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PubMed1999

Pharmacologic effects of calcium channel blockers on restenosis.

The understanding and control of the healing process after percutaneous transluminal coronary angioplasty (PTCA) and of the pathogenesis of restenosis are incomplete. To date, only stent implantation has been shown to successfully reduce the rate of restenosis. Calcium channel blockers have positive effects on a number of processes that may be associated with restenosis, including reduction of platelet aggregation, minimization of vasospasm, and inhibition of mitogens. Clinical trials have therefore been performed to assess the effect of calcium channel blockers on restenosis and ischemia. A meta-analysis of five restenosis trials investigating calcium channel blockers demonstrated a 30% reduction in the risk for restenosis. The Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) is therefore assessing the effect of amlodipine, a long-acting, third-generation calcium channel blocker in angioplasty patients. Therapy (amlodipine 5 mg with a forced titration to 10 mg once daily, or placebo), is begun 2 weeks before angioplasty and is continued for 4 months after the procedure. The rationale of CAPARES is that amlodipine may offer anti-ischemic protection before, during, and after angioplasty, may have more beneficial effects on restenosis and various clinical end points than calcium channel blockers used in previous trials, and may improve the long-term outcome of PTCA therapy.

Angioplasty, Balloon, Coronary↗
PubMed2001

[Calcium channel blockers in the treatment of cardiovascular disease].

Drugs classified as calcium channel blockers (CHBs) are now among the most frequently prescribed drugs for the treatment of cardiovascular disease. Although the currently available CCBs have major differences in their structural and cardiovascular effects, they share the common property of blocking the transmembrane flow calcium ions through voltage gated L-type channels. These drugs have been approved for the treatment of hypertensive heart disease: they reduce left ventricular hypertrophy and improve its sequelae, such as ventricular dysrhythmias, impaired filling and contractility, and myocardial ischemia. Long-acting CCBs have been shown to reduce mortality and morbidity in elderly patients with systolic hypertension, appear to be extremely useful in patients with cyclosporin-induced hypertension, and can be used as alternatives to ACE inhibitors in patients with hypertension and concomitant diabetes mellitus, renal disease, Raynaud's phenomenon or migraine. Long-acting dihydropyridine have been shown to be effective and safe in the treatment classic angina pectoris and vasospastic angina, supraventricular arrhythmias, particularly reentrant AV-nodal tachycardia, others to be beneficial in patients with congestive heart failure, and all of them have potential for decreasing atherogenesis.

Calcium Channel Blockers↗
PubMedDate not supplied

Treating hypertension in the diabetic patient: therapeutic goals and the role of calcium channel blockers.

Although many drugs effectively control hypertension in patients with diabetes mellitus, the risk of aggravating the diabetic process and inducing new complications can negate the benefits of reduced blood pressure. This article discusses the current status of antihypertensive therapy in diabetic patients and focuses on the use of calcium channel blockers that safely reduce blood pressure while having a neutral or beneficial effect on the diabetic state and related medical complications. While both calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors are suitable agents for the primary treatment of diabetic hypertension, the beneficial effects of calcium channel blockers on glucose homeostasis, lipid metabolism, and renal function support their routine use as alternatives to ACE inhibitors. Among the three classes of calcium channel blockers, second-generation dihydropyridines offer advantages over older calcium channel blockers because the second-generation drugs provide greater vascular selectivity and less direct myocardial depression.

Aged↗
PubMed1987

Effects of calcium, calcium channel blockers and Bay K 8644 on contractions induced by muscarinic receptor stimulation of isolated bladder muscle from rabbit and man.

