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PubMed1986

Beneficial effects of calcium channel blockers and calmodulin binding drugs on in vitro renal cell anoxia.

Proximal tubules (PSTs) of the S1, S2 and S3 segments and cortical collecting tubules (CCTs) were microdissected individually from rabbit kidneys and cultured for 7 days in hormonally defined media. Anoxia was induced by incubation of cultures in normal medium for 45 min at 25 degrees C in an atmosphere of nitrogen and cell death was measured by nigrosine dye uptake. After 45 min of anoxia and a 4- to 6-hr incubation in normal Ca++-containing media, cells from all segments were dead. Addition of calcium channel blockers verapamil and nifedipine (5 X 10(-7) and 10(-6) M, respectively) for the first 2 hr after anoxia to the incubation media was associated with a 60 +/- 8 and 33 +/- 7% survival of PST cells (5 hr after anoxia), p less than .05. Verapamil at 5 X 10(-8) M caused a 42 +/- 4% survival whereas nifedipine at 10(-7) M was not effective on the survival rate of PST cells (5 hr after anoxia). These calcium channel blockers also afforded protection from anoxic cell death for CCT cells. The role of calmodulin in anoxic cell injury was studied by means of calmodulin binding drugs, trifluoperazine and W7 [N-(6-aminohexyl)-5-chloronapthalene-sulfonamide]. Addition of trifluoperazine (5 X 10(-7) M) and W7 (5 X 10(-7) M to both PST and CCT cells during the 2-hr reflow period after 45 min of anoxia increased viability by 58 +/- 3 and 62 +/- 3%, respectively (P less than .05) at 5 hr postanoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Aminoalkynyldithianes. A new class of calcium channel blockers.

Several dithiane derivatives, prepared as intermediates for compounds structurally related to the therapeutically useful antimuscarinic agent oxybutynin, were effective inhibitors of calcium ion induced contraction of guinea pig ileal strips and of KCl-induced calcium entry into neuronal cells. Although the first member of this series, 2-[5-(diethylamino)-3-pentynyl]-1,3-dithiane (2a), was only marginally effective, its condensation product with diphenyl ketone, i.e. 2-[5-(diethylamino)-3-pentynyl]-2-(a,a-diphenyl-a- hydroxymethyl)-1,3-dithiane (3a), demonstrated weak, but significant, calcium channel antagonist activity. As part of a structure-activity relationship (SAR) study, various structural analogues of 2a and 3a were prepared and examined for calcium antagonist properties. In addition to these structural types, ring bridged (tricyclic) congeners of 3, i.e. 4, related bicyclic compounds 5, dehydroxylated derivatives 6, some homologous 2-[[[(N,N-disubstituted-amino)methyl]2- phenyl-1,3-dithianes (7), and a series of 2-[6-[N,N-disubstituted-amino)methyl]-1-hydroxy-1-phenyl- 4-hexynyl]-1,3-dithianes (8) were prepared and studied for calcium channel blocking activity. In general, greatest potency was noted in the tricyclic series 4; however, a definitive SAR could not be established. A structural similarity between several potent calcium antagonists having the structures 7c, 8b, and 8d and the well-known calcium channel blockers verapamil and tiapamil suggests these compounds may act at the same site. Compounds in the other classes (2-6) failed to show clearly defined SAR and their potency differed markedly in two tests for calcium channel antagonist activity. These results may indicate that the dithiane derivatives 2-6 produce their effects in a manner differing from that of the calcium channel antagonists diltiazem, verapamil, and nitrendepine.

Animals↗
PubMed1995

Effects of a new calcium channel blocker, MPC-1304, on blood pressure, serum lipoproteins and serum carbohydrate metabolism in patients with essential hypertension.

The effects of MPC-1304, a new calcium channel blocker, on blood pressure, serum lipoproteins, and carbohydrate metabolism were compared with those of atenolol in a group of patients with mild to moderate essential hypertension. Systolic and diastolic pressures were significantly decreased by both MPC-1304 and atenolol administration. Serum levels of apolipoproteins A-I and A-II were significantly increased after 8-12 weeks of MPC-1304 treatment, but were unchanged during a similar period of atenolol treatment. Neither drug induced any significant change in other lipoprotein parameters, fasting blood sugar, immunoreactive insulin, C-peptide or HbA1c. No serious side-effects or abnormal laboratory values were observed during the course of administration of either drug. These findings indicated that MPC-1304 is as efficacious as an antihypertensive drug and is without adverse effect on lipoprotein or carbohydrate metabolism.

Adult↗
PubMed1990

The effect of calcium channel blockers on the cyclosporine dose requirement in renal transplant recipients.

Thirteen patients found to be hypertensive following renal transplantation were treated with either a calcium channel blocker or other antihypertensive therapy for control of blood pressure. Immunosuppression was either with cyclosporine and prednisone alone or with cyclosporine, azathioprine, and prednisone. Patients had weekly or biweekly cyclosporine whole-blood levels measured by radioimmunoassay drawn approximately 12 h after their last dose. Patients treated with cyclosporine and prednisone alone had their cyclosporine dosage adjusted to maintain their cyclosporine level between 400 and 900 ng/mL between 1 and 6 months following transplantation. Patients treated with cyclosporine, azathioprine, and prednisone had their cyclosporine level adjusted to be between 100 and 400 ng/mL during this same time period. Cyclosporine levels were significantly higher in verapamil-treated patients and significantly lower in nifedipine-treated patients as compared to controls. The dose of cyclosporine administered was significantly lower in the verapamil-treated patients and higher in the nifedipine-treated patients than controls. Normalizing the whole-blood cyclosporine level for the dose of cyclosporine, and verapamil-treated patients had a significantly greater, and the nifedipine-treated patients a significantly lower value than control patients. These data suggest the verapamil treatment results in significantly higher levels of cyclosporine whereas nifedipine therapy may actually result in lower cyclosporine levels for a given dose of cyclosporine than seen in patients not exposed to these drugs.

Adult↗
PubMed2000

The beneficial effects of calcium channel blockers on long-term kidney transplant survival are independent of blood-pressure reduction.

There is a growing body of evidence suggesting that calcium channel blockers (CCB) exert beneficial effects on kidney transplant survival. However, it is not completely understood if these agents act independently of blood-pressure reduction. In the present study, the 5-yr follow-up of 45 kidney transplant recipients receiving CCB during the 60-month follow-up period was compared to that of recipients with lower blood pressure and an antihypertensive treatment without CCB. During the whole follow-up, systolic (127.4 +/- 2.5 vs. 139.4 +/- 2.1 mmHg, p < 0.05) as well as diastolic blood pressure (78.8 +/- 1.1 vs. 84.8 +/- 1.8 mmHg, p < 0.05) was higher in the group receiving CCB. Moreover, in CCB-treated recipients, a significant (p < 0.05) higher increase in proteinuria was detected (from 759 +/- 120 to 1690 +/- 359 mg/24 h vs. 180 +/- 45 to 340 +/- 45 mg/24 h). Despite higher blood pressure and higher proteinuria, the increase in serum creatinine in the group of CCB-treated recipients was significantly lower (0.01 mg/dL/month) in comparison to that of the controls (0.02 mg/dL/month, p < 0.05). Moreover, the 5-yr transplant survival was significantly higher in CCB-treated recipients (62.3 vs. 31.8%, p < 0.05). The results of the present study further support the beneficial effects of CCB in kidney transplant recipients, which are independent of blood-pressure reduction.

Antihypertensive Agents↗
PubMed2002

Calcium channel blocker use and mortality among patients with end-stage renal disease.

BACKGROUND: Patients on dialysis suffer from alarming rates of cardiovascular disease. While calcium channel blockers (CCBs) are prescribed widely to patients with end-stage renal disease (ESRD) for the treatment of hypertension, the long-term outcomes associated with the use of these medications are not known. We sought to determine the association between CCB use and mortality among a cohort of ESRD patients. METHODS: Data were utilized from the United States Renal Data System Dialysis Morbidity and Mortality Wave II, a randomly selected prospective cohort of 4065 ESRD patients who began dialysis in 1996. Clinical data, including medication information, were collected 60 days after the start of dialysis. Subsequent survival status and cause of death were ascertained. The Cox proportional hazards model was used to estimate the relative risk of death associated with CCB use. RESULTS: Data from 3716 patients (91.4%) were available for analysis. Fifty-one percent of the study patients were prescribed a CCB. The use of a CCB was associated with a 21% lower risk of total mortality (RR 0.79, CI 0.69 to 0.90) and a 26% lower risk of cardiovascular specific mortality (RR 0.74, CI 0.60 to 0.91). For patients with pre-existing cardiovascular disease, CCB use was associated with a 23% (RR 0.77, CI 0.65 to 0.91) and 32% (RR 0.68, CI 0.53 to 0.87) lower risk of total and cardiovascular mortality, respectively. CONCLUSION: After controlling for known risk factors and potential confounders, CCBs were found to be associated with a lower risk of mortality among ESRD patients.

Adult↗
PubMed1993

The calcium channel blocker amlodipine raises serum dehydroepiandrosterone sulfate and androstenedione, but lowers serum cortisol, in insulin-resistant obese and hypertensive men.

To determine whether the calcium channel blocker amlodipine improves glucose tolerance and alters serum adrenal androgen and glucocorticoid levels in insulin-resistant men, 24 obese and hypertensive men were enrolled into a single blind, placebo-controlled study. An amlodipine group (n = 12) and a placebo group (n = 12) were studied before and after treatment with either amlodipine (5 mg) or placebo capsule twice daily for 7 days by determining serum insulin, glucose, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and cortisol in the fasting state and during an oral glucose tolerance test. Amlodipine treatment 1) lowered fasting serum insulin (from 273 +/- 19 to 200 +/- 17 pmol/L; P < 0.0005) and glucose (from 5.4 +/- 0.1 to 5.1 +/- 0.1 mmol/L; P < 0.02), 2) reduced the area under the curve for glucose (from 1342 +/- 25 to 1198 +/- 23 mmol/L.min; P = 0.0001) and the area under the curve for insulin (from 155.5 +/- 7.8 to 103.9 +/- 4.3 nmol/L.min; P = 0.0001) during the oral glucose tolerance test, 3) increased fasting serum DHEA-S (from 5.19 +/- 0.37 to 7.95 +/- 0.58 mumol/L; P = 0.0001) and androstenedione (from 5.65 +/- 0.65 to 6.83 +/- 0.53 nmol/L; P < 0.01), and 4) decreased fasting serum cortisol (from 538 +/- 35 to 494 +/- 26 nmol/L; P < 0.05). Fasting serum androstenedione declined slightly in the placebo group (from 5.96 +/- 0.60 to 5.74 +/- 0.57 nmol/L; P < 0.005), but no change occurred in glucose tolerance, fasting serum DHEA-S, or cortisol. We conclude that amlodipine treatment improves glucose tolerance, reduces fasting and glucose-stimulated serum insulin levels, increases serum DHEA-S and androstenedione levels, and decreases circulating cortisol.

Adult↗
PubMed1995

Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin MVIIA.

The three-dimensional solution structure of omega-conotoxin MVIIA, a 25-mer peptide antagonist of N-type calcium channels, was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 13 converged structures of omega-conotoxin MVIIA were obtained on the basis of 273 experimental constraints, including 232 distance constraints obtained from nuclear Overhauser effect (NOE) connectivities, 22 torsion angle (phi, chi 1) constraints, and 19 constraints associated with hydrogen bonds and disulfide bonds. The atomic root mean square difference about the averaged coordinate positions is 0.47 +/- 0.08 A for the backbone atoms (N, C alpha, C) and 1.27 +/- 0.14 A for all heavy atoms of the entire peptide. The molecular structure of omega-conotoxin MVIIA is composed of a short triple-stranded antiparallel beta-sheet. The overall beta-sheet topology is +2x, -1, which is the same as that reported for omega-conotoxin GVIA, another N-type calcium channel blocker. The orientation of beta-stranded structure is similar to each other, suggesting that the conserved disulfide bond combination is essential for the molecular folding. We have recently determined by using alanine substitution analyses that Tyr 13 is essential for the activity of both toxins. On the basis of functional and structural analysis, it is shown that both omega-conotoxin MVIIA and GVIA retain a similar conformation to locate Tyr 13 in the appropriate position to allow binding to N-type calcium channels. These results provide a molecular basis for understanding the mechanism of calcium channel modulation through the toxin-channel interaction and insight into the discrimination of different subtypes of calcium channels.

Amino Acid Sequence↗
PubMed1997

Calcium channel blockers in cerebral ischaemia.

Ischaemic stroke usually results from the obstruction of a major cerebral vessel which leads to a decrease in cerebral blood flow, and a subsequent reduction in ATP. This energy loss leads to impaired cellular function due to reduced ATP-dependent processes and a disruption in ionic gradients across membranes. Under these conditions, there is a significant efflux of K+ from cells producing cellular depolarisation and the movement of extracellular calcium into cells through calcium channels. It is this increase in intracellular calcium that leads to the 'calcium toxicity' that has been associated with cerebral ischaemia. Increased intracellular calcium triggers the break-down of phospholipids, proteins and nucleic acids. This is activated by calcium-dependent phospholipases, proteases and endonucleases, and contributes to structural and functional damage of the cell membrane, which compromises cell function and facilitates cell death. Calcium channel blockers are used routinely to treat cardiovascular disease and hypertension. Although some experimental studies over the last decade suggest efficacy/benefit in the treatment of experimental ischaemic stroke, clinical data do not bear this out. This article discusses the role of voltage-operated calcium channel blockers in stroke, and reviews much of the available experimental and clinical data.

Journal Article↗
PubMed2000

Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).

BACKGROUND: The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension. METHODS: We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55-80 years with hypertension (blood pressure > or = 150/95 mm Hg, or > or = 160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 mg [corrected] plus amiloride 2.5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25-50 mg or enalapril 5-10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat. FINDINGS: Primary outcomes occurred in 200 (6.3%) patients in the nifedipine group and in 182 (5.8%) in the co-amilozide group (18.2 vs 16.5 events per 1000 patient-years; relative risk 1.10 [95% CI 0.91-1.34], p=0.35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p<0.0001), but serious adverse events were more frequent in the co-amilozide group (880 vs 796, p=0.02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0.81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0.33% [-0.7 to 1.4]). INTERPRETATION: Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy.

Aged↗
PubMed1983

The effects of lesions in the rat hippocampus suggest the association of calcium channel blocker binding sites with specific neuronal population.

The binding of calcium antagonists in the rat hippocampal formation was studied using autoradiography. Hippocampal slices were labeled in vitro with [3H]PN 200-110. High densities of binding sites for calcium antagonists were found in the molecular layer of the dentate gyrus and in the CA3 subfield of the hippocampus. After ablation of the granule cells by local injection of colchicine a marked decrease in the number of [3H]PN 200-110 binding sites density was observed on these areas, while binding to other parts of the hippocampal formation and brain was spared. These results strongly suggest the localization of high densities of calcium channels to the granule cells of the dentate gyrus.

Animals↗
PubMed2003

An L-type calcium channel blocker, nimodipine influences trauma induced spinal cord conduction and axonal injury in the rat.

The influence of the potent L-type Ca[2+] channel antagonist Nimodipine on spinal cord evoked potentials (SCEP) and axonal injury following trauma to the spinal cord was examined in a rat model. Spinal cord injury (SCI) was produced by an incision into the right dorsal horn of the T10-11 segments under urethane anaesthesia (1.5 g/kg, i.p.). SCEPs were recorded by epidural electrodes placed over the T9 (rostral) and T12 (caudal) segments after stimulation of the right tibial and sural nerves. SCI induced a pronounced decrease of the SCEP negative amplitude in the rostral (T9) recordings immediately after trauma. Axonal injury seen as degradation of myelin basic protein (MBP) immunostaining and myelin vesiculation at the ultrastructural level was most pronounced at 5 h. Continuous administration of Nimodipine (2 microg/kg/min, i.v.) from 30 min prior to injury until sacrifice markedly attenuated the changes in SCEP amplitude and latency. Axonal damage, loss of MBP, and myelin vesiculation were much less evident in the nimodipine treated traumatised rats. These observations suggest that Ca[2+] channels play an important role in the trauma induced alterations in SCEP and axonal injury, and indicate a therapeutic value of Ca[2+] blockers in SCI.

Animals↗
PubMed1986

Calcium channel blockers and motility disorders of the esophagus.

In animal experiments, esophageal smooth muscle, including the lower esophageal sphincter (LES) has been shown to be dependent on extracellular calcium both for tone and agonist induced contractions. Calcium channel blockers (CCB) suppress contractile activity, and block both resting and stimulated calcium influx. In normal man as well as in patients with hypercontractility disorders of the esophagus, such as achalasia and diffuse esophageal spasm, CCBs have been shown to reduce LES pressure and esophageal contractions, and also to cause symptomatic improvement. Controlled clinical trials on their effectiveness are lacking, but the therapeutic principle seems promising.

Animals↗
PubMedDate not supplied

[The effect of calcium channel blockers on the effects of ethanol in the immobilization of mice].

A model of the depressive behavior was used to study the action of the calcium channel blockers combined with ethanol. The ethanol dose used (2 g/kg, per os) caused behavioral changes by the depressive type. From two drugs fendilin (20 mg/kg) and nifedipine (10 mg/kg) showing the antidepressive activity in the test the ethanol effect was counteracted only by the nifedipine. Other drugs, such as cinnarizine (50 mg/kg), verapamil (25 mg/kg), flunarizine, and sabeluzol (10 mg/kg), did not produce a significant effect.

Animals↗
PubMed2004

Calcium channel blockers in the treatment of disease.

Over the last 20 years the combination of patch clamp and molecular biology techniques have resulted in an explosion in our knowledge of the different calcium channel types and their roles in physiology. A crucial component to this advance has been the discovery of specific blockers for different calcium channel types. These blockers have not only permitted researchers to assign specific functions to different channel types, but their specificity allowed them to be used to treat diseases that resulted from enhanced calcium channel function. In some cases, the enhanced calcium channel function is secondary to other problems leading to increased cellular excitability. The specificity of calcium channel blockers, however, has provided a means to treat symptoms of the pathophysiology until more effective treatments become available to address the underlying problems. The goal of this review is to introduce the various types of calcium channels, their primary physiologic roles, drugs that block these channels, and diseases that are currently being treated with these drugs.

Animals↗
PubMed1990

Endothelial cell thromboxane production and its inhibition by a calcium-channel blocker.

Vascular endothelium has been established as a major source of prostacyclin production. Whether endothelial cells are also capable of synthesizing thromboxane A2 remains controversial. Suppression of such endothelial thromboxane synthesis would be beneficial for short-term patency of vascular grafts. This study examined the production of thromboxane A2 by endothelial cells and its modulation by the calcium-channel blocker nifedipine in vitro. The results indicate that (1) endothelial cells spontaneously secrete thromboxane A2, (2) this production can be enhanced severalfold in the presence of arachidonic acid, and (3) the calcium-channel blocker nifedipine significantly inhibits thromboxane production without demonstrable toxicity to the endothelial cells.

Animals↗
PubMed2002

Enhancement of glomerular platelet-derived growth factor beta-receptor tyrosine phosphorylation in hypertensive rats and its inhibition by calcium channel blocker.

The molecular mechanism of glomerular injury in hypertension remains to be clarified. In this study, to examine the possible role of platelet-derived growth factor (PDGF) receptors in hypertensive glomerular injury, we specifically measured glomerular PDGF receptor tyrosine phosphorylation in various models of hypertensive rats using immunoprecipitation and Western blot analysis. A high-salt diet significantly enhanced glomerular PDGF beta-receptor tyrosine phosphorylation of Dahl-salt sensitive rats (DS-rats) without an increase in its protein levels, and this enhancement was associated with an elevation of blood pressure and glomerular injury. Stroke-prone spontaneously hypertensive rats (SHRSP) at hypertensive phase also had higher glomerular PDGF beta-receptor tyrosine phosphorylation levels than control Wistar-Kyoto rats (WKY), while SHR did not. Thus, DS-rats and SHRSP, which are well known to represent severe glomerular injury, had the enhanced PDGF beta-receptor tyrosine phosphorylation, while SHR, a hypertensive model without significant glomerular injury had no increased tyrosine phosphorylation. Treatment of DS-rats or SHRSP with benidipine, a calcium channel blocker, significantly lessened the increase in glomerular PDGF beta-receptor tyrosine phosphorylation, reduction of urinary protein and albumin excretion. These results suggest that the enhanced activation of glomerular PDGF beta-receptors may be responsible for the development of hypertensive glomerular injury and that the suppression of this receptor activation by a calcium channel blocker may contribute to its renal protective effects.

Albuminuria↗
PubMed1999

Calcium channel blockers activate the interleukin-6 gene via the transcription factors NF-IL6 and NF-kappaB in primary human vascular smooth muscle cells.

BACKGROUND: Calcium channel blockers (CCB) of all subclasses: the dihydropyridines, benzothiazepines, and phenylalkylamines, at nanomolar concentrations, have been shown to up-regulate interleukin-6 (IL-6) mRNA. We investigated the underlying molecular mechanism responsible for IL-6 induction in response to the CCB amlodipine, diltiazem, and verapamil in primary human vascular smooth muscle cells (VSMC). METHODS AND RESULTS: All 3 CCB directly activated transcription of the human IL-6 gene in primary human VSMC in a time- and dose-dependent manner, as demonstrated by luciferase reporter gene assays using a 651-bp fragment of the human IL-6 gene promoter. Deletion analysis of the IL-6 promoter revealed that CCB inducible promoter activity was localized to a 160-bp fragment directly upstream of the transcriptional start site of the IL-6 gene. Known transcription factor consensus sequences within this fragment include a NF-IL6 and a NF-kappaB site. Site-directed mutagenesis suggested that both transcription factors had positive regulatory activity and cooperatively transmitted induction of the IL-6 gene by CCB. The data are confirmed by electrophoretic mobility shift analyses using nuclear extracts from CCB-stimulated and control primary VSMC. CCB of all subclasses increased DNA binding of NF-IL6 and NF-kappaB as early as 30 minutes after stimulation with the drugs. This effect was independent of intracellular calcium concentrations because calcium-free medium did not increase NF-IL6 or NF-kappaB activity. CONCLUSIONS: The results demonstrate that CCB of all 3 subclasses are capable of activating NF-IL6 and NF-kappaB. CCB may thus directly regulate cellular functions by affecting the activity of transcription factors independent of changes of intracellular calcium concentrations, an observation that is of interest considering the biological effects induced by CCB.

CCAAT-Enhancer-Binding Proteins↗