Calcium channel blockers--under a cloud?
Explore the source record for details and available documents.
Calcium Channel Blockers↗
SEARCH · Search PubMed
Results for “Calcium Channel Blockers”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Inhibition of oxidized LDL aggregation with the calcium channel blocker amlodipine: role of electrostatic interactions.
Atherogenic low-density lipoproteins (LDL) are characterized by elevations in cholesterol content and increased electronegativity, factors that contribute to aggregation and foam cell formation. This study was designed to test the effect of the positively charged calcium channel blocker (CCB) amlodipine on the aggregation properties of oxidized LDL lipids. Large unilamellar vesicles (LUVs) (100 nm diameter) labeled with a non-exchangeable marker [3H]cholesteryl hexadecyl ether were prepared with lipids extracted from human LDL following oxidation. The LUVs were shown to bind, in a reversible fashion, to charged diethylaminoethyl Sephadex columns. The addition of amlodipine inhibited binding of the oxidized LDL lipids in a dose-dependent fashion with an IC(50) in the nanomolar range as a result of its high lipophilicity and positively charged amino group (pK(a) of 9.02). The activity of amlodipine was reproduced in model membranes that contained fixed amounts of charged phospholipid (glycerophospholipid) in a concentration-dependent manner. By contrast, drugs lacking a formal positive charge, including CCBs (felodipine, nifedipine, diltiazem, verapamil) and an angiotensin-converting enzyme-inhibitor (ramiprilate) had no effect on the column binding of the modified, electronegative lipids. These effects of amlodipine on LDL lipid aggregation and electrostatic properties may represent a novel antiatherosclerotic mechanism of action.
Amlodipine↗
Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction.
The Studies of Left Ventricular Dysfunction (SOLVD) assessed the effect of enalapril in patients with systolic left ventricular dysfunction (LVD). We performed retrospective analyses of the association between calcium channel blocker (CCB) use and fatal and nonfatal myocardial infarction (MI) in these patients. MI occurred in 11.5% of 845 patients receiving CCBs versus 7.5% of 2551 patients not receiving CCBs in the enalapril group and in 14.4% of 874 patients receiving CCBs versus 9.3% of 2527 patients not receiving CCBs in the placebo group. By multivariate Cox regression analysis, adjusting for comorbidity, cause and severity of LVD, heart failure, and concomitant drug use, CCB use was an independent predictor of MI (relative risk [RR] 1.37, confidence interval [CI] 1.14 to 1.63). The increase in MI risk was greater among patients with a higher heart rate (RR 1.46, CI 1.14 to 1.86) and lower blood pressure (RR 1.45, CI 1.14 to 1.86). The adjusted risk ratio for all-cause mortality associated with CCB use was 1.14 (CI 1.00 to 1.28; p = 0.0454). In this analysis of patients with LVD, CCB use was associated with significantly increased risk of fatal or nonfatal MI.
Angiotensin-Converting Enzyme Inhibitors↗
Use of calcium channel blockers after stroke is not associated with poor outcome: a cohort from the registry of the Canadian stroke network.
BACKGROUND: Control of hypertension is essential for the secondary prevention of stroke. Although several trials have assessed the role of calcium channel blockers (CCBs) in the acute stroke, few address their safety and efficacy in secondary prevention. The recovery process after stroke requires neurite outgrowth, which may be dependent on activation of calcium channels and NMDA receptors. We asked whether treatment of hypertension using CCBs is safe during the recovery of patients following stroke and whether it contributes to their functional outcome. METHODS: The Registry of the Canadian Stroke Network provided access to information from 1545 patients with ischemic stroke. Primary outcome variables were mortality and functional outcome, which was assessed using the Stroke Impact Scale-16. RESULTS: Patients discharged on CCB had a 2.5% 6-month mortality rate compared with 5.5% in those who were not on CCB at discharge (OR 0.38, 95% CI 0.17-0.88). There was no change in 6-month mortality with respect to treatment with ACE-I, B-blockers or diuretics at discharge. Patients that were admitted on CCB had improved SIS-16 at 6-months if they were also discharged on CCB, as compared with patients who had their CCB discontinued (73.8 veas 66.8, p = 0.032). CONCLUSIONS: CCB treatment at the time of discharge did not impede functional recovery, and was associated with reduced mortality and improved SIS-16 at 6 months.
Aged↗
Raynaud's phenomenon: pathophysiologic features and treatment with calcium-channel blockers.
Raynaud's phenomenon may be associated with severe pain, functional disability and digital infarction, particularly in patients with underlying vascular disease. The pathophysiologic features of Raynaud's phenomenon are complex although vasospasm contributes to the production of digital ischemia in most cases. Calcium-channel blockers have been shown to produce arteriolar vasodilation and an increase in peripheral blood flow. They have been used to treat patients with Raynaud's phenomenon in several prospective, randomized, double-blind, placebo-controlled trials. Low doses of verapamil were ineffective but both diltiazem and nifedipine produced subjective improvement in 60 to 90% of cases. Objective measures of digital blood flow were not improved. Patients without underlying vascular disease responded more readily to therapy than patients with scleroderma. Adverse effects were uncommon and seldom necessitated discontinuation of therapy. These data suggest that nifedipine and diltiazem provide effective short-term improvement in symptoms for most patients with Raynaud's phenomenon.
Calcium Channel Blockers↗
[Effect of calcium channel blockers on developing nervous syndrome of high pressure and nitrogen narcosis in mice].
In the experiments conducted on mice which prior to compression in a heliox environment have been injected the blockers of various types of calcium channels (flunarezine, verapramil and nifedipine) as well as bemethyl (actoprotector) and oxymethacye (antioxidant) there escaped detection of noticeable effect of these drugs on developing the high pressure nervous syndrome (HPNS). On exposure to the hyperbaric nitrogen-oxygen environment verapromil (phenylalkulamine blocker of L-type calcium channels) had a protection effect with respect to a convulsive component of the nitrogen narcosis.
Animals↗
The effects of monotherapy or combined therapy with an angiotensin converting enzyme inhibitor following initial treatment with calcium channel blockers on residual cardiovascular abnormalities.
The effects of sequential therapy with angiotensin-converting enzyme inhibitor (cilazapril) on left ventricular (LV) mass, LV diastolic function, and carotid artery distensibility were evaluated in 90 hypertensive patients whose blood pressure controlled below 140/90 mmHg with a calcium channel blocker monotherapy. The possibility of predicting the efficacy of cilazapril based on evaluation of biochemical and genetic markers of the renin-angiotensin system was examined. Before cilazapril therapy, LV diastolic function and carotid artery distensibility were significantly impaired in 32 patients with residual LV hypertrophy compared with patients without LV hypertrophy. Cilazapril improved the LV mass in these patients with LV hypertrophy and improved LV diastolic function in a subset of 20 patients with elevated plasma renin activity. Patients with residual LV hypertrophy accompanied by cardiovascular functional abnormalities. Subsequent treatment with cilazapril significantly improved LV morphology and function in those with residual LV hypertrophy or elevated plasma renin activity.
Aged↗
Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs.
Cloned HERG and KvLQT1-IsK K+ channels have been expressed in mammalian cells and assayed as a target for calcium channel blockers. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them that lead to long QT syndromes. HERG is blocked 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), whilst being insensitive to nitrendipine, diltiazem or verapamil. This work may help to understand the mechanisms of action of verapamil in certain ventricular tachycardias as well as some of the deleterious adverse cardiac events associated with bepridil and mibefradil.
Animals↗
Proposed synergistic effect of calcium channel blockers with lipid-lowering therapy in retarding progression of coronary atherosclerosis.
Lipid-lowering therapy now has undoubtedly proven to be an effective therapeutic modality to retard the progression of coronary atherosclerosis. An additional approach for prevention of the progression of atherosclerosis is calcium channel blocker (CCB) treatment. Evidence indicating that CCBs inhibit atherosclerosis is less unequivocal than the clear evidence for lipid-lowering therapy. Many investigations support the view that a number of key processes in atherosclerosis may be influenced by CCBs. From the "negative" and "positive" studies with CCBs performed in animals and humans we must conclude that apparently some, but not all, types or stages of the atherosclerotic process are inhibited by CCBs. To assess whether lipid-lowering therapy and CCB treatment may have an additive or synergistic beneficial effect on human atherosclerosis, which is conceivable because their anti-atherosclerotic properties differ, data from the angiographic lipid-lowering trial REGRESS (pravastatin vs. placebo) were reviewed. In REGRESS, patients in the pravastatin group had significantly less progression if cotreated with CCBs as compared with those with no CCB cotreatment, whereas in the placebo (no pravastatin) group no effect of CCB treatment was observed. With respect to angiographic new lesion formation, in the pravastatin group there were 50% less patients with new angiographic lesions if cotreated with CCBs as compared with no CCB cotreatment, whereas in the placebo (no pravastatin) group, again, no significant effect of CCB treatment was observed. No beneficial effects of CCB treatment on clinical events were observed during the 2-year study follow-up. In view of the correlation between angiographic progression and subsequent clinical events as demonstrated in several large trials, it is not unrealistic to also anticipate in this population, a beneficial effect on clinical events with longer follow-up. Although the REGRESS trial was not designed to evaluate combination therapy, the results suggest that addition of CCBs to HMG-CoA reductase inhibitor therapy (pravastatin) acts synergistically in retarding the progression of established coronary atherosclerosis. These results appear to warrant prospective randomized trials to determine in a more definitive manner the merits of this combination in the prevention of progression of coronary atherosclerosis. Currently a number of studies in these fields are being designed or are already underway.
Anticholesteremic Agents↗
Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
BACKGROUND: This study was performed to determine whether, in high-risk hypertensive patients with a reduced glomerular filtration rate (GFR), treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of renal disease outcomes compared with treatment with a diuretic. METHODS: We conducted post hoc analyses of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertensive participants 55 years or older with at least 1 other coronary heart disease risk factor were randomized to receive chlorthalidone, amlodipine, or lisinopril for a mean of 4.9 years. Renal outcomes were incidence of end-stage renal disease (ESRD) and/or a decrement in GFR of 50% or more from baseline. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease equation, was stratified into normal or increased (> or =90 mL /min per 1.73 m(2), n = 8126), mild reduction (60-89 mL /min per 1.73 m(2), n = 18 109), or moderate-severe reduction (<60 mL /min per 1.73 m(2), n = 5662) in GFR. Each stratum was analyzed for effects of the treatments on outcomes. RESULTS: In 448 participants, ESRD developed. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking amlodipine in the mild (relative risk [RR], 1.47; 95% confidence interval [CI], 0.97-2.23) or moderate-severe (RR, 0.92; 95% CI, 0.68-1.24) reduction in GFR groups. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking lisinopril in the mild (RR, 1.34; 95% CI, 0.87-2.06) or moderate-severe (RR, 0.98; 95% CI, 0.73-1.31) reduction in GFR groups. In patients with mild and moderate-severe reduction in GFR, the incidence of ESRD or 50% or greater decrement in GFR was not significantly different in patients treated with chlorthalidone compared with those treated with amlodipine (odds ratios, 0.96 [P = .74] and 0.85 [P = .23], respectively) and lisinopril (odds ratios, 1.13 [P = .31] and 1.00 [P = .98], respectively). No difference in treatment effects occurred for either end point for patients taking amlodipine or lisinopril compared with those taking chlorthalidone across the 3 GFR subgroups, either for the total group or for participants with diabetes at baseline. At 4 years of follow-up, estimated GFR was 3 to 6 mL /min per 1.73 m(2) higher in patients assigned to receive amlodipine compared with chlorthalidone, depending on baseline GFR stratum. CONCLUSIONS: In hypertensive patients with reduced GFR, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Participants assigned to receive amlodipine had a higher GFR than those assigned to receive chlorthalidone, but rates of development of ESRD were not different between the groups.
Aged↗
Do calcium channel blockers and HMG-CoA reductase inhibitors attenuate allograft arteriopathy?
Recent epidemiologic studies of the risk factors for early and late phases of transplant coronary artery disease (TxCAD) have identified metabolic abnormalities such as hyperlipidemia and insulin resistance as important risk factors, independent of rejection. In randomized trials, calcium channel blockers and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were shown to decrease coronary artery intimal thickening and stenosis. Furthermore, HMG-CoA reductase inhibitors significantly decreased allograft loss during the first year after transplantation, resulting in a survival benefit, independent of TxCAD and cholesterol lowering. Prevention of acute allograft failure is consistent with known immunomodulatory actions of HMG-CoA reductase inhibitors, and the effects of calcium blockers in preventing TxCAD might have an immunologic basis by virtue of alterations of cyclosporine pharmacodynamics. Hence these two strategies for targeting antigen-independent mechanisms should lead to a significant reduction in the incidence of TxCAD, a goal that has until this time defied all the advances in immunosuppression during the past three decades of heart transplantation.
Adjuvants, Immunologic↗
Myocardial protection through cold cardioplegia using diltiazem, a calcium channel blocker.
During two hours of aortic clamping, two groups of 10 dogs each were given an intermittent infusion of a cold solution in the aortic root. In one group, the solution contained 20 mEq per liter of potassium chloride (KCl) and in the other, a calcium channel blocker (diltiazem). Left ventricular (LV) performance was measured by calculation of LV pressure, left ventricular end-diastolic pressure (LVEDP), cardiac index (CI), and stroke-work index (SWI). Regional myocardial function was assessed through ultrasonic crystals implanted in the subendocardial areas of both the left anterior descending (LAD) and circumflex coronary arteries. Dogs receiving KCl displayed deterioration of LV performance as evidenced by a return of maximal LV pressure, maximal rate of rise of LV pressure (dP/dtmax), CI, and SWI to 74 +/- 4%, 87 +/- 5%, 74 +/- 6%, and 59 +/- 6%, respectively, of the initial (before clamping) values. Animals that received diltiazem, on the other hand, had for the same variables a return to 85 +/- 4%, 99 +/- 7%, 129 +/- 8%, and 111 +/- 10% of the initial values. The rate of relaxation (peak negative dP/dt) decreased in both groups but less in dogs receiving diltiazem. Regional function in the area of the LAD and circumflex arteries showed little change in either group. We conclude that cold cardioplegia with a solution containing KCl or diltiazem protects the myocardium during prolonged ischemic cardiac arrest. Return of LV function on the whole is superior when diltiazem is used.
Animals↗
Influence of the angiotensin II receptor antagonist losartan on diuretic-induced metabolic effects in elderly hypertensive patients: comparison with a calcium channel blocker.
OBJECTIVE: Diuretic therapy frequently induces undesirable biochemical changes and side effects. We compared metabolic effects of a low-dose diuretic (D) given in combination with an angiotensin II receptor antagonist, losartan (L), with those resulting from a diuretic given in combination with a calcium channel blocker, slow-release nifedipine (N). MATERIAL AND METHODS: Thirty-seven elderly patients with mild to moderate hypertension (mean age: 71 +/- 3 years) were treated with either L+D (n = 18) or N+D (n = 19) for 1 year. Diuretic therapy included low-dose trichlormethiazide or low-dose furosemide in numbers of patients that were similar between L+D and N+D groups. Blood pressure, serum electrolytes, uric acid, blood glucose, renal function and lipid parameters were measured at baseline, 6 months and 1 year. RESULTS: Effective blood pressure control was observed in both groups at 6 months, and with further improvement at 1 year. Serum potassium was significantly decreased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but not in the L+D group. Serum uric acid was significantly increased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but had minimally decreased at 1 year in the L+D group (p < 0.1). Blood glucose, renal function and lipid parameters did not change in either group. CONCLUSION: The combination of losartan and low-dose diuretics effectively treated hypertension in elderly patients while minimizing the metabolic consequences of diuretic therapy. Larger trials will be necessary to confirm this finding.
Aged↗
[Comparative effects of calcium channel blockers and L-arginine on chronic intermittent hypoxic pulmonary hypertension in rats].
Experiments were carried on rats to study the preventive effects of calcium channel blockers Nitrendipine, Nifedipine and L-Arginine (L- Arginine is the physiological precursor of nitric oxide in endothelium-dependent relaxation) on chronic intermittent hypoxia induced pulmonary hypertension, on the right ventricular hypertrophy and pulmonary vascular pathologic changes. The results showed (1) Nitrendipine, Nifedipine and L-arginine played significant role in preventing chronic hypoxic pulmonary hypertension and the right ventricular hypertrophy. (2) There was no significant difference between Nitrendipine, Nifedipine and L- arginine in preventing hypoxic pulmonary hypertension (P > 0.05). (3) Nitrendipine was better than Nifedipine in reducing the hypoxic pulmonary hypertension.
Animals↗
Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI.
Diffusion-weighted magnetic resonance imaging (DWI) is capable of noninvasively imaging acute cerebral ischemia. We demonstrate the utility of this technique by evaluating SNX-111, a novel N-type calcium channel blocker with potential neuroprotective properties, in a rodent model of transient focal ischemia. Twenty-four Sprague-Dawley rats weighing between 310-350 g underwent occlusion of the middle cerebral artery (MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes following MCAO, animals were randomized to receive SNX-111 5 mg/kg intravenously over 1 h vs. placebo. DWI and T2-weighted MRIs (T2W) were performed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fractions of increased signal intensity on the DWI and T2W images were measured. DWI area fractions at 1.5 and 24 h were also normalized to the initial, pre-treatment scans. Apparent diffusion coefficients (ADC) were calculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) staining was performed on brains at 24 h and infarct area fractions were measured. SNX-111 treated animals showed significantly improved 1.5-h DWI scan ratios compared to controls (ratios of 1.06 +/- 0.25 vs. 2.98 +/- 0.78 SNX vs. controls respectively, P < 0.05). A trend toward improved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs. 4.12 +/- 1.6, N.S.) DWI, T2W and TTC area fractions at 24 h also showed trends favoring a neuroprotective effect of SNX-111. Bright areas on DWI corresponded to ADC decreases of about 30% compared to the non-ischemic hemisphere. These decreases were the same in both treatment groups and at each time point. DWI, T2W and TTC area fractions at 24 h were strongly correlated (r = 0.98, DWI and TTC; r = 0.99, T2W and TTC; r = 0.97, T2W and DWI, P < 0.0001). We conclude that in this ischemic model, SNX-111 provides early neuroprotection and that serial DWI is a useful way of demonstrating this.