In isolated bladder smooth muscle from both rabbit and man, carbachol-induced contractions were reduced by the calcium channel blocker nifedipine, whereas the calcium channel promotor Bay K 8644 had no effect. In nominally calcium-free medium containing 10(-4) M EGTA, carbachol-induced contractions were reduced by 69% (rabbit) and 87% (man). These contractions were abolished by nifedipine, whereas Bay K 8644 significantly increased their amplitude, in rabbit preparations almost to control level. Electrical field stimulation produced contractions which could be suppressed by scopolamine by about 50% (rabbit) and more than 90% (man). These contractions were abolished by calcium-free medium (10(-4) M EGTA), suppressed by nifedipine, but significantly enhanced by Bay K 8644. The depressant effects of nifedipine, verapamil and diltiazem were reversed by Bay K 8644. The calcium channel blockers relaxed K+-induced contractions to base line, and this action was counteracted by Bay K 8644, less effectively when relaxations were induced by diltiazem. It is concluded that contractions produced by muscarinic receptor stimulation are primarily dependent on calcium bound to the outside of the membrane of the smooth muscle, and/or coming from the extracellular medium. Electrically evoked, scopolamine sensitive contractions seem to be mediated by a mechanism different from that of contractions produced by exogenously added muscarinic receptor agonist. The present data support the view that combined blockade of muscarinic receptors and calcium channels is an effective way of inhibiting bladder contractions in both rabbit and man.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Nisoldipine--a new calcium channel blocker for hypertension.

Nisoldipine (Sular-Zeneca), a dihydropyridine calcium-channel blocker structurally similar to nifedipine, has been approved for marketing by the US Food and Drug Administration. It is available in an oral extended-release formulation for treatment of hypertension.

Animals↗
PubMed1987

Calcium-channel blockers and the hepatorenal syndrome.

It is suggested that calcium-channel blockers may be the agents of choice for treating the renal dysfunction associated with the hepatorenal syndrome because these agents may be effective in reversing the episodic renal vasospasm which characterizes this disorder.

Calcium Channel Blockers↗
PubMed2003

Differential effects of dihydropyridine calcium channel blockers in kainic acid-induced experimental seizures in rats.

The anticonvulsant effects of the dihydropyridine calcium channel blockers nifedipine, nicardipine and nimodipine were studied on experimental seizures induced by intra-hippocampal injection of kainic acid (KA) in chloralhydrate anesthetized Wistar rats. The rats were anesthetized and placed in a stereotaxic apparatus. After midline incision four screw electrodes were placed over the left and right frontal and parietal cortex and KA was injected into left dorsal hippocampus via 5-microliter Hamilton microsyringe. The changes in electroencephalograph (EEG) activity and EEG power spectra were recorded in basal conditions and 5, 10, 15, 30 and 60 min following KA injection. KA-induced excitatory changes in the surface EEG activity were associated with the marked increase in EEG power spectra in the frequency range from 14.5-22 Hz. Pretreatment with nifedipine, nicardipine and nimodipine revealed that they exerted certain differences in their anticonvulsant properties. Nimodipine significantly delayed the onset of seizures and prevented the KA-induced changes in EEG and in EEG power spectra in all recorded channels and in a dose dependent manner. Nifedipine exerted significant anticonvulsant effect only in channel four, while nicardipine was ineffective. Our results suggest that anticonvulsant action of some dihydropyridine calcium channel blockers, especially nimodipine may be in part independent of its antagonism on L-type voltage-gated calcium (Ca(2+)) channels.

Animals↗
PubMed1994

Comparison of various calcium channel blockers on guinea-pig isolated common bile duct.

1. The inhibitory effects of various calcium channel blockers; nifedipine, verapamil, diltiazem and a heterogenous compound, dantrolene, have been investigated on isolated common bile duct from guinea-pig. 2. All the compounds tested induced a concentration-dependent reduction of the amplitude of contractile response to electrical stimulation or increasing the calcium concentration of the bathing media. 3. Nifedipine was the most potent compound whereas the least potent was dantrolene; verapamil and diltiazem had intermediate potency. 4. The IC50 values for these compounds were calculated as: nifedipine 3.68 x 10(-9) M; verapamil, 4.93 x 10(-8) M; diltiazem, 4.2 x 10(-7) M; and dantrolene 5.51 x 10(-5) M. 5. All the compounds displaced the concentration-response curve of calcium chloride to the right in a concentration-dependent manner. Among the compounds studied, nifedipine had the highest and dantrolene had the lowest potency. 6. These results indicate the striking pharmacological effects of the calcium channel blockers on the common bile duct and may indicate a possible role for these compounds in the treatment of biliary colic.

