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PubMed1987

Low-dose fentanyl analgesia modified by calcium channel blockers in cardiac surgery.

The hypothesis that calcium channel blockers can potentiate and prolong the anti-nociceptive effects of opioids was tested. Forty-five men scheduled for aorto-coronary bypass operation received fentanyl according to their individual demands (haemodynamics, clinical parameters). The patients were allocated at random into three groups receiving either nimodipine 1.0 microgram kg-1 min-1 (Group 1, n = 15), nifedipine 0.70 microgram kg-1 min-1 (Group 2, n = 15), or no calcium channel blocker (Group 3, n = 15). Cerebral activity was monitored using a computerized spectral analysing system before and during the operation. The total amount of fentanyl required was significantly lower in the nimodipine group than the control group (-71%, P less than 0.001), whereas the nifedipine group did not differ from the control group. Quality of intra-operative anaesthesia was comparable in the three groups with respect to clinical observations (amnesia, sweat, tears, pupils), and the post-operative course was similar in all patients as well. Cerebral activity during the nimodipine-supplemented opioid anaesthesia was higher in the faster frequency bands (13-30 Hz). Power level in the beta range was most pronounced in Group 1, whereas power in the alpha range was similar in the calcium channel-blocker groups. The major conclusion was that nimodipine but not nifedipine administration can reduce fentanyl requirements during surgical procedures without influencing the quality of anaesthesia.

Analgesia↗
PubMed2004

Protective effects of a selective L-type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death.

Amyloid beta protein (Abeta)- and human group IIA secretory phospholipase A(2) (sPLA(2)-IIA)-induced neuronal cell death have been established as in vitro models for Alzheimer's disease (AD) and stroke. Both sPLA(2)-IIA and Abeta causes neuronal apoptosis by increasing the influx of Ca(2+) through L-type voltage-sensitive Ca(2+) channel (L-VSCC). In the present study, we evaluated effects of a selective L-VSCC blocker, S-(+)-methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitro-phenyl)thieno[2,3-b]pyridine-5-carboxylate (S-312-d), on Abeta- and sPLA(2)-IIA-induced neuronal apoptosis in primary cultures of rat cortical neurons. S-312-d significantly rescued cortical neurons from Abeta- and sPLA(2)-IIA-induced cell death. Both cell death stimuli caused the appearance of apoptotic features such as plasma membrane blebs, chromatin condensation, and DNA fragmentation. S-312-d completely suppressed these apoptotic features. Before apoptosis, the two death ligands markedly enhanced an influx of Ca(2+) into neurons. S-312-d significantly prevented neurons from sPLA(2)-IIA- and Abeta-induced Ca(2+) influx. Furthermore, the neuroprotective effect of S-312-d was more potent than that of another L-VSCC blocker, nimodipine. On the other hand, blockers of other VSCCs such as the N-type and P/Q-type calcium channels had no effect on the neuronal cell death, apoptotic features and Ca(2+) influx. In conclusion, we demonstrated that S-312-d rescues cortical neurons from Abeta- and sPLA(2)-IIA-induced apoptosis.

Amyloid beta-Peptides↗
PubMed1998

HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers.

We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/IsK K+ channels. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in transfected COS cells, HERG is blocked in a concentration-dependent manner by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM), and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1/IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K+ channels HERG and KvLQT1/IsK, which represent together the cardiac delayed rectifier K+ current, are sensitive targets to calcium channel blockers. This work may help in understanding the mechanisms of action of verapamil in certain ventricular tachycardia, as well as some of the deleterious adverse cardiac events associated with bepridil.

Animals↗
PubMed1998

Catalepsy induced by calcium channel blockers in mice.

It is known that calcium channel blockers induce Parkinsonism. In this study, amlodipine-, diltiazem-, and verapamil-induced catalepsy was investigated in mice. All of these three calcium channel blockers induced catalepsy. Dopamine D1, D2, and mACh receptor occupancies were estimated under the same conditions, and the affinities of these drugs for each receptor were also estimated in vitro. Intensity of catalepsy was predicted by dopamine D1, D2, and mACh receptor occupancies with the dynamic model which had already been constructed and was compared with the observed values. The predicted and the observed values were comparable (r = 0.98, p < 0.001). In conclusion, the dynamic model considering D1, and D2, and mACh receptor occupancy may be useful for quantitative prediction of drug-induced catalepsy.

Amlodipine↗
PubMed1990

Yawning induced by apomorphine, physostigmine or pilocarpine is potentiated by dihydropyridine calcium channel blockers.

Previous studies have shown that dihydropyridine (DHP) calcium channel blockers can potentiate yawning induced by apomorphine in rats. The present study was undertaken to examine whether or not this interaction was seen with other compounds that induce yawning or if it represented a specific interaction with dopaminergic mechanisms. Yawning induced by apomorphine (40 micrograms/kg SC), physostigmine (50 micrograms/kg SC) or pilocarpine (1 mg/kg SC) was dose-dependently potentiated by the DHP calcium channel blocker nifedipine (1.25-10 mg/kg IP). Nimodipine (1.25-5 mg/kg IP) and nitrendipine (1.25-5 mg/kg IP) also significantly increased the yawning response. The DHP calcium channel blockers alone induced only a low incidence of yawning. The effects of nifedipine on physostigmine-induced yawning were reversed by the DHP calcium channel activator BAY K 8644 which also inhibited yawning induced by physostigmine (100 micrograms/kg SC) and pilocarpine (2 mg/kg SC). In contrast to the DHP compounds, diltiazem (2.5-10 mg/kg IP) and verapamil (2.5-10 mg/kg IP) failed to potentiate yawning. Sulpiride (10 mg/kg SC) antagonised the nifedipine potentiation of apomorphine-induced yawning but not that of physostigmine-induced yawning; atropine (2.5 mg/kg SC) antagonised both effects. These results support the hypothesis that this effect of dihydropyridine compounds is not dependent on, nor mediated through, dopaminergic mechanisms.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2003

Calcium-channel blockers and end-stage renal disease: pharmacokinetic and pharmacodynamic considerations.

PURPOSE OF REVIEW: To characterize the pharmacokinetics and pharmacodynamics of the different calcium-channel blockers. RECENT FINDINGS: Calcium-channel blockers have been in use for some time in the end-stage renal disease population. Their primary use has been as antihypertensive and antianginal therapies. In this regard, they are effective agents. Recently, it has been noted that dialysis-related hypotension occurs less frequently in calcium-channel blocker treated patients. Also, access patency and overall patient survival are improved with calcium-channel blocker therapy. SUMMARY: Calcium-channel blockers are useful agents for the control of hypertension in end-stage renal disease patients and appear to favorably influence survival in this population. Calcium-channel blockers are not dialyzable and their pharmacokinetics do not substantially change with renal failure therefore they do not require dose adjustment based on level of renal function. Too few studies exist to determine if individual calcium-channel blockers differ in their effects. Prospective, randomized, controlled clinical trials are needed in the end-stage renal disease population to better understand the role of calcium-channel blockers in the excess cardiovascular disease burden of this population.

Biological Availability↗
PubMed2005

Gingival overgrowth with calcium-channel blockers. Treatment options.

Gingival overgrowth induced by calcium channel blockers can cause significant disfigurement and functional difficulty since it interferes with eating and speech, prevents effective plaque control, and disturbs occlusal relationships. It occurs more in young and male patients. The aim of this paper is to study the physiopathology of gingival overgrowth induced by calcium channel blockers and propose different choices of treatment.

Algorithms↗
PubMed2002

Underutilization of aspirin, beta blockers, angiotensin-converting enzyme inhibitors, and lipid-lowering drugs and overutilization of calcium channel blockers in older persons with coronary artery disease in an academic nursing home.

BACKGROUND: We report the prevalence of use of aspirin, beta blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers, statins, and calcium channel blockers in older persons with coronary artery disease (CAD) in an academic nursing home. METHODS: We investigated the prevalence of use of aspirin, beta blockers, ACE inhibitors or angiotensin II type 1 receptor blockers, lipid-lowering drugs, and calcium channel blockers in older persons with a mean age of 77 +/- 9 years, in an academic nursing home with documented CAD and no contraindications to the use of aspirin, beta blockers, ACE inhibitors or angiotensin II type 1 receptor blockers, and lipid-lowering drugs. RESULTS: CAD was documented in 77 of 255 persons (30%). Of 77 persons with CAD, 48 persons (62%) were treated with aspirin, 45 persons (58%) with ACE inhibitors or angiotensin II type 1 receptor blockers, 44 persons (57%) with beta blockers, 21 persons (27%) with calcium channel blockers, and 16 persons (21%) with statins. Of the 61 persons with CAD not treated with statins, serum low-density lipoprotein (LDL) cholesterol was measured in only 22 persons (36%) and was increased in 14 of the 22 persons (64%). CONCLUSIONS: These data show underutilization of aspirin, beta blockers, ACE inhibitors, lipid-lowering drugs, and measurement of serum LDL cholesterol and overutilization of calcium channel blockers in older persons with CAD in an academic nursing home.

Academic Medical Centers↗
PubMed2001

Contraction of human colonic circular smooth muscle cells is inhibited by the calcium channel blocker pinaverium bromide.

UNLABELLED: The effects of L-type calcium channel blockers (CCBs) selective for the gastrointestinal tract (pinaverium) or non-selective (nicardipine and diltiazem), were investigated on CCK-, CCh- or KCl-induced contraction of smooth muscle cells (SMC) isolated from the circular muscle layer of normal or of inflamed human colons. In the normal tissue colon, whatever the contractile agent used, CCK-8 (1nM), CCh (1nM) or KCl (20mM), a micromolar concentration of pinaverium significantly inhibited contraction (88.36%, 93.10%, 93.92% inhibition respectively); this effect was concentration-dependent for CCh (IC50 = 0.73 +/- 0.08nM) and for CCK (IC50 = 0.92 +/- 0.12nM). In parallel, both nicardipine and diltiazem inhibit significantly contraction of isolated SMC. In inflamed colons, pinaverium (1 microM) display a significant higher efficacy than diltiazem or nicardipine to reduce cell contraction induced by CCK-8 or by KCl. In addition, RT-PCR experiments were performed to evidence tissue specificity of the L-type calcium channel. They revealed the expression of the messenger of the a-1 subunit L-type calcium channel (binding site of such CCBs), consistent with the expression of the rbC-2 splice variant of the alpha1-C gene. IN CONCLUSION: (i) the inhibition by calcium channel blockers of agonist-induced contractile activity suggest a modulation of SMC contraction upon extracellular calcium via 'L-type' voltage-dependent calcium channel; (ii) this study provides a rationale for the clinical use of pinaverium in colonic motor disoders affecting the contractility of SMC, since it appeared to decrease the contraction even in pathological situation; and (iii) RT-PCR experiments confirms the presence in human colon SMC of the alpha-1 subunit mRNA of calcium channel.

Adult↗
PubMed1989

Calcium channel blockers. Potential medical benefits and side effects.

Calcium channel blockers are recently developed antihypertensive drugs. In terms of mechanisms of action, their specificity is not so well established as that of angiotensin converting enzyme inhibitors but is better understood than that for diuretics or adrenergic-inhibiting drugs. Calcium channel blockers were originally developed for treatment of angina but were found to lower arterial pressure as well. Three of them are now in wide use in the United States; their therapeutic spectrum in regard to type of hypertension is broad. Sublingual nifedipine has replaced intravenously administered vasodilators as immediate treatment of severe hypertension, and all three drugs, given orally, have been shown to be effective in mild, moderate, and severe hypertension. The three drugs available in this country are verapamil, diltiazem, and nifedipine. Pharmacological studies have shown that verapamil has the most negative chronotropic and inotropic effects of the three, with nifedipine producing the most vasodilation and having the potential for causing reflex tachycardia. Actually in practice, these various pharmacological differences have proved to have less significance than previously thought, and the drugs seem to have about equal antihypertensive effectiveness. Comparisons of calcium entry blockers with other drugs have shown them to be equally effective in whites as propranolol but more effective in blacks. Responsiveness appears to be related, as well, to pretreatment plasma renin activity and age. Thus, the antihypertensive effect is directly related to age and inversely related to plasma renin activity. The side effects mostly relate to vasodilation, reflex tachycardia, palpitations, headache, and edema; they are not frequent, and the drugs are well tolerated.

Blood Pressure↗
PubMed1997

Synthesis and biological activity of two new calcium-channel blockers, mebudipine and dibudipine.

Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mM)-treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.

Animals↗
PubMed1990

Antiatherogenic effects of calcium-channel blockers: possible mechanisms of action.

Calcium-channel blockers (Ca blockers), such as nifedipine, verapamil, diltiazem, flunarizine, and their respective derivatives, have been reported to suppress the formation of arterial lesions in animals fed atherogenic diets. The fact that structurally unrelated Ca blockers exert similar antiatherogenic effects may suggest that the drugs act by a calcium-channel-dependent mechanism. However, in cell culture experiments in which putative antiatherosclerotic effects were observed only in the presence of a very high drug concentration (greater than 10 microM), calcium-channel-independent mechanisms are likely. It does not appear that Ca blockers act predominantly by altering coronary risk factors such as arterial pressure or hypercholesterolemia. On the other hand, current evidence is accumulating that Ca blockers may act by suppressing chemotaxis and the proliferation of cells involved in lesion formation. Recent reports indicate that relatively low concentrations (less than 1 microM) of nifedipine may promote the release of cholesterol from fat-laden smooth cells and macrophages. Controlled clinical trials are needed to determine whether Ca blockers have utility in the prevention of the progression of atherosclerosis in humans.

Animals↗
PubMed2000

The effect of calcium channel blockers on cerebral oxygenation during tracheal extubation.

UNLABELLED: Calcium channel blockers are effective in stabilizing systemic hemodynamics during tracheal extubation. However, they may increase cerebral blood flow (CBF) during tracheal extubation because of cerebral vasodilation, even if systemic arterial blood pressure decreases. In this study, we observed changes in cerebral oxygenation during tracheal extubation by using near-infrared spectroscopy and evaluated the effect of nicardipine and diltiazem on the resultant changes. We studied 45 women undergoing elective gynecologic surgery. After surgery, the patients were randomly allocated to three groups (n = 15 each): saline (control), 0.02 mg/kg nicardipine, and 0.2 mg/kg diltiazem. After 2 min, we started to aspirate secretions for 2 min and then, extubated the trachea. Changes in cerebral oxygenated hemoglobin (HbO(2)) and deoxygenated hemoglobin were measured during the extubation procedure for 9 min after drug treatment. Systemic hemodynamics, including mean arterial blood pressure, heart rate, end-tidal CO(2), end-tidal sevoflurane concentration, and peripheral arterial oxygen saturation were also monitored. During extubation, HbO(2) increased significantly, presumably caused by the increase in CBF. Changes in deoxygenated hemoglobin were minimal. Compared with the control, nicardipine and diltiazem significantly inhibited the increase in mean arterial blood pressure. On the contrary, they significantly enhanced the increase in HbO(2). In conclusion, calcium channel blockers may increase CBF during extubation, even if these drugs stabilize systemic hemodynamics. IMPLICATIONS: This study is a preliminary report evaluating the changes in cerebral oxygenation during the tracheal extubation. Cerebral oxygenated hemoglobin increased significantly, presumably caused by the increase in cerebral blood flow during extubation. In addition, these changes were enhanced by calcium channel blockers.

Blood Pressure↗
PubMed1998

Alteration of rat cerebral microvascular eicosanoid formation by isradipine, a calcium channel blocker.

We studied the influence of the calcium channel blocker isradipine on cerebral microvascular and aortic eicosanoid synthesis. The rat cerebral microvascular eicosanoid formation was assessed by means of bioassay, radioimmunoassay and radio thin layer chromatography from endogenous as well as from exogenous (20:4) radiolabelled substrate. The in vitro as well as the in vivo (0.3 mg/kg/day for 1 week) effect of isradipine was examined. Isradipine increased significantly (P < 0.01) both conversion to and formation of PGI2 and its derivative 6-oxo-PGF1alpha respectively, as well as PGD2-production, while TXB2-synthesis was diminished. The conversion to the other metabolites was not affected to a significant extent. These findings indicate that isradipine enhances PGI2-generation in aorta and cerebral microvessels from both exogenous and endogenous substrate and PGD2 from endogenous substrate, a phenomenon shown to underlie the antiatherosclerotic actions of this calcium channel blocker.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Potentiation of vincristine effect in human and murine gliomas by calcium channel blockers or calmodulin inhibitors.

The effects of calcium channel blockers and calmodulin inhibitors on vincristine cytotoxicity were studied in vitro with five glioma cell lines: three human glioblastomas, one rat glioma, and one mouse ependymoblastoma. One human glioblastoma and the rat glioma were resistant to vincristine in contrast to other glioma cells. The resistance to vincristine was considerably decreased by nontoxic or marginally toxic concentrations of calcium channel blockers or calmodulin inhibitors, although the former was more effective than the latter. In the presence of verapamil, the vincristine cytotoxicity, as measured by cell doubling times, increased 90- and 84-fold in the vincristine-resistant human glioblastoma and rat glioma, respectively. The decrease in the resistance to vincristine was related to a marked increase in the intracellular level of that drug, probably mediated by inhibiting its outward transport. The in vivo studies showed that verapamil or nicardipine administered daily with vincristine for 10 days significantly enhanced the chemotherapeutic effect of vincristine in an intracranially transplanted rat glioma model. An approximately 32% to 118% increase in life span occurred with 15 mg/kg/day of verapamil, depending on the doses of vincristine.

Animals↗
PubMed2004

Mechanism of vasoselective action of mebudipine, a new calcium channel blocker.

In previous studies, mebudipine, a newly synthesized dihydropyridine calcium channel blocker, showed a considerable vasoselective action. To investigate the mechanism of this property, the pattern of inhibitory action on the KCl-induced contraction in isolated rat aortic rings and the effect of changing resting membrane potential on the potency of this compound were considered. In addition, its chronotropic and inotropic actions were also studied. Mebudipine inhibited KCl-induced contractions. Its inhibitory effect was progressive and needed time to reach maximum. Incubation of the aortic rings in depolarizing physiological solution (high potassium, zero calcium) resulted in the augmentation of mebudipine effect. The potency of mebudipine in inhibiting aortic contractions and its time- and voltage-dependent action were significantly greater than those of nifedipine. In comparison with nifedipine, mebudipine showed a greater negative chronotropic effect, but in the case of negative inotropism, the reverse relation was observed. It is concluded that mebudipine has a greater time- and voltage-dependent inhibitory effect, as compared to nifedipine and this property could explain its prominent vasoselective action. It has also marked negative chronotropic effect and minor negative inotropic action. With regard to the above findings, mebudipine might have a selective and protective calcium channel blocking effect in ischemic regions (ischemia-selectivity), and the potential to be used in cardiovascular diseases without causing harmful effects such as reflex tachycardia and heart failure which have sometimes been seen with the older agents.

Animals↗
PubMed1997

Use of calcium channel blockers and breast carcinoma risk in postmenopausal women.

BACKGROUND: The use of calcium channel blockers in an elderly population recently was reported to be associated with the incidence of cancer. The Cardiovascular Health Study, a multisite observational cohort study, provided the opportunity to investigate the epidemiologic association between the use of calcium channel blockers and breast carcinoma risk in 3198 women age > or = 65 years. METHODS: Standard questionnaires and clinical procedures were administered at four study sites annually from 1989-1990 to 1993-1994. Drug usage was assessed by a medication inventory and hospitalizations for 75 incident invasive breast carcinoma cases were identified using International Classification of Diseases-9 Clinical Modification codes. Time-dependent Cox proportional hazards regression models were used to assess associations between incident breast carcinoma and the use of specific antihypertensive medication including calcium channel blockers. RESULTS: In adjusted Cox proportional hazards models, an elevated risk of breast carcinoma was associated with use of calcium channel blockers (hazard ratio [HR]: 2.57; 95% confidence interval [CI], 1.47-4.49). This association persisted when the comparison group was users of other antihypertensive medication. No associations between the use of other antihypertensive medication with incident breast carcinoma were found. Associations were enhanced by assessment of high dose at baseline (HR: 4.42; 95% CI, 1.37-14.27) and when calcium channel blockers were combined with estrogen use (HR: 4.48; 95% CI, 1.58-12.75). The association was found to be strongest for the use of estrogens with immediate release calcium channel blockers (HR: 8.48; 95% CI, 2.99-24.08). CONCLUSIONS: Although the number of cases was limited in this observational study, associations found between the use of calcium channel blockers and incident invasive breast carcinoma warrant further investigation. Site specific carcinomas should be included as an outcome of ongoing and planned long term clinical trials using calcium channel blockers.

Age Factors↗