Animals↗
Selectivity of phenytoin and dihydropyridine calcium channel blockers for relaxation of the basilar artery.
We addressed the questions of whether or not phenytoin is a direct vasodilator and if it is selective for brain blood vessels, by studying the relaxant effects of phenytoin on isolated segments of canine basilar, femoral, and brachial arteries. Two dihydropyridine calcium channel blockers, nifedipine and PY 108-068, were also studied for comparison with phenytoin and to test for cerebral selectivity. Blood vessels were contracted with K+, prostaglandin F2 alpha, or serotonin. Phenytoin relaxed the basilar artery with low potency (pD2, 4.71 +/- 0.14) and moderate selectivity. Phenytoin also antagonized Bay K 8644 contractions of basilar artery in a noncompetitive manner. Basilar arteries contracted with 60 mM K+ were the most sensitive to nifedipine (pD2, 8.72 +/- 0.18), followed by the mesenteric (pD2, 8.24 +/- 0.07), femoral (pD2, 8.04 +/- 0.18), and brachial (pD2, 7.66 +/- 0.23) arteries. A similar pattern was observed in potassium-depolarized arteries relaxed by PY 108-068. The calcium dependence of contraction was studied using intact muscles depolarized in 60 mM K+ as well as chemically skinned basilar artery. Mean pD2 values for Ca2+-induced contractions of intact, depolarized arteries were not different (basilar, 4.15 +/- 0.13; mesenteric, 4.04 +/- 0.07; femoral, 4.24 +/- 0.11). The mean Ca2+ EC50 of chemically skinned basilar arteries was 8.7 X 10(-7) M, which is similar to the Ca2+ sensitivity of other skinned smooth muscles. The beneficial effect of phenytoin in treating cerebral ischemia may be due in part to relaxation of vascular smooth muscle. The dihydropyridines were potent smooth muscle relaxants with selectivity for the basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
The effect of temperature on hydrogen bonding in crystalline and amorphous phases in dihydropyrine calcium channel blockers.
PURPOSE: To investigate the effect of temperature on hydrogen bonding in a series of structurally related amorphous and crystalline compounds to gain a better molecular-level understanding of structural differences in the various phases. METHODS: FT-infrared spectra of seven 1,4-dihydropyridine calcium channel blockers were obtained at temperatures between 0 and 200 degrees C using a temperature-controlled attenuated total reflection accessory. Thermal behavior was characterized using differential scanning calorimetry. RESULTS: Hydrogen bonding was investigated by monitoring the position of the NH stretching vibration, where an increase in peak wavenumber was taken to indicate a weakening of hydrogen bonding. Heating resulted in a reduction in hydrogen bonding strength, which was greatest for liquids and less for glassy and crystalline phases. For the amorphous samples, a plot of NH peak position vs. temperature displayed a discontinuity in the region of the glass transition (determined using differential scanning calorimetry) indicating that hydrogen bonding weakened abruptly as the material passed through the glass transition. This effect was more pronounced for some samples than for others. CONCLUSIONS: The variation in the decrease in hydrogen-bonding interactions with increasing temperature for the different phases is consistent with greater configurational freedom as one moves from crystal to glass to liquid.
Calcium Channel Blockers↗
Antiatherosclerotic effects of calcium channel blockers.
Hypertension is a constellation of abnormalities, including metabolic disorders. The current approach to treatment of hypertension should not be dictated solely by measures to lower blood pressure. It must also take into consideration the effect of antihypertensive drug treatment on the development of atherosclerosis and many other important factors. Evidence from rabbit models and cell cultures indicates that calcium channel blockers are antiatherogenic through a variety of mechanisms. In addition to preserving endothelial function, these agents inhibit the following: Platelet aggregation Migration of monocytes and smooth-muscle cells into the intima Incorporation of low-density lipoprotein cholesterol into these cells Matrix formation Calcium overload in atherosclerotic lesions However, additional studies are needed to delineate the antiatherogenic effects of these and other antihypertensive agents.
Animals↗