Animals↗
PubMed1995

Effect of calcium-channel blocker on tumour necrosis factor alpha (TNF alpha) production in cyclosporin-treated renal transplant recipients.

PURPOSE OF THE STUDY: The influence of calcium-channel blocker treatment on in-vitro TNF alpha production by peripheral blood mononuclear cells (PBMC) from renal transplant recipients treated with cyclosporin was studied. DESIGN: We compared spontaneous and OKT3-induced TNF alpha production of 12 renal transplant recipients treated with calcium-channel blocker therapy with that of 18 renal transplant recipients who were never treated with a calcium antagonist. RESULTS: The two groups were similar with regards to age, time after transplantation, dosage of immunosuppressive drugs, and blood cyclosporin levels. Spontaneous (481 +/- 161 versus 319 +/- 74 pg/ml, n.s.) and OKT3-induced (745 +/- 182 versus 632 +/- 112 pg/ml, n.s.) TNF alpha production were similar in both groups. CONCLUSIONS: The results indicate that in cyclosporin-treated renal transplant recipients calcium-channel blockers do not affect TNF alpha production.

Adult↗
PubMed1997

[What role to assign for calcium channel blockers in the treatment of arterial hypertension in 1997?].

What is the place of calcium channel blockers in the treatment of hypertension (HT)? And, more importantly, what is the place of any molecule recognised as being effective to reduce blood pressure figures in the treatment of HT? Beyond the hypotheses which have dominated the rational approach up until now, suggesting a possible answer to these two questions, medical practice is developing towards evidence-based medicine. This opposes two lines of logic:--that which argues that the benefit of treatment of HT is exclusively related to a reduction of blood pressure figure obtained with the use of the most effective molecule or class which is best tolerated in a given clinical context; that which argues that it is impossible to prescribe widely and indefinitely molecules whose real effect on the clinical prognosis of HT and long-term safety are unknown. This new logic no longer recognizes the reduction of blood pressure figures independently of the means used to achieve this reduction as the exclusive guarantee of the benefit of treatment and proposes that treatments which are widely prescribed must have a more detailed clinical evaluation file than that authorized by current practice. Calcium channel blockers were recently adopted as the main subject of this opposition between two logics, probably because several molecules of this class, evaluated in therapeutic trials conducted outside of the context of HT, demonstrated harmful cardiovascular effects and that case-control studies in the context of HT have indicated the possibility of extracardiac adverse effects. It therefore seems useful to try to redefine their place in the treatment of HT in the light of this recent debate and, more importantly, to extend the discussion to several principles of the pharmacological treatment of HT. Leaving current controversies to one side, this review is designed to present several elements of these opposing logics.

Calcium Channel Blockers↗
PubMed1986

Calcium channel blockers and treatment of hypertension.

Over the past years, research efforts have been focused on the pathophysiologic role of calcium ions, and the implication for the potential role of calcium channel blockers in the management of essential hypertension. Numerous studies have shown that nifedipine and verapamil are effective antihypertensive agents, initial experience with diltiazem is also encouraging. The magnitude of blood pressure reduction with these drugs is related to the pre-treatment blood pressure. In refractory hypertension, combination with other antihypertensive agents provide additive effect. In the elderly population and in patients with ischemic heart disease, supraventricular arrhythmia, bronchospastic disease, peripheral vascular disease or diabetes mellitus, the calcium channel blockers offer potential advantages over other antihypertensive agents. Experimental studies also suggest that these drugs may reverse ventricular hypertrophy. When long-term safety with these drugs is documented from well-controlled clinical trials, the calcium channel blockers may be our first line of therapy for the management of hypertension.

Antihypertensive Agents↗
PubMed2000

Evaluation of calcium channel blockers as potential hepatoprotective agents in oxidative stress injury of perfused hepatocytes.

The aim of this study was to investigate the effects of calcium channel blockers on tertbutyl hydroperoxide (TBH) induced liver injury using isolated perfused rat hepatocytes. Rat hepatocytes were immobilized in agarose threads and perfused with Williams E medium. Hepatocyte injury was induced by the addition of tertbutyl hydroperoxide (1 mM) to the perfusion medium 30 min after the addition of either verapamil or diltiazim. Hepatocyte injury was observed by monitoring the functional and metabolic competence of hepatocytes or by ultrastructural morphological examination of hepatocytes. Verapamil (0.5 mM) reduced lactate dehydrogenase leakage in TBH-injured hepatocytes as compared to the controls (154+/-11% vs. 247+/-30%). Lipid peroxides production was reduced after verapamil pretreatment as compared to the controls and oxygen consumption was increased by pretreatment of hepatocytes with verapamil. Verapamil pretreatment increased the protein synthesis activity at both levels of granular endoplasmic reticulum and free polysomes in cytoplasm and decreased ATPase activity. Diltiazem was qualitatively effective as verapamil. It is concluded that in hepatocyte oxidative injury, calcium channel blockers exhibited hepatoprotective properties. The hepatoprotective effect of calcium channel blockers was accompanied by a decrease in ATPase activity, which may implicate a normalization of Ca2+i after TBH intoxication.

Adenosine Triphosphatases↗
PubMed1993

1-Benzazepin-2-one calcium channel blockers--VI. Receptor-binding model and possible relationship to desmethoxyverapamil.

We have prepared a series of potent antihypertensive 1-benzazepin-2-one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem 2. Structural studies and the preparation of conformationally constrained analogs of 1-benzazepin-2-ones have led us to postulate a receptor-bound conformation for both 1 and 2. We believe that these compounds bind to the calcium channel protein in an MI ("inboard") binding conformation in which the amine of the side chain is placed over the heptagonal benzazepione ring and in close proximity to the phenyl methyl ether pharmacophore. This receptor-bound conformation places the side chain amine and methyl ether pharmacophores in the same spatial relationship as 3-methoxyphenylethalamine. Combined with our SAR, this binding model rationalizes literature findings that desmethoxyverapamil can demonstrate pharmacology typical of both phenylalkylamine (PA) and benzothiazepinone (DTZ) calcium channel blockers. Simple experiments are proposed to test the hypothesis that desmethoxyverapamil can bind at the benzothiazepinone site on the calcium channel.

Animals↗
PubMed2005

Comparison of the direct negative dromotropic effect of a new calcium channel blocker, cilnidipine, with that of nicardipine.

We encountered a 91-year-old woman with atrial fibrillation complicating bradycardia while she was receiving therapy with an L/N-type calcium channel blocker, cilnidipine, for hypertension, which is an unusual observation for the dihydropyridine class of calcium channel blockers. Therefore, we compared the dromotropic effect of cilnidipine with that of an L-type calcium channel blocker, nicardipine, which has a similar hypotensive activity. The canine isolated, blood-perfused atrioventricular node preparation was used. Cilnidipine as well as nicardipine slowed atrioventricular nodal conduction in a dose-related manner. However, the dromotropic action of cilnidipine was about five times less potent than that of nicardipine. These experimental results may suggest that we experienced an atypical clinical event of cilnidipine in a very old woman; otherwise one can speculate that the N-type calcium channel inhibitory component of cilnidipine might have played a role in exerting the negative dromotropic effect in this patient.

Aged↗
PubMed2006

Behavioral and electrophysiological studies of chronic oral administration of L-type calcium channel blocker verapamil on learning and memory in rats.

It has been shown that L-type voltage dependent calcium channels (VDCCs) have important role in learning and memory. In vivo and in vitro electrophysiological recordings of hippocampal neurons have demonstrated their involvement in long-term potentiation (LTP), