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PubMed1989

Improvement in post-traumatic spinal cord blood flow with a combination of a calcium channel blocker and a vasopressor.

We have recently shown that nimodipine, a calcium channel blocker, can increase spinal cord blood flow (SCBF) in normal rats and can improve SCBF after spinal cord trauma if the mean systemic arterial pressure (mSAP) is restored to normal levels by the vasopressor, adrenalin. The present study is a further analysis of the improvement in post-traumatic SCBF (measured with the hydrogen clearance technique) with the combination of adrenalin and nimodipine. In addition, image analysis was used to study the potential risk of this combination for exacerbating intramedullary hemorrhage in the injured spinal cord. SCBF, mSAP, and other physiologic parameters were measured preinjury, postinjury, and post-treatment. A 53.0-gram clip compression injury at the T1 spinal segment was delivered for 1 minute to three treatment groups (saline, adrenalin, and adrenalin plus nimodipine) comprised of five rats each. Injury caused a marked decline in SCBF and mSAP. Treatment with adrenalin alone or combined with nimodipine (1.5 micrograms/kg/min IV) improved mSAP to 100-125 mm Hg. However, adrenalin alone failed to improve SCBF, whereas nimodipine plus adrenalin produced a marked improvement of approximately 60% in post-traumatic SCBF. Morphometric analysis showed no significant difference between per cent area or volume of hemorrhage between the three treatment groups, although there was a trend for increased hemorrhage in the adrenalin-alone group perhaps due to the higher post-traumatic mSAP in this group. Further studies are required to find the minimal elevation in mSAP produced by a vasopressor that would still cause an improvement in post-traumatic SCBF by nimodipine, and to determine whether this combination improves function after spinal cord injury.

Animals↗
PubMed2002

Nitric oxide plays an insignificant role in direct vasodilator effects of calcium channel blockers in healthy humans.

Several experimental studies have suggested that the vasodilatory effects of calcium channel blockers (CCBs) are due in part to an endothelium-dependent mechanism. However, it remains unknown whether CCBs directly augment liberation of endothelium-derived dilator substances such as nitric oxide (NO) in the human vasculature. The aim of this study was to examine whether CCBs of several kinds directly increase the bioavailability of NO in forearm resistance vessels. Twenty-four healthy men (mean age 30 +/- 2 years) were randomly assigned to three study groups (n = 8 in each), and each group was assigned one of three first-generation CCBs (nifedipine, nicardipine, diltiazem). Subdepressor doses of CCBs [4, 8, 16, 24, and 36 (diltiazem only) nmol/min; for 2 min in each dose] were infused intra-arterially, and forearm blood flow (FBF) was determined plethysmographically. After control FBF responses to CCBs had been measured, a NO synthase inhibitor (N(G)-monomethyl-L-arginine: L-NMMA) was infused intra-arterially, and the FBF response to CCBs was again determined. Further, as a positive control for NO stimulation, acetylcholine (ACh) was also examined before and after L-NMMA in each group. Systemic blood pressure and heart rate did not change significantly during the study protocol. The FBF responses to these CCBs did not differ before and after NO synthase inhibition by L-NMMA (FBF at maximum doses: nifedipine, 8.0 +/- 0.8 vs. 7.3 +/- 0.7; nicardipine, 7.3 +/- 1.5 vs. 6.5 +/- 1.3; diltiazem, 5.7 +/- 0.7 vs. 4.2 +/- 0.7 ml/min per 100 ml: all not significant), although FBF responses to ACh were significantly reduced by L-NMMA. In conclusion, direct NO liberation does not make a significant contribution to the vasodilation associated with first-generation CCBs in healthy human resistance vessels.

Adult↗
PubMed1992

Calcium channel blockers prevent stress-induced ulcers in rats.

Gastric mucosal damage induced by cold and restraint stress caused increase in gastric lipid peroxidation (LP) and decrease in gastric glutathione levels. Two calcium-channel blockers, verapamil and nicardipine, prevented stress-induced increase in gastric LP, as well as ulcer formation. Both calcium-channel blockers protected against stress-induced ulcers, and inhibition of LP may be among their mechanisms of action.

Animals↗
PubMed1986

Calcium-induced damage of skeletal muscle fibers is markedly reduced by calcium channel blockers.

Vascular perfusion of rat hind limbs with a Ca2+-free physiological solution containing ethylenediaminetetraacetate, when followed by a physiological solution with normal concentration of Ca2+, caused a marked rise of creatine kinase (CK) in the venous effluent. When calcium channel blockers were present in the perfusing solutions, no rise of CK occurred. On histological sampling of perfused muscles, CK rise was roughly correlated with muscle fiber damage of the appropriate muscles. Removal of calcium from the plasmalemma of muscle fibers appears to prevent closure of calcium channels, making the muscle fibers susceptible to a deleterious influx of extracellular calcium. This influx can be prevented by the presence of calcium channel blockers in the perfusates.

Animals↗
PubMed1988

Effect of various calcium channel blockers on three different models of limbic seizures in rats.

Voltage-dependent calcium channel-blockers were studied for their ability to modulate limbic seizures induced in rats by injection of quinolinic acid and kainic acid into the hippocampus or by hippocampal kindling. Flunarizine, at 40 mg/kg (but not 20 mg/kg), reduced the total number of seizures and total time spent in seizures induced by quinolinic acid by 75%; at 60 mg/kg, both parameters were reduced more than 90%, while at 80 mg/kg seizures induced by kainic acid were not affected. Forty and 60 mg/kg of flunarizine protected hippocampal-kindled rats from fully developed convulsions (Stage 5). Nifedipine, at 20 and 40 mg/kg, was ineffective on seizures induced by both quinolinate and kainate. However, at 20 mg/kg, 57% of the kindled animals were protected from Stage 5 and total protection was achieved at 40 mg/kg. Verapamil, at 40 mg/kg, reduced by respectively, 88% and 78%, the total number of seizures and the total time spent in seizures induced by quinolinic acid, but had no effect on seizures induced by kainate and Stage 5 seizures. The results suggest that, while seizures induced by kainic acid were refractory to all voltage-dependent calcium channel blockers, binding sites affected by flunarizine and verapamil in the brain may selectively facilitate ictal activity induced by quinolinic acid. Binding sites for dihydropyridine might contribute to the increased hippocampal excitability in kindled animals. The role of calcium entry through voltage-dependent calcium channels in the occurrence of seizures in these models of limbic epilepsy is discussed.

Amino Acids↗
PubMed1993

Conformationally constrained calcium channel blockers: novel mimics of 1-benzazepin-2-ones.

In order to test a hypothesis that the seven-membered ring of the benzothiazepinone (diltiazem) and benzazepinone calcium channel blockers serves primarily to orient two critical pharmacophores in space, a series of novel, conformationally constrained bicyclo[2.2.2]octyl amines 3 which severely restrict the relative orientations available to the amine and methoxyphenyl groups was prepared. All compounds which positioned the pharmacophores on the same face of the molecule demonstrated vasorelaxant activity and affinity for the diltiazem receptor equal to or greater than racemic diltiazem 1 or the corresponding benzazepione 2. In addition, compound 3d was equipotent to (+)-diltiazem in its ability to reduce ischemic/reperfusion injury in an in vitro model of myocardial ischemia. However, 3d is significantly less cardiodepressive at an equivalent antiischemic dose. Therefore, the original receptor binding hypothesis led to the design and synthesis of novel calcium channel blockers with unique biological properties.

Animals↗
PubMed2001

Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

BACKGROUND: Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. OBJECTIVE: The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. METHODS: A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. RESULTS: Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. CONCLUSIONS: Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination of amlodipine/ benazepril can be successfully accomplished in the majority of patients.

Adult↗
PubMed2004

3D QSAR studies on T-type calcium channel blockers using CoMFA and CoMSIA.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of isoxazolyl compounds as a potent T-type calcium channel blockers. A set of 24 structurally similar compounds served to establish the model. Four different conformations of the most active compound were used as template structures for the alignment, three of which were obtained from Catalyst pharmacophore modeling and one by using SYBYL random search option. All CoMFA and CoMSIA models gave cross-validated r(2) (q(2)) value of more than 0.5 and conventional r(2) value of more than 0.85. The predictive ability of the models was validated by an external test set of 10 compounds, which gave satisfactory pred r(2) values ranging from 0.577 to 0.866 for all models. Best predictions were obtained with CoMFA std model of Conformer no: 3 alignment (q(2)=0.756, r(2)=0.963), giving predictive r(2) value of 0.866 for the test set. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands accounting for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, hydrophobic and hydrogen bonding fields.

Calcium Channel Blockers↗
PubMed2003

Calcium channel blockers: a potential cause of false-positive captopril renography.

PURPOSE: The purpose of the study was to review the causes of false-positive and false-negative captopril Tc-99m MAG3 renograms performed to evaluate renovascular hypertension at the authors' institution. METHODS: From May 2000 to January 2002, 77 patients were referred for evaluation of possible renovascular hypertension with captopril Tc-99m MAG3 renography. If the findings of the captopril study were abnormal, a baseline study was performed 3 days later. The captopril studies were retrospectively reviewed and correlated with available renal arteriography, magnetic resonance angiography, and duplex Doppler sonography studies and clinical follow-up. Renal artery stenosis greater than 70% on an arteriogram and 60% on Doppler studies or magnetic resonance angiography was considered positive for renovascular hypertension. RESULTS: There were five false-negative and four false-positive studies. The five patients who had the false-negative captopril studies underwent arteriography, which showed renal artery stenosis, and a stent was placed in two of them. The four false-positive captopril studies were proved by negative arteriograms in three and negative magnetic resonance angiography in one. Three patients with false-positive studies had bilateral renal function impairment after captopril and were taking calcium channel blockers at the time of the captopril study. One patient had a left nephrectomy and was also taking calcium channel blockers. CONCLUSION: Chronic intake of calcium channels blockers is a potential cause of bilateral symmetric false-positive captopril renography.

Adult↗
PubMed1995

Effects of calcium channel blockers on NIH 3T3 fibroblasts expressing the Ha-ras oncogene.

NIH 3T3 fibroblasts expressing the ras oncogene (+ras cells) respond to bradykinin, bombesin or serum with sustained oscillations of cell membrane potential reflecting oscillations of intracellular calcium activity and subsequent activation of calcium-sensitive K+ channels. In contrast, identical cells not expressing the oncogene (-ras cells) respond to bradykinin with a single, transient hyperpolarization of the cell membrane. Furthermore, +ras cells are characterized by a serum-independent proliferation, an increase in cell volume and a marked reorganization of the cytoskeleton. It has been shown previously that the calcium channel blocker nifedipine, but not verapamil and diltiazem, inhibits oscillations of cell membrane potential as well as proliferation. In this study, we have examined the effect of several calcium channel blockers (bepridil, nifedipine, verapamil, diltiazem) on the proliferation, volume and cytoskeletal reorganization of +ras cells. Bepridil (10 mumol/l), which is also shown here to inhibit oscillations of cell membrane potential, and nifedipine (10 mumol/l) caused a decrease in cell number, whereas verapamil and diltiazem (10 mumol/l each) resulted in growth rates which did not differ from untreated +ras cells. The increase in cell volume as observed in untreated +ras cells was also observed for cells treated with verapamil and diltiazem, whereas cell volumes of +ras cells treated with bepridil and nifedipine were markedly reduced and similar to the values obtained for -ras cells. In addition, bepridil and nifedipine markedly inhibited cytoskeletal rearrangement, i.e depolymerization of actin-containing stress fibers. This inhibitory effect was not observed for verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗
PubMed1990

Randomised prospective study on renal effects of two different contrast media in humans: protective role of a calcium channel blocker.

Contrast media affect renal hemodynamics. Hyperosmolality is regarded as the major factor responsible for renal hemodynamic changes. In this study, the role of osmolality was evaluated in 30 hospitalized patients without risk factors during intravenous pyelography. Contrast media with low and high osmolality were used. In addition, nifedipine was administered before infusion of high-osmolality contrast to evaluate the role of calcium ions in radiocontrast-induced changes of renal hemodynamics. Hyperosmolar contrast reduced renal plasma flow and glomerular filtration rate. Calcium channel blocker prevented changes of renal hemodynamics. Hyperosmolality appears the most likely factor affecting renal hemodynamics during hyperosmolar radiocontrast infusion. Calcium channel blocker may prevent renal changes due to hyperosmolar medium.

Adult↗
PubMed2001

Calcium channel blocker D-cis-diltiazem does not slow retinal degeneration in the PDE6B mutant rcd1 canine model of retinitis pigmentosa.

PURPOSE: D-cis-diltiazem, a calcium channel blocker, has been reported to enhance photoreceptor survival in the rd mouse, a model of retinitis pigmentosa (RP) resulting from mutation of the PDE6B gene. We tested the hypothesis that diltiazem treatment would similarly rescue the canine rcd1 model of RP, which is also caused by a null mutation in the PDE6B gene. METHODS: D-cis-diltiazem was delivered orally twice daily to rcd1 affected dogs beginning at 4 weeks of age; untreated age-matched rcd1 dogs served as controls. At 14 weeks, electroretinograms (ERG) were performed on all animals; 14 dogs were euthanized at this age, and 2 dogs at 25 weeks of age. Eyes were enucleated, fixed, and processed for routine histological examination. RESULTS: No significant differences were found in ERG or histopathologic parameters between diltiazem-treated and untreated rcd1 dogs. Neither rcd1 group showed a rod b-wave; ERGs evoked by single white flashes (dark- or light-adapted) and flicker were also identical between groups. Similarly, treated and untreated animals did not differ in the degree of preservation of the photoreceptor layer, confirmed in cell counts within the outer nuclear layer. CONCLUSIONS: Treatment of rcd1 affected dogs with D-cis-diltiazem did not modify the photoreceptor disease when results were assessed using either ERG or histopathologic criteria. The positive photoreceptor-rescue effect of calcium channel blockers reported in the rd mouse was thus not generalizable to another species with retinal degeneration due to mutation in the PDE6B gene. Caution needs to be exerted in extrapolation to the comparable human forms of RP.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1985

Hemodynamic effects of calcium channel blockers at rest and during exercise in essential hypertension.

The main hemodynamic disturbance occurring in patients with essential hypertension is an increase in the total peripheral resistance. In young patients with hypertension, this disturbance is clearly seen during muscular exercise, even though the calculated resistance might be normal during rest. This article reports results of studies on the long-term hemodynamic effects of two calcium channel blockers, verapamil and nifedipine, in patients with mild to moderate hypertension. Twenty-five men, aged 20 to 64 years, with diastolic blood pressures between 100 and 120 mm Hg before treatment were studied at rest and during exercise on ergometer bicycles. Blood pressure was recorded intra-arterially, and cardiac output was measured. After this initial study, 10 patients were treated with verapamil (from 40 to 80 mg, three times daily) and 15 patients with nifedipine (long-acting form, from 40 to 80 mg daily). After one year, the hemodynamic study was repeated. Both drugs induced a reduction in blood pressure and in the total peripheral resistance without any reduction in the cardiac index. Verapamil reduced heart rate, particularly during exercise, but this effect was compensated by an increase in the stroke volume. The hemodynamic profile of these two calcium channel blockers clearly differs from the hemodynamic effects of beta blockers.

Adult↗
PubMed2004

Different effects of calcium channel blockers on matrix metalloproteinase-2 expression in cultured rat cardiac fibroblasts.

The cardiac effects of calcium channel blockers (CCBs) related to cardiac remodeling are inconsistent. Matrix metalloproteinases (MMPs) contribute to tissue remodeling. Cardiac fibroblasts play an important role in the regulation of collagen degradation by MMPs. Using gelatin zymography, Western blotting, Griess reagent, and a calcium kit-fluo 3, we investigated the effects of nifedipine, verapamil, diltiazem, and amlodipine on MMP-2 expression and further elucidate the mechanisms in cultured rat cardiac fibroblasts. Nifedipine increased and amlodipine decreased the expression of MMP-2; however, neither verapamil nor diltiazem altered MMP-2 expression. Nifedipine also increased nitrite production, and this increase was blunted by a nitric oxide (NO) synthases inhibitor (L-NAME). Nifedipine-induced MMP-2 expression was also blunted by L-NAME. An NO donor (sodium nitroprusside) induced MMP-2 expression. Data indicated that nifedipine might increase MMP-2 expression through a possible NO-dependent pathway. Amlodipine had no influence on nitrite production. The amlodipine-induced decrease of MMP-2 expression was abolished by two protein tyrosine kinase inhibitors, genistein and herbimycin A, indicating that amlodipine might decrease MMP-2 expression through a possible protein tyrosine kinase pathway. None of the four CCBs could alter the fluoscence intensity of fluo 3, indicating that the effects of CCBs on MMP-2 expression were independent of the variation in intracellular C2+ concentration. Our findings revealed that different CCBs exerted different effects on MMP-2 expression in cardiac fibroblasts.

Amlodipine↗
PubMed1987

Sodium intake, high blood pressure, and calcium channel blockers.

Although there is much circumstantial and some direct clinical evidence suggesting that a high consumption of salt predisposes patients to the development of essential hypertension, the mechanism by which such consumption causes high blood pressure is not clear. It has been suggested that due to an inherited abnormality in renal sodium excretion, high salt intake triggers an increase in the levels of sodium transport inhibitor. Although this may help to restore sodium balance, it may also increase the concentration of intracellular sodium in arteriolar smooth muscle and, thereby, stimulate smooth muscle reactivity. It has been shown that intra-arterial infusion of calcium channel blockers into the forearm produces an enhancement of forearm blood flow that is proportional to the degree of hypertension. Other studies have demonstrated a linear relationship between the degree of hypertension and the magnitude of blood pressure reduction following treatment with a calcium channel blocker. These clinical findings, combined with evidence from studies in animals, suggest that a functionally abnormal response of smooth muscle cells to calcium channel blockers occurs as blood pressure increases. Whether this functional abnormality is related to an increased level of intracellular calcium and/or inhibition of the sodium pump is not known. The short-term blood pressure lowering effect of nifedipine appears to be enhanced when sodium intake is increased.

Animals↗
PubMedDate not supplied

Solid-phase synthesis of omega-agatoxin IVA, a P-type calcium channel blocker.

omega-Agatoxin IVA, isolated from the venom of funnel web spider Agelenopsis aperta, blocks potently and selectively P-type calcium channels. This toxin, composed of 48 amino acids and containing 8 cysteine residues, was synthesized by the solid-phase procedure. The Cys residues were protected by acetamidomethyl (Acm) groups which were removed by mercuric acetate. During treatment with mercuric acetate, a by-product was detected, involving modification of tryptophan residues by the Acm groups. This side reaction can be completely prevented by addition of an excess of tryptophan in the reaction medium during Acm deprotection. The resulting peptide was submitted to an oxidative refolding, in different conditions, in order to determine the most favourable protocol. After formation of the four disulphide bonds, the toxin was purified by successive preparative HPLC, on two different supports, and fully characterized by analytical HPLC, capillary electrophoresis, amino acid analysis, mass spectrometry and Edman degradation. It was found to block the P-type calcium channel with a similar biological potency as described for the natural product.

Animals↗
PubMed1998

Pretreatment with isradipine, a calcium-channel blocker, does not attenuate the acute behavioral effects of ethanol in humans.

The acute subject-rated, performance-impairing, and physiological effects of ethanol (0, 0.5, and 1 g/kg) were examined after pretreatment with isradipine (0, 5, and 10 mg) in nine healthy volunteers. Volunteers received 1 of the 9 ethanol-isradipine combinations during each of nine experimental sessions. Ethanol alone produced prototypical subject-rated drug effects (e.g., increased ratings of "Drunk," "Good effects," and "Like drug") and impaired performance. Isradipine alone also produced significant subject-rated drug effects (e.g., increased ratings of "Drug effect," "Bad effects," "High," and "Stimulated"), but did not impair performance. Isradipine pretreatment generally did not significantly alter the subject-rated or performance-impairing effects of ethanol. Isradipine alone, but not ethanol alone, significantly decreased systolic and diastolic blood pressure. The ethanol-isradipine combinations generally produced significantly greater decreases in blood pressure than were observed with isradipine alone. Breath-alcohol levels were significantly lower after isradipine pretreatment, which suggests isradipine altered the bioavailability of ethanol. The present findings extend previous studies with humans that examined the behavioral effects of ethanol after pretreatment with other calcium-channel blockers, including nifedipine, nimodipine, and verapamil. Whereas the available studies suggest that calcium-channel blockers would not be useful pharmacological adjuncts in the management of ethanol abuse, more research is needed. Future studies should use self-administration and drug discrimination procedures adapted for use with humans to determine if calcium-channel blockers can attenuate any of the behavioral effects of ethanol.

Adult↗