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At least 577 records · Page 32Linked to original sources
PubMed1992

Different effects of L-, N- and T-type calcium channel blockers on striatal dopamine release measured by microdialysis in freely moving rats.

Using a microdialysis method, we have investigated effects of the voltage-dependent calcium channel blockers, verapamil, nicardipine, omega-conotoxin and flunarizine on the dopamine release and metabolism in the striatum of freely moving rat. Perfusion of verapamil (1-300 microM) and nicardipine (1-100 microM), an L-type calcium channel blocker, into the striatum through the dialysis membrane showed a dose-dependent decrease of dopamine release in the dialysate and slight increase of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Treatment of omega-conotoxin (0.1, 1 microM), an N-type channel blocker, decreased about 50% basal dopamine release and slightly decreased DOPAC and HVA levels. Treatment with flunarizine (10 microM), an T-type channel blocker, did not affect the dopamine release and metabolism. From these data, it appears that treatments of the L- and N-type voltage-dependent calcium channel blockers in rat striatum suppress basal dopamine release, but T-type blocker does not suppress it, suggesting that L-, N- and T-type calcium channels regulate in vivo dopamine release in a different mechanism.

Animals↗
PubMed1986

Acquired vs innate multidrug resistance and the effect of calcium channel blockers.

Innate drug resistance as well as acquired multidrug resistance are directly related to ineffectiveness and failure of the cancer chemotherapy. The mechanisms of such resistance, especially those of innate resistance, have not been fully elucidated. We have established vincristine (VCR)- and Adriamycin (ADM)-resistant sublines of human myelogenous leukemia K562 by continuous drug exposure. These resistant sublines contained double minute chromosomes and express a glycoprotein with a 180,000 dalton M.W. Analysis of VCR and ADM sensitivities of several isolated clones from these resistant sublines revealed a tight relationship between these two resistant mechanisms. However, ADM resistant sublines are always highly resistant to VCR, but VCR resistant sublines are not necessarily highly resistant to ADM, suggesting the presence different mechanisms of ADM and VCR resistance. Calcium channel blockers inhibit the drug efflux in these resistant tumor cells, thereby overcoming of drug resistance. Greater potentition was observed with antitumor agents to which VCR- and ADM-resistant cells were highly cross-resistant. Calcium channel blockers always show higher potentiation with VCR than ADM, and the clones with greater resistance to VCR generally accumulated less VCR and generally possessed a higher rate of VCR efflux. These results might indicate that a major mechanism of VCR resistance could be a defficiency in drug transport and this mechanism can be reversed by calcium channel blockers, while the ADM resistance mechanisms are partly related to drug efflux and only this mechanism of the ADM resistance can be modulated by calcium channel blockers. Calcium channel blockers also potentiate the drug effects, especially that of vinca alkaloids, in innately resistant tumors cells, indicating that such innate resistant cells also share a similar resistance mechanism to that observed in acquired drug resistance. From these results, the mechanisms of acquired and innate drug resistance are discussed.

Animals↗
PubMedDate not supplied

Effects of calcium channel blockers on impairment of brain function in senescence-accelerated mice.

The effects of the L-type calcium channel blockers, nicardipine, nimodipine, nilvadipine and amlodipine, on brain dysfunction were examined in senescence-accelerated-prone mice. A disturbed brain function in passive avoidance response, forced swimming, rota-rod and traction tests was observed in senescence-accelerated-prone mice compared to senescence-accelerated-resistant mice. A single oral administration of the four calcium channel blockers tested had little effect on the brain dysfunction in senescence-accelerated-prone mice. In contrast, the daily oral administration of nicardipine (1 and 3 mg/kg), nimodipine (3 mg/kg) and nilvadipine (3 mg/kg), once a day for three weeks, prolonged the shortened latency of step-through in the passive avoidance response and falling time in rota-rod tests. Brain dysfunction in forced swimming and traction tests was not influenced by repeated administration of these blockers. Repeated administration of amlodipine for three weeks in senescence-accelerated-prone mice showed little pharmacological actions in all four tests. Thus, we found that repeated administration of nicardipine, nimodipine and nilvadipine ameliorated the brain dysfunction in these mice. Furthermore, the present study suggests that senescence-accelerated-prone mice can be used as an appropriate model for evaluating the pharmacological effects of calcium channel blockers on brain dysfunction.

Amlodipine↗
PubMed1996

Interactions of calcium channel blockers with non-depolarising muscle relaxants in vitro.

The effects of two calcium channel blockers (verapamil and nicardipine) on indirectly elicited muscle twitch and possible interactions between these drugs and non-depolarising muscle relaxants (vecuronium, atracurium, pancuronium) were investigated using isolated rat phrenic nerve-hemidiaphragm preparations. Both verapamil 10(-5) M and nicardipine 10(-6) M caused significant depression of twitch amplitude. Verapamil significantly increased vecuronium- and atracurium-induced neuromuscular block, but not that produced by pancuronium. Nicardipine potentiated atracurium-induced neuromuscular block but had no effect on pancuronium- and vecuronium-induced twitch depression. Neostigmine 10(-6) M did not produce any significant changes in the maximal recovery of twitch depression induced with calcium channel blockers and muscle relaxants combinations; also, neostigmine had no effect on maximal recovery time of twitch depression.

Animals↗
PubMed1993

Effects of adenosine in combination with calcium channel blockers in patients with primary pulmonary hypertension.

OBJECTIVES: The purpose of this study was to evaluate the effects of vasodilator combination therapy in patients with primary pulmonary hypertension. BACKGROUND: Calcium channel blockers and adenosine have each been shown to be effective in reducing pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. However, the effects of combining these vasodilators have not been studied. METHODS: To test the combination, 12 patients were placed on oral nifedipine and 3 on diltiazem therapy, using a dose titrated to maximal effect (mean nifedipine dose 103 +/- 24 mg, mean diltiazem dose 300 +/- 49 mg). Patients were then given maintenance doses of the calcium channel blocker at half the cumulative loading dose at 6-h intervals. One hour after the maintenance dose of calcium blocker, all patients received an infusion of adenosine, starting with 50 micrograms/kg per min and increasing by 50 micrograms/kg per min at 2-min intervals to a maximally tolerated dose (180 +/- 63 micrograms/kg per min). RESULTS: Ten patients responded to calcium channel blockers (defined as a > or = 20% decrease in pulmonary vascular resistance), with a 16% decrease in mean pulmonary artery pressure (p = 0.057), a 39% decrease in pulmonary vascular resistance (p = 0.002) and a 24% increase in stroke volume (p = 0.007). Five patients were nonresponders, with no significant changes in pulmonary artery pressure, pulmonary vascular resistance, cardiac index or stroke volume. In the calcium channel blocker responders, the combination of adenosine and calcium blocker reduced pulmonary vascular resistance by 49%, increased stroke volume by 33% and decreased mean pulmonary artery pressure by 14% compared with drug-free baseline values. In nonresponders, combination therapy resulted in nonsignificant changes in pulmonary artery pressure and pulmonary vascular resistance. CONCLUSIONS: Adenosine has the ability to further decrease pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension who respond to calcium channel blockers. Those who fail to respond to these agents have little added effect from adenosine.

Adenosine↗
PubMed2004

Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension.

BACKGROUND: The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends initial combination therapy for patients whose blood pressure (BP) is >20/10 mm Hg above goal. This study evaluated the efficacy and safety of initial combination therapy versus that of monotherapy in patients with stage 2 hypertension, who by definition meet the JNC 7 recommendation for initial combination antihypertensive therapy. METHODS: This multicenter, double-blind, 12-week study randomized 364 patients with stage 2 hypertension to fixed-dose combination therapy with amlodipine besylate/benazepril HCl (5/20 mg/d titrated to 10/20 mg/d) or amlodipine besylate monotherapy (5 mg/d titrated to 10 mg/d). RESULTS: Significantly more patients randomized to combination therapy (74.2%) compared with those randomized to monotherapy (53.9%; P <.0001) achieved the primary end point (reductions in systolic BP > or =25 mm Hg, if baseline systolic BP was <180 mm Hg, or > or =32 mm Hg, if baseline systolic BP was > or =180 mm Hg). Significantly more patients randomized to combination therapy compared with monotherapy attained BP goals of <140/90 mm Hg (61.0% v 43.3%; P =.0007) and < or =130/85 mm Hg (35.7% v 19.1%; P =.0004). Among patients with baseline systolic BP > or =180 mm Hg, combination therapy resulted in significantly greater reductions in systolic BP compared with monotherapy (-42.3 v -30.4 mm Hg; P =.001). More than 90% of patients in each group were titrated to the higher dose. Both treatments were well tolerated. CONCLUSIONS: Combination therapy was well tolerated and resulted in significantly greater BP reductions and attainment of BP goals compared with monotherapy in patients with stage 2 hypertension. This evidence supports the recommendation of combination therapy as first-line treatment in stage 2 hypertension.

Adult↗
PubMed1995

Nitrendipine treatment in women with polycystic ovarian syndrome: evidence for a lack of effects of calcium channel blockers on insulin, androgens, and sex hormone-binding globulin.

It has been shown that in vitro calcium channel blockers may regulate insulin secretion, and in vivo studies have demonstrated that they can reduce the degree of hyperinsulinemia and ameliorate the insulin-resistant state in subjects (particularly men) with obesity and hypertension. It is also commonly accepted that hyperinsulinemia may be an important factor responsible for the development of hyperandrogenism in obese women with polycystic ovarian syndrome (PCOS). We, therefore, investigated whether the administration of nitrendipine, a widely used calcium channel blocker, may improve both insulin levels and hyperandrogenism in a group of seven insulin-resistant hyperinsulinemic women with obesity and PCOS. They were treated for 7-8 days with oral nitrendipine (10 mg, twice daily) or placebo using a double blind, cross-over design. Before and after treatment, blood samples were obtained for androgen and sex hormone-binding globulin determinations, and an oral glucose tolerance test was performed, measuring glucose and insulin. Both nitrendipine and placebo failed to decrease basal and stimulated insulin levels. Moreover, no significant variations in testosterone, dehydroepiandrosterone sulfate, or sex hormone-binding globulin concentrations were observed after either treatment. Therefore, these data fail to support previous suggestions that calcium channel blockers may play a role in the treatment of hyperandrogenism and hyperinsulinemia in obese women with PCOS.

Adult↗
PubMed1992

Interaction between stannous chloride and calcium channel blockers in frog neuromuscular transmission.

We have investigated the interactions between stannous chloride (SnCl2) and calcium (Ca) channel blockers on endplate potentials (e.p.p.) and on miniature endplate potentials (m.e.p.p.) to determine which type of channel (among L-, N-, and T-type) participates in the SnCl2-induced increase in Ca entry into motor nerve terminals. The e.p.p. amplitude augmented by 30 microM SnCl2 was decreased by cumulative addition of 10 microM CdCl2 or 0.5 microM omega-conotoxin but not by 10 microM NiCl2 or 5 microM nicardipine. The SnCl2 (30 microM)-induced rise in m.e.p.p. frequency in high-potassium medium was reduced by 0.5 microM omega-conotoxin but not by 5 microM nicardipine. These results suggest that activation of the N-type Ca channel is involved in the SnCl2-induced increase in Ca entry into the nerve terminals.

Animals↗
PubMed2001

Comparison of L-type and mixed L- and T-type calcium channel blockers on kidney injury caused by deoxycorticosterone-salt hypertension in rats.

The efficiency of calcium channel blockers (CCBs) in the treatment of chronic renal disease (CRD) is controversial. In this study, we investigated whether combined T- and L-type CCBs, using mibefradil (30 mg/kg/d), provided superior protection versus traditional L-type voltage-gated CCBs, using amlodipine (10 mg/kg/d), in the deoxycorticosterone acetate (DOCA)-salt model of high glomerular blood pressure (P(GC)) and rapidly developing kidney damage. After 4 to 5 weeks of DOCA-salt, amlodipine did not reduce proteinuria (protein, 341 +/- 90 versus 482 +/- 54 mg/24 h; P = not significant) or degree of glomerular damage (20% +/- 4% versus 28% +/- 6% damaged glomeruli; P = not significant) compared with untreated rats. Conversely, mibefradil reduced proteinuria and glomerular damage versus untreated DOCA-salt rats (protein, 244 +/- 75 mg/24 h; P < 0.02; damaged glomeruli, 11% +/- 3%; P < 0.05). Both CCBs had similar antihypertensive actions, returning blood pressure to the untreated sham value. Of note, P(GC) also was reduced by a similar extent (and to the sham value) with both mibefradil (58 +/- 2 mm Hg; P < 0.001) and amlodipine (61 +/- 2 mm Hg; P < 0.005) versus untreated DOCA-salt rats (70 +/- 1 mm Hg). This study shows that combined T- and L-type CCBs provide superior protection against CRD in the DOCA-salt model compared with L-type CCBs alone. However, this protection was not hemodynamic because similar systemic and glomerular antihypertensive responses occurred with both mibefradil and amlodipine. Although mibefradil was withdrawn from the market because of adverse drug interactions not associated with CCBs, other mixed channel blockers may provide an alternative or adjunctive therapy to angiotensin-converting enzyme inhibition in CRD.

Amlodipine↗
PubMed1985

Effect of slow calcium channel blockers on the electromechanical activity of frog myocardium in the presence of epinephrine.

The calcium channels blockers fenihidine (3.5 X 10(-5) mol/l), ryosidine (10(-5) mol/l), D-600 (10(-5) mol/l) and Mn ions (2 X 10(-3) mol/l or 5 X 10(-3) mol/l) block contraction force and shorten the duration of action potentials of the frog myocardial ventricle strand under normal conditions. When contraction force and the duration of action potentials were restored by epinephrine (10(-5) mol/l), these agents were unable to suppress these parameters. The increase in both contraction force and the duration of action potentials induced by epinephrine were blocked by acetylcholine. Recording by voltage clamp of inward calcium current (Ica) of the frog atrial trabeculae it was found that fenihidine decreases Ica activated by epinephrine to a smaller extent than observed at normal conditions. Let as assume that epinephrine increases Ica by means of increasing number of calcium channels so these data support the proposed existence of as many as two calcium channel fractions in frog myocardium, which differ in the sensitivity to calcium channels blockers.

Action Potentials↗
PubMed1999

Prevalence of gingival overgrowth induced by calcium channel blockers: a community-based study.

BACKGROUND: The prevalence of gingival overgrowth induced by chronic medication with calcium channel blockers is uncertain. Although there have been several studies examining this question, the results are conflicting, with previous estimates ranging from 20% to 83%. There have been only 2 studies examining the prevalence of overgrowth induced by diltiazem and amlodipine, with estimates of 74% and 3.3%, respectively. METHODS: The current study aimed to address the problems associated with these studies by examining a sample of patients taking one of 3 calcium channel blockers, who were drawn from a community-based population in northeastern England. Nine hundred eleven (911) subjects were recruited from general medical practices in the area. Of these, 442 were taking nifedipine, 181 amlodipine, and 186 diltiazem. In addition, 102 control subjects were examined. Drug and demographic data for each subject were recorded. The periodontal condition of all subjects was assessed including plaque index, papillary bleeding index, and a photograph of the anterior gingivae for subsequent analysis of overgrowth severity. RESULTS: More than six percent (6.3%) of subjects taking nifedipine were seen to have significant overgrowth. This overgrowth was statistically greater than the amount of overgrowth seen in either of the other 2 drug groups or the control population. The prevalence of gingival overgrowth induced by amlodipine or diltiazem was not statistically significant when compared to the control group. The severity of overgrowth within the nifedipine group was found to be related to the amount of gingival inflammation and also to the gender of the subject, with males being 3 times as likely to develop overgrowth than females. CONCLUSIONS: The prevalence of clinically significant overgrowth related to chronic medication with calcium channel blockers is low, i.e., 6.3% for nifedipine. Males are 3 times as likely as females to develop clinically significant overgrowth. The presence of gingival inflammation is an important cofactor for the expression of this effect.

Adult↗
PubMed2003

Calcium channel blockers for inhibiting preterm labour; a systematic review of the evidence and a protocol for administration of nifedipine.

OBJECTIVE: To assess the effects on maternal, fetal and neonatal outcomes of nifedipine (and other calcium channel blockers) administered as a tocolytic agent to women in preterm labour. METHODS: Standard methods of the Cochrane Collaboration and its Pregnancy and Childbirth Review Group were used. All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in preterm labour between 20 and 36 weeks' gestation, were considered. MAIN RESULTS: The systematic review includes 12 randomised controlled trials with a total of 1029 participating women. No trials were identified in which calcium channel blockers were compared with a placebo or no alternative tocolytic treatment. Calcium channel blockers appear to be more effective than betamimetic agents in prolonging pregnancy for 7 days or longer, are much less likely to cause maternal side-effects and are associated with reduced neonatal morbidity. CONCLUSION: Calcium channel blockers (especially nifedipine) can be considered safer and more effective tocolytic agents than betamimetics.

Calcium Channel Blockers↗
PubMed1988

Interaction between propranolol and calcium channel blockers in cardiac and vascular smooth muscle.

The ability of the beta-receptor antagonist propranolol to influence the response of isolated cardiac and vascular smooth muscle to several classes of calcium channel blockers was examined. For comparison, the interactions between propranolol and other classes of negative inotropic and vasorelaxant agents was also evaluated. The results of these studies demonstrate that propranolol pre-treatment significantly enhances the in vitro response to the dihydropyridine calcium channel blocker nifedipine, but not the thiazapine calcium channel blocker diltiazem. This enhancement was unrelated to the negative inotropic or vasorelaxant properties of these agents. In addition, propranolol pre-treatment of rat cortical membranes also enhanced the affinity of nifedipine for the 3H-nitrendipine binding site, but did not alter the effect of diltiazem on 3H-nitrendipine binding. These observations suggest that a direct interaction may exist between beta-receptor antagonists and dihydropyrine-type calcium channel blockers. This interaction may be an important factor in selecting drug therapy for conditions such as hypertension and angina.

Animals↗
PubMed1993

Calcium channel blockers in the management of low-tension and open-angle glaucoma.

Fifty-six patients with either open-angle or low-tension glaucoma who were concurrently taking calcium channel blockers were compared to similar groups not taking such medications for a mean follow-up period of 3.4 years. Serial stereoscopic optic nerve photographs and visual fields of all patients were evaluated for evidence of glaucomatous progression. In patients with low-tension glaucoma, there was a significant difference in the progression of visual field defects, with only two of 18 eyes (11%) of patients taking calcium channel blockers, compared to ten of 18 eyes (56%) of controls showing new visual field defects. Similarly, low-tension glaucoma patients taking calcium channel blocker therapy demonstrated no evidence of progressive optic nerve damage, compared to eight of 18 control eyes (44%). In contrast, patients with open-angle glaucoma taking calcium channel blockers showed no marked difference in the progression of glaucoma, compared to controls. These findings suggest that calcium channel blockers may be useful in the management of low-tension glaucoma.

Administration, Oral↗
PubMed1994

Benefits and demerits of antihypertensive therapy by high-dose calcium channel blocker in severely hypertensive rats.

This study examined the protective effects of a calcium channel blocker, nisoldipine (NSL), against organ damage secondary to severe hypertension. Severe hypertension was induced in male 7-week-old spontaneously hypertensive rats (n = 21) by heminephrectomy and substitution of 1% NaCl solution for drinking water. They were fed a chow containing 0%, 0.03% (low dose) or 0.1% (high dose) NSL for 12 weeks. The systolic blood pressures after 12 weeks were 228 mmHg in the control group, 201 in the low dose NSL group and 188 in the high dose NSL group. Body weight gain was blunted in the high dose NSL group (at 12 weeks: control 289g; low dose NSL 286; high dose NSL 263, p < 0.04). Although a further reduction in cardiac weight was seen in the high dose NSL rate (low NSL -5.2%, p < 0.05; high NSL -9%, p < 0.01), reductions in aortic thickness did not differ between the 2 doses (low NSL -18%, p < 0.001; high NSL -17%, p < 0.001). Moreover, dose-dependent effects of NSL treatment were absent for such endpoints as plasma creatinine (low NSL -15%, p < 0.04; high NSL -17%, p < 0.05), glomerular filtration rate (low NSL +21%, p < 0.05; high NSL +20%, p < 0.03) and urinary protein excretion (low NSL -22%, p < 0.05; high NSL -29%, p < 0.02). Thus, a high dose calcium channel blocker hampered growth and did not further improve vascular wall thickening or renal injury in severely hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Calcium channel blockers inhibit amiloride-stimulated short-circuit current in frog tadpole skin.

The larval frog skin has a very high electrical resistance and a corresponding low rate of transepithelial ion transport. Amiloride, a blocker of sodium transport in adult skin, transiently stimulates rather than inhibits short-circuit current (Isc) across larval skin. The time course and concentration response to amiloride and the effects of calcium channel blockers on Isc were studied with larval frog skin mounted in modified Ussing chambers. The amiloride (1 mM) transient was markedly blunted if the skin was previously exposed to low amiloride (0.01-0.1 mM) concentrations. The calcium channel blockers verapamil, nitrendipine, diltiazem, W-7, and lanthanum all blocked the amiloride transient. Diltiazem itself caused a rapid transient in Isc, indicating that it may be a partial agonist. These data suggest that the amiloride-stimulated cation channels rapidly desensitize in a manner similar to the acetylcholine receptor. The decline in Isc after amiloride stimulation could be caused by amiloride block of the open channel. Blockade of amiloride stimulation by well-known calcium channel blockers suggests that these larval cation channels may have some characteristics in common with calcium channels.

Amiloride↗
PubMed2002

L-Cysteine based N-type calcium channel blockers: structure-activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models.

This study was performed to determine the structure-activity relationships (SAR) of L-cysteine based N-type calcium channel blockers. Basic nitrogen was introduced into the C-terminal lipophilic moiety of L-cysteine with a view toward improvement of its physicochemical properties. L-Cysteine derivative 9 was found to be a potent and selective N-type calcium channel blocker with IC(50) of 0.33 microM in calcium influx assay using IMR-32 cells and was 15-fold selective for N-type calcium channels over L-type channels. Compound 9 showed improved oral analgesic efficacy in the rat formalin induced pain model and the rat chronic constriction injury (CCI) model, which is one of the most reliable models of chronic neuropathic pain, without any significant effect on blood pressure or neurological behavior.

Administration, Oral↗