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PubMed2001

Effects of the calcium channel blocker verapamil and sulphydryl reducing agent dithiothreitol on atractyloside toxicity in precision-cut rat renal cortical and liver slices.

The effects of dithiothreitol (DTT), a sulfhydryl-containing agent and verapamil (VRP), a calcium channel blocker as possible cytoprotectants against the atractyloside-induced toxicity were characterized in rat kidney and liver slices in vitro using multiple markers of toxicity. Precision-cut slices (200 microM thick) were either incubated with atractyloside (2 mM) or initially preincubated with either DTT (5 mM) or VRP (100 microM) for 30 min followed by exposure to atractyloside (2 mM) for 3 h at 37 degrees C on a rocker platform rotated at approximately 3 rpm. All of the toxicity parameters were sensitive to exposure to atractyloside, but treatment with DTT or VRP alone did not provide any indication of damage to the tissues. Preincubation of slices containing either DTT or VRP for 30 min provided total protection against atractyloside-induced increase in LDH leakage in both kidney and liver slices. Increased induction of lipid peroxidation by atractyloside in liver slices was completely abolished by DTT and VRP. Both DTT and VRP provided partial protection against atractyloside-induced inhibition of gluconeogenesis in both kidney and liver slices. Atractyloside-induced ATP depletion in both kidney and liver slices was partially abolished by VRP but not DTT. The significant depletion of GSH in the kidney slices by atractyloside was completely reversed by DTT only, while VRP alone reversed the same process in liver slices. Decreased MTT reductive capacity and significant increase in ALT leakage caused by atractyloside in liver slices was partially reversed. Complete protection was achieved with both DTT and VRP against atractyloside-induced inhibition of PAH uptake in kidney slices. These findings suggest that both DTT and VRP exert cytoprotective effects in atractyloside-induced biochemical perturbation, effects that differ in liver and kidney. The effect of these agents on atractyloside has provided us with a further understanding of the molecular mechanism of its action.

Adenosine Triphosphate↗
PubMedDate not supplied

Refractory adenosine-sensitive congenital His bundle tachycardia: response to calcium-channel blockers.

The congenital form of His bundle tachycardia is an uncommon pediatric arrhythmia. We report the case of a 7-year-old child with tachycardiomyopathy. The incessant arrhythmia, detected in infancy, was resistant to amiodarone and beta-blockers. During electrophysiologic study, the tachycardia converted to sinus rhythm with intravenous adenosine and diltiazem. Subsequently, the child is maintaining sinus rhythm on oral verapamil. Calcium-channel blockers should be considered for the treatment of this arrhythmia, which is often resistant to multiple antiarrhythmic drugs.

Adenosine↗
PubMed1999

Effect of calcium channel blockers on cerebral ischemia-induced hyperactivity in Mongolian gerbils.

When both common carotid arteries of Mongolian gerbils were occluded for 5 min to produce ischemic insult, locomotor activity was increased the following day. The effect of calcium channel blockers on this ischemia-induced hyperactivity was investigated. Nimodipine, at doses of 5, 10, and 20 mg/kg, dose dependently and significantly decreased ischemia-induced hyperactivity. Nicardipine significantly decreased ischemia-induced hyperactivity and doses of 10 and 20 mg/kg. Nifedipine and flunaridine also significantly decreased ischemia-induced hyperactivity at doses of 20 mg/kg. Verapamil had no effect on ischemia-induced hyperactivity at a dose of 20 mg/kg. These findings suggest that ischemia-induced hyperactivity is related to calcium channels. These relationship between calcium channels and dopaminergic function is discussed.

Animals↗
PubMed1990

Chronic treatment by the calcium channel blocker +/- PN 200-110 in the rat counteracts the stimulations of pituitary weight, prolactin release and pituitary C-kinase activity induced by a chronic estradiol treatment, in vivo.

In order to investigate whether a calcium channel blocker could modulate the protein kinase C activity in normal and estradiol pretreated rat pituitary, female Wistar rats were treated or not (controls) with +/- PN 200-110 (3 mg.kg-1.day-1, sc) for 8 days or with estradiol cervical implants for 8 or 15 days, alone or in combination with PN 200-110 the last 8 days. Estradiol treatment induced a significant increase in plasma prolactin levels and pituitary weight. PN 200-110 administered to normal rats did not modify these parameters, whereas it reduced the effects of the 15 days estradiol treatment on prolactin levels (53.1 +/- 4.9 vs 95.0 +/- 9.1 micrograms/l, p less than 0.0001) and pituitary weight (19.9 +/- 0.4 vs 23.0 +/- 0.6 mg, p less than 0.001), to values statistically comparable to those measured after 8 days of estradiol treatment. PN 200-110 alone did not induce any change in protein kinase C activity as compared with controls. In contrast, PN 200-110 treatment significantly counteracted the large increase in soluble activity and the decrease in the particulate one induced by estradiol between day 8 and day 15. We conclude that PN 200-110 opposed the stimulatory effects of chronic in vivo estradiol treatment on plasma prolactin levels and pituitary weight and that this regulation was related to a concomitant modulation of the protein kinase C activity.

Animals↗
PubMed1985

Modification of experimental atherosclerosis by calcium-channel blockers.

The process of atherosclerosis, although not completely understood, is being clarified. A unifying hypothesis holds that the initial event is endothelial injury, followed by platelet aggregation and release reactions. This leads to smooth muscle cell migration into the intima and replication, with subsequent secretion of elastin, collagen and glycosaminoglycans (which binds lipids). Several animal studies have shown that calcium plays an important role in this process. Many drugs with diverse properties can inhibit experimental atherosclerosis. These drugs appear to reduce intracellular calcium. The calcium-channel blockers nifedipine, diltiazem and verapamil, which decrease intracellular calcium, also protect animals from experimental atherosclerosis. The relevance of these animal models to human atherosclerosis is uncertain, and there are very few studies concerning regression of atherosclerosis by interfering with calcium fluxes. Further studies will be needed to clarify these points.

Animals↗
PubMed1992

Effects of calcium and calcium-channel blocker methoxyverapamil on the beta-adrenoceptors in myocardial cells in vitro.

The possible relationship between methoxyverapamil (D600) as a calcium-channel blocker and the beta-adrenoceptors was investigated on heart cells grown in culture, using [3H]CGP-12177 as a radioligand. Treatment with D600 (20 micrograms/mL) for 24 hr caused a decrease of 30% in the [3H]CGP-12177 binding sites. Scatchard analysis showed that the Bmax is similar in control and D600-treated cells, but the Kd in D600-treated cells increases. The effect of D600 on the isoproterenol-induced adenylate cyclase activation was examined and it was found that the D600 prevented the increase in cAMP obtained by isoproterenol treatment. These results indicate that the action of D600 on the beta-adrenoceptors is a competitive inhibition of the [3H]CGP-12177 binding sites. We investigated the effect of Ca2+ in the growth medium on the level of beta-adrenoceptors. Heart cells grown for 24 hr in Ca(2+)-free medium showed a decrease of 36% in the [3H]CGP-12177 binding sites without changing the dissociation constant. This decrease is probably a result of reduction in synthesis of the receptors. The level of receptors returned to control values following replenishment with normal growth medium. These results show that calcium is essential for the development of the beta-adrenoceptors in heart cells in vitro.

Animals↗
PubMed1992

Perturbation effect of eight calcium channel blockers on liposomal membranes prepared from rat brain total lipids.

EPR spectroscopy of phosphatidylcholine or stearic acid labeled at the doxyl group at the 16-carbon position was used to compare the perturbation effect of eight calcium channel blockers (CB) on overall dynamics/disorder of the hydrophobic part of liposome membranes prepared from rat brain total lipids at the drug/lipid molar ratio of 1/2. Nifedipine (NIF), nimodipine, niludipine and nitrendipine had a minor effect on the dynamics/disorder of the liposome membranes, whereas the disordering effect of verapamil (VER), mepamil, gallopamil and diltiazem was more pronounced. Concentration dependence of the overall disordering effect of VER on liposomal membranes was found at the VER/lipid ratio greater than 0.02 and for the tranquilizer thioridazine greater than 0.005. VER exerted a disordering effect at the hydrophobic part of synaptosomal membranes at concentrations greater than or equal to 0.32 mmol/l, whereas NIF did not exhibit a disordering effect even at concentrations of 10-20 mmol/l.

Animals↗
PubMed1991

Calcium channel blockers and behavioral sensitization.

Behavioral sensitization to amphetamine-induced stereotypy was previously shown to consist of two separable phenomena, induction and expression, both of which involve the excitatory amino acids (EAA). In the present experiments, the calcium channel blockers (CCB), nifedipine, diltiazem and verapamil, were shown to block both phenomena; these results are similar to those reported earlier for DNQX, an antagonist of the non-N-methyl-D-aspartate receptors for the EAA. The CCB, like DNQX, affect only that percentage of the stereotypic response which results from the sensitization reaction, without affecting the quantitative portion of the response attributable to the acute effect of amphetamine. The results support previous conclusions that the sensitization response consists of two quantitative components, only one of which involves the EAA. The antagonism exhibited by the CCB suggests that behavioral sensitization involves Ca++ and L-type calcium channels.

Amphetamine↗
PubMed1985

Treatment of Raynaud's phenomenon with calcium channel blockers.

Raynaud's phenomenon may cause severe digital pain and functional disability, particularly in patients with underlying connective tissue diseases. The pathophysiology of Raynaud's phenomenon is varied, but digital ischemia is an essential element. Because calcium channel blockers cause 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. Verapamil was ineffective in low doses, but both nifedipine and diltiazem produced subjective improvement. In placebo-controlled studies with nifedipine, the frequency of vasospastic episodes per two weeks decreased from 14.7 episodes during placebo therapy to 10.8 during nifedipine therapy (p less than 0.05). This response was more pronounced in patients without underlying vascular disease. Moderate or marked subjective improvement occurred in 60 percent of the patients receiving nifedipine and in only 13 percent of patients receiving placebo. Adverse effects were mild. It is concluded that nifedipine is an effective short-term therapy for most patients with Raynaud's phenomenon.

Calcium Channel Blockers↗
PubMed1993

Protective effect of the calcium channel blocker diltiazem on hepatic function following warm ischemia.

The purpose of this study was to investigate the protective effect of a calcium channel blocker diltiazem (DTZ) on hepatic ischemic injury using a canine model. Hepatic ischemia was induced by temporary clamping of hepatic afferent blood vessels for 60 min with establishment of a portojugular bypass. The administration of DTZ at a dose of 70 micrograms/kg bolus i.v. injection before hepatic ischemia and thereafter via the portal vein at a dose of 10 micrograms/kg/min well restored the hepatic blood flow (HBF, 92 +/- 5%; P < 0.01) and arterial ketone body ratio (AKBR, 1.15 +/- 0.16; P < 0.01) 1 hr after interruption compared with untreated controls (HBF, 61 +/- 7%; AKBR, 0.53 +/- 0.09). In addition, the increase of plasma lactate level and the decrease of mean arterial pressure were significantly suppressed after ischemia (P < 0.05). We concluded that DTZ has a protective effect on ischemia-induced hepatic damage and might be useful in the prevention of primary graft failure caused by warm ischemia in liver transplantation.

Animals↗
PubMed1992

Comparison of converting enzyme inhibitor and calcium channel blocker in SHR with nephrotoxic serum nephritis.

In order to compare the protective effects of angiotensin converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) on the renal function in experimental nephritis, nephrotoxic serum nephritis was induced in male spontaneously hypertensive rats (SHR). The above drugs were then chronically administered to different groups, as follows: the ACEI-treated group (n = 7) received captopril (150 mg/kg/day), and the CCB-treated group (n = 6) was given both nifedipine (40 mg/kg/day) and nisoldipine (20 mg/kg/day). The control group (n = 8) received a placebo. Although the control group developed marked hypertension and proteinuria, the rats treated with either ACEI or CCB demonstrated a significant and equivalent decrease in mean arterial pressure and urinary protein excretion. At 15 weeks after the injection of nephrotoxic serum, all rats were anesthetized with Inactin, and the glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. In the control group, GFR and RPF were markedly attenuated. However, both were preserved at much higher levels in the ACEI-treated group, and GFR was also maintained to a similar degree in the CCB-treated group. Histological studies were carried out after the clearance studies. As a result, it was found that the ACEI treatment significantly limited the development of glomerulosclerosis, whereas CCB modestly ameliorated the glomerular structural lesions. Moreover, ACEI significantly reduced the serum cholesterol, while CCB did not exert such an effect. These results suggest that both ACEI and CCB have a therapeutic effect in experimental glomerulonephritis models which are accompanied by hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1990

Calcium channel blockers for kidney protection.

Acute postischemic renal failure (ARF) is a major complication in surgery and in particular in renal transplantation. Calcium channel blockers (CCBs) are able to prevent or ameliorate ARF in different experimental models when given before ischemic injury. Because ARF, which is observed in 20-60% of graft recipients, carries the risk of undetected rejections and nephrotoxic injury and is also expensive, we tested the hypothesis, suggested by animal experiments, that there is also a beneficial effect of CCBs when given after ischemic injury. A total of 134 recipients of first or second cadaver grafts were randomly assigned to a diltiazem pretreatment (DZ) or control (C) group. Kidney grafts were pretreated immediately prior to transplantation by reperfusion with 500 ml Euro-Collins (preservation fluid), with or without DZ. The DZ patients also received a 74-h infusion of DZ (0.12 mg/kg/h), starting 2 h prior to surgery. DZ was continued (90 mg b.i.d. p.o.) until day 30. Immunosuppression consisted of low-dose steroids and cyclosporine A (CSA) (10 mg/kg p.o.). CSA was instituted 6 h after surgery and later adjusted to achieve whole-blood trough levels of 300-600 ng/ml [by polyclonal radioimmunoassay (RIA)]. A total of 129 patients were available for efficacy analysis. There were no significant differences concerning donor demographics, human lymphocyte antigen (HLA) match, or ischemic times. ARF was defined as a need for dialysis in the first week. Our data show a significant reduction in ARF in grafts pretreated with DZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1990

Baroreceptor activity in man during administration of the calcium channel blocker felodipine.

The mechanisms responsible for the resetting of the baroreceptor reflex during long-term administration of 1,4 dihydropyridine calcium channel blockers are incompletely understood. The present study investigated the effect of 10 mg per day of felodipine on arterial blood pressure (BP), heart rate (HR), urinary norepinephrine, and cardiac beta-1-receptor sensitivity in 10 healthy volunteers. Blood pressure heart rate and urinary norepinephrine were determined during control and on days 1,4, and 14 of felodipine administration. Dose response curves of intravenous bolus injections of isoproterenol were performed on the same days to measure cardiac beta-1-receptor sensitivity. Felodipine significantly reduced the blood pressure from 131 +/- 6/74 +/- 3 mm Hg (mean +/- s.e.m.) to 123 +/- 6/65 +/- 2 mm Hg on day 1 (p less than 0.01). The blood pressure remained decreased during the entire protocol. The initial increase in the heart rate (62 +/- 5 to 67 +/- 4 min-1) remained elevated on day 4 and returned within the control range by day 14 (63 +/- 4 min-1) in spite of unchanged felodipine plasma levels (1.71 +/- 1.13 ng/ml (day 1) and 1.66 +/- 0.66 ng/ml (day 14). Urinary norepinephrine rose significantly with short-term felodipine administration (62 +/- 12 versus 50 +/- 6 micrograms/24 h; p less than 0.01). With long-term felodipine administration this value returned to pretreatment levels (55 +/- 12 micrograms/24 h). Cardiac beta-1-receptor sensitivity was not changed at any point of the protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Effects of a calcium channel blocker on spontaneous neural noise and gross action potential waveforms in the guinea pig cochlea.

The effects of the L-type Ca2+ channel blocker nimodipine on the spectrum of the spontaneous neural noise (SNN) and the waveform of the gross sound-evoked compound action potential (CAP) were investigated by perilymphatic perfusion in the guinea pig cochlea. Both the SNN and the CAP were reversibly suppressed by nimodipine. The percentage reduction in SNN was dose-dependent in a manner very similar to the results obtained with the measures of CAP threshold changes. The reduction in the peak SNN caused by 10 microM nimodipine was the same as that caused by 500 microM kainic acid, which totally eliminated any neural responses. For 1 microM nimodipine there was an apparent dissociation between the SNN and CAP changes such that the SNN could be markedly suppressed with only very small changes in CAP thresholds. These results imply that spontaneous release of neurotransmitter from the inner hair cell is more sensitive to block of calcium channels than evoked release. There was no evidence for any marked shift caused by nimodipine, in the position of the main (900 Hz) spectral peak in the SNN. Comparison of the CAP waveform before and after nimodipine perfusion showed that the CAP waveforms were unchanged despite the change in sensitivity. These data do not support the notion of any significant postsynaptic site of action of nimodipine. The data hence provide further support for an exclusively presynaptic role for L-type Ca2+ channels in the regulation of both evoked and spontaneous neurotransmitter release from inner hair cells.

Action Potentials↗
PubMed1992

Effects of calcium channel blockers on renal function in mice.

Tumor blood flow modification is currently under investigation as a possible means of optimizing current cancer therapies, with particular respect to improving the efficacy of bioreductive agents. A variety of calcium channel blockers have been shown to modify tumor perfusion in model systems, and may be valuable as potentiators of both bioreductive and conventional drugs. We report the effects of nifedipine, verapamil, flunarizine, and cinnarizine on renal function in C3H mice, assayed by clearance of simultaneously injected 51Cr ethylenediamine tetraacetate. Nifedipine at 10 mg kg-1 blocked 51Cr ethylenediamine tetraacetate clearance for 30 min and reduced its subsequent rate of clearance by a factor (+/- 2 se) of 2.4 +/- 0.6. At 1 mg kg-1 it reduced the rate of clearance by a factor of 1.2 +/- 0.2. Verapamil at 10 mg kg-1 blocked 51Cr ethylenediamine tetraacetate clearance for 10 min and reduced its subsequent rate of clearance by a factor of 1.5 +/- 0.3, but had no effect at 1 mg kg-1. Flunarizine had no effect at 50 mg kg-1 or at 5 mg kg-1, but cinnarizine at 50 mg kg-1 reduced clearance rate by a factor of 1.2 +/- 0.1. The data show that some of these vasoactive agents, nifedipine and verapamil in particular, can severely compromise renal function and may, therefore, affect the plasma pharmacokinetics of co-administered drugs that are cleared by the kidney.

Animals↗
PubMed1996

Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy.

Treatment of hypertension with ACE inhibitors in diabetic patients reduces proteinuria and slows progression of nephropathy compared with agents that do not maintain declines in proteinuria. Calcium channel blockers (CCBs) have variable effects on proteinuria; their long-term effects on progression of diabetic nephropathy are not known. The current study examines the hypothesis that CCBs that maintain reductions in proteinuria slow progression of nephropathy associated with non-insulin dependent diabetes mellitus (NIDDM) by a degree comparable to ACE inhibitors, given similar levels of blood pressure control. To test this hypothesis we randomized 52 patients with NIDDM associated nephropathy and hypertension, mean age of 63 +/- 8 years, to either the ACE inhibitor, lisinopril (N = 18), nondihydropyridine CCBs (NDCCBs), verapamil SR (N = 8) or diltiazem SR (N = 10), or the beta blocker, atenolol (N = 16). Goal blood pressure was < or = 140/90 mm Hg. Patients were followed for a mean period of 63 +/- 7 months. The primary end point was change in creatinine clearance (CCr) slope in each group. There was no significant difference in mean arterial pressure reduction among the groups over the study period (P = 0.14). The mean rate of decline in CCr was greatest in the atenolol group (-3.48 ml/min/year/1.73 m2; P < 0.0001). There was no difference in the CCr slopes between lisinopril and NDCCBs groups (P = 0.36). Proteinuria was reduced to a similar extent in the lisinopril and NDCCBs groups (P > 0.99). Therefore, in persons with renal insufficiency secondary to NIDDM, similar levels of blood pressure control with either lisinopril or NDCCBs slowed progression of renal disease to a greater extent than atenolol. Moreover, this enhanced slowing of renal disease progression correlated with sustained and significant reductions in proteinuria, findings not observed in the atenolol group.

Aged↗
PubMed2000

Ankle edema formation during treatment with the calcium channel blockers lacidipine and amlodipine: a single-centre study.

All studies suggesting a lower incidence of edema on lacidipine than on amlodipine are based on subjective scoring. Therefore, we have compared edema formation on two dihydropyridine calcium channel blockers, using an accurate method for quantitative assessment of foot volume. In a randomized study, we treated 62 patients with essential hypertension for 12 weeks starting with either lacidipine 4 mg o.d. (n = 30) or amlodipine 5 mg o.d. (n = 32). At 6 weeks, the doses were increased to that maximally allowed (lacidipine 6 mg, n = 18; amlodipine 10 mg, n = 12) if trough diastolic blood pressure response was insufficient (>90 mmHg and decrease < 10 mmHg). Edema, scored visually, occurred more frequently (p = 0.02) on amlodipine (15/32) than on lacidipine (6/30); this was confirmed by an increase of foot volume above the 95% upper limit of normal variation in 15 patients on amlodipine and in only five patients on lacidipine (p = 0.01). In the whole group of patients, both the increases of foot volume and the decreases of blood pressure just failed to be significantly different between amlodipine and ]acidipine (foot volume, +3.3+/-1.0% on amlodipine and +1.2+/-0.5% on lacidipine, p = 0.08; mean arterial pressure, -11+/-1% on amlodipine and -8+/-1% on lacidipine, p = 0.052). In patients requiring dose increase, the increase of foot volume on amlodipine was more pronounced (p < 0.05), and the antihypertensive effect was larger (p < 0.05) than on lacidipine. In conclusion, our data show a higher incidence of edema on amlodipine than on lacidipine, which has to be explained at least partly by a comparably higher dose c.q. a larger antihypertensive effect of amlodipine. Other mechanisms might have contributed to these differences and need to be explored.

Adolescent↗
PubMed1994

Picrotoxin-induced epileptic activity in hippocampal and neocortical slices (guinea pig): suppression by organic calcium channel blockers.

Epileptic activity induced by the GABAA receptor antagonist bicuculline is known to be blocked by organic calcium antagonists. To further analyse the mechanism underlying convulsant activity induced by substances reducing GABA-mediated synaptic transmission, the effect of organic calcium channel blockers on epileptic activity induced by the GABAA channel blocker picrotoxin in hippocampal and neocortical slices of guinea pigs were investigated. Verapamil and flunarizine suppressed paroxysmal depolarization shifts (PDS) of single neurons and accompanying epileptic field potentials (EFP). As a measure of drug action the repetition rate of epileptic events were used. The depression down to 10% the initial value (90% depression) is indicated. In the hippocampus verapamil suppressed PDS/EFP within 70 +/- 16 min (40 mumol/l) and within 39 +/- 5 min (60 mumol/l). This suppression was reversible with washout of verapamil. Flunarizine irreversibly blocked EFP/PDS within 108 +/- 14 min (18 mumol/l). In the neocortex verapamil reversibly suppressed EFP within 146 +/- 6 min (40 mumol/l) and 127 +/- 26 min (60 mumol/l). Flunarizine irreversibly blocked EFP within 181 +/- 30 min (3 mumol/l) and 109 +/- 13 min (18 mumol/l). The results suggest that voltage dependent calcium channels are essentially involved in picrotoxin-induced epileptic activity.

Animals↗