-dependent manner. The pIC50 values for these compounds acting on electrically stimulated common bile duct were calculated as: dibudipine: 8.50 +/- 0.17; mebudipine: 8.27 +/- 0.20; nifedipine: 7.96 +/- 0.07. The compounds also antagonized the contractile response of K+-depolarized guinea-pig common bile duct to cumulative concentration of calcium. However the inhibitory effect of these compounds were not significantly different.
Animals↗
The effects of dauricine and verapamil as calcium channel blockers on the plasma concentration of 6-keto-prostaglandin F1 alpha and thromboxane B2 during cardiopulmonary bypass.
Three groups of ten dogs underwent 80 minutes cardiopulmonary bypass. Two of the three groups were administered dauricine, as a new calcium channel blocker, and verapamil, as a generally recognized calcium channel blocker, respectively, from 15 minutes pre-bypass to the end of the bypass procedure (a period of 95 minutes). By means of radioimmunoassay plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) as the stable metabolites of prostacyclin and thromboxane A2 were surveyed. During the aortic clamping the hemodynamic changes were recorded. The dauricine and verapamil groups showed markedly inhibited generation of excessive 6-keto-PGF1 and TxB2, a narrowed ratio of TxB2 to 6-keto-PGF1 alpha, as well as a reduced total systemic peripheral resistance within the perfusion period. These results suggest that dauricine and verapamil have a salutary effect in extracorporeal circulation. The possible mechanisms are discussed.
6-Ketoprostaglandin F1 alpha↗
[Studies on residual cardiovascular dysfunction in patients receiving long-term antihypertensive treatment of calcium channel blockers: with special reference to left ventricular hypertrophy, and impairments of left ventricular diastolic function and carotid arterial distensibility].
Residual cardiovascular dysfunctions including left ventricular hypertrophy, and impairment of left ventricular diastolic function and carotid arterial distensibility were investigated in hypertensive patients treated with calcium channel blockers for more than 1 year. Ultrasonographic examinations of the heart and carotid artery were performed in patients treated with calcium channel blocker alone for more than 1 year (n = 45) and in age-, sex- and weight-matched control subjects (n = 29). The following parameters were obtained: left ventricular mass index, cardiac diastolic function (A/E ratio) and carotid arterial distensibility (Distens). Hypertensive subjects were re-examined under the same conditions with the same parameters after 10 +/- 5 months. Patients with hypertension revealed no significant changes in these three parameters after 10 +/- 5 months Patients with left ventricular hypertrophy (n = 20) revealed significant impairments in diastolic function and carotid arterial distensibility (A/E = 1.42 +/- 0.25, Distens = 2.4 +/- 1.3% kPa) compared to those without left ventricular hypertrophy (n = 25) (A/E = 1.18 +/- 0.29, Distens = 3.8 +/- 1.7% kPa, p < 0.05). Patients without left ventricular hypertrophy had significantly impaired cardiovascular functions compared to the normal control group (A/E = 1.03 +/- 0.27, Distens = 6.3 +/- 2.2% kPa, p < 0.05, p < 0.01 respectively). Therefore, only reduction of blood pressure with calcium channel blocker may not be enough to improve cardiovascular organ damage, especially in patients with residual left ventricular hypertrophy, and such residual functional deteriorations must be corrected probably with another pharmaceutical modality.
Aged↗
Mass media release of medical research results: an analysis of antihypertensive drug prescribing in the aftermath of the calcium channel blocker scare of March 1995.
BACKGROUND: Disclosure of medical research results to the public creates tension between lay medical reporters and the medical profession. OBJECTIVE: To explore the early effect of media attention on the risks associated with short-acting calcium channel blockers (CCBs) for treating hypertension after publication at a national meeting and following publication. DESIGN: Time-series analysis of prescription claims data. SETTING AND DATA SOURCE: National third-party pharmaceutical benefits manager. PATIENTS: Employed or retired persons and their families, 18 years of age or older, receiving prescription benefits from 1 of 4 national companies that contracted with the pharmaceutical benefits manager exclusively for prescription drug coverage. MEASUREMENTS: Prescription claims for antihypertensive drugs by fill date converted to a percentage of all cardiovascular drug claims. Data were grouped into weekly intervals before and immediately after the national release of negative information about CCBs on March 10, 1995 and following publication of the results on August 23, 1995. RESULTS: The most prevalent antihypertensive drugs were diuretics (21% of cardiovascular prescription claims) and calcium channel blockers (19%). A 10% decline in prescriptions filled for CCBs occurred 4 weeks following the intense media attention. Only prescriptions for long-acting calcium channel blockers declined. Alpha-1-blocker prescriptions increased by approximately the same amount that prescriptions for CCBs declined, suggesting substitution of one drug for the other. Changes in diuretic or beta-blocker prescriptions filled were not statistically significant. No immediate change in other cardiovascular drug classes occurred following journal publication. CONCLUSIONS: Intense media publicity regarding a controversial study measurably and unpredictably changed prescription claims.
Adolescent↗
Interaction between calcium channel blockers and sweetening agents on morphine-induced analgesia in mice by formalin test.
1. Calcium is known to be an important ion in the modulation of nociception and inflammation. Previous research has shown that mice drinking sweet-tasting solutions such as sucrose, saccharin and aspartame exhibit significant changes in morphine-induced analgesia in both phases of the formalin test. 2. In this study, the role of calcium channel blockers on the effectivity of a 12-day regimen of different sweetening agents (sucrose 32%, saccharin 0.08% and aspartame 0.16%) on the alteration of the morphine response has been investigated. 3. Male albino mice weighing 20-27 g were used for experiments. Animals were given 12 days to adapt to dietary conditions. Animals were given morphine (1.5, 3, 6, 9 mg/kg) subcutaneously 30 min before observation. Nifedipine (5 mg/kg), verapamil (5 mg/kg) and diltiazem (10 mg/kg) were administered intraperitoneally 20 min before morphine injection. 4. Recording of the early phase started immediately and lasted for 10 min after formalin injection. Recording of the late response started 20 min after formalin injection and lasted for 10 min. 5. Calcium channel blockers potentiated the antinociceptive effects of sweetening agents and diminished the antagonistic effects of these compounds on morphine-induced analgesia in the early and late phases of the formalin test. 6. It is proposed that calcium has a role for the interactive effects of sweetening agents and morphine on pain sensitivity.
Analgesics↗
Antiarrhythmic agent amiodarone possesses calcium channel blocker properties.
Amiodarone possesses multiple pharmacologic properties, including peripheral and coronary vasodilatation, negative inotropy, and negative chronotropic and dromotropic effects. These properties are shared by the group of drugs termed calcium channel blockers. We examined the interaction of amiodarone with receptors for the 1,4-dihydropyridine (DHP) calcium blockers in rat and rabbit myocardial membrane particulates. Amiodarone displaced specifically bound [3H]nitrendipine in both rat and rabbit preparations in a competitive, concentration-dependent manner at a single class of binding sites (Ki approximately 0.27 micxroM). Calcium channel activity was determined pharmacologically in a tissue bath with electrically stimulated rabbit right ventricular strips, KCl-induced aortic ring contraction, and 45Ca2+ uptake in K(+)-depolarized cultured rat cardiomyocytes. Amiodarone completely inhibited myocardial contraction (EC50 = 1.7 microM), completely antagonized depolarization-induced aortic ring contraction (EC50 = 24 nM), and significantly reduced (29% vs. control) 45Ca2+ uptake into cultured cells. The calcium channel blocking effects of amiodarone may contribute significantly to its pharmacologic profile.
Amiodarone↗
Correlation between the negative inotropic potency and binding parameters of 1,4-dihydropyridine and phenylalkylamine calcium channel blockers in cat heart.
Partially purified plasma membranes were prepared from cat ventricle. The purification factors for the calcium channel ligands (+)-3H-PN 200-110, 3H-nimodipine (1,4-dihydropyridines) and (-)-3-H-desmethoxyverapamil (a phenylalkylamine) were 3.1-, 3.4- and 2.9-fold, respectively, whilst beta-adrenoceptors labelled with (-)-3H-dihydroalprenolol were purified 3.0-fold. (+)-3H-PN 200-110 bound to 930 +/- 140 fmol/mg of membrane protein with a dissociation constant of 70 pmol/l at 25 degrees C. Under the same conditions 3H-nimodipine bound to 490 +/- 24 fmol/mg of sites with a KD of 120 pmol/l. (-)-3-H-desmethoxyverapamil bound to 530 +/- 55 fmol/mg of sites with a KD of 2.47 nmol/l. Twelve 1,4-dihydropyridines were evaluated for binding inhibition constants (Ki) with (+)-3H-PN 200-110 and 13 phenylalkylamines with (-)-3-H-desmethoxyverapamil in radioligand binding assays. Of the twelve 1,4-dihydropyridines evaluated (+/-)-nitrendipine was the most potent with a Ki-value of 280 pmol/l, nifedipine had a Ki-value of 500 pmol/l and the weakest drug tested, (+/-)-Bay b 4328, had a Ki-value of 14.3 nmol/l. The EC50-values of the same 1,4-dihydropyridines to inhibit the electrically driven cat papillary muscle were 77- to 3,450-fold higher and little correlation existed between Ki and EC50-values. Thirteen phenylalkylamines were tested for their potency to inhibit (-)-3-H-desmethoxyverapamil binding. The most potent phenylalkylamine with respect to negative inotropy was (+/-)-D 595 with an EC50-value of 794 nmol/l, the least potent substance was (+/-)-Sz 45 with an EC50-value of 39.8 mumol/l. The binding inhibition constants for the phenylalkylamines were 13- to 322-fold lower than the values for negative inotropy, but a significant positive correlation between the Ki and EC50-values (n = 12, r = 0.84) was observed. The absolute differences may reflect the state-dependent binding of phenylalkylamines to the channel. QSAR analysis revealed nearly identical correlations between physicochemical substituent properties on the one hand and binding affinities or functional potency on the other hand. In both cases the electronic properties (F-constant) of ring substituents mainly determine the variance in potency.
Animals↗
Effects of calcium channel blockers on ouabain-induced oscillatory afterpotentials in organ-cultured young embryonic chick hearts.
Ouabain induces oscillatory afterpotentials (OAPs) in organ-cultured young (3 day old) embryonic chick hearts. Since increased [Ca]i resulting from an inhibition of the Na pump by ouabain triggers oscillatory movements of Ca2+ (i.e. OAPs) intracellularly, Ca2+ influx through the cell membrane, which tends to increase [Ca]i, may be important in developing the OAPs. Therefore, in the present experiments, effects of calcium channel blockers on ouabain-induced OAPs in organ-cultured 3 day old embryonic chick hearts were examined. Automaticity was suppressed by elevating [K]o to 6 mM. To induce the OAPs, the preparations were stimulated (0.5 Hz) in the presence of ouabain (2.5-6.3 microM). The calcium channel blockers (10 microM) depressed the OAPs in the following order of potency: bepridil greater than verapamil greater than nifedipine greater than diltiazem. This order of potency of the calcium channel blockers in depressing the OAPs was the same as that for drug penetration into the cells, but different from that for depressing slow action potentials: nifedipine greater than diltiazem greater than verapamil greater than bepridil (our previous findings). These results suggest that an intracellular site of action of the calcium channel blockers is important for depression of the OAPs, and suppression of the slow inward Ca2+ current cannot be the sole mechanism for suppression of the OAPs by these drugs.
Action Potentials↗
Calcium channel blockers and myocardial infarction: a case--control study in a Japanese hospital.
PURPOSE: To examine the relationship of the use of calcium channel blockers (CCBs) in hypertensive patients to myocardial infarction in Japan, where CCBs are prescribed much more frequently than in Europe and America. DESIGN: We conducted a nested case-control study using a hospital information system in Japan. SUBJECTS: Cases were hypertensive patients who were repeat visitors to Tokyo University Hospital as of April 1996 and had an incidence of fatal or non-fatal myocardial infarction between 1996 and 1999. Controls were hypertensive patients individually matched to cases by sex, age and history of angina pectoris. RESULTS: The study consisted of 16 cases, who were matched to 80 controls. Of the 80 control patients, 54 (68%) received CCBs. On the other hand, all but one of 16 cases received CCBs and the crude odds ratio of myocardial infarction associated with the use of calcium channel blockers was as high as 7.0 (0.9-55.3). The odds ratio was reduced to 4.9 (0.6-42.4) when adjusted by diabetes and diastolic blood pressure. CONCLUSIONS: Although the crude odds ratio of myocardial infarction associated with CCBs was high, the ratio was reduced when adjusted by known confounding factors, suggesting a mechanism of confounding by indication. In addition, the results obtained in this study using records from a single hospital should not be generalized.
Aged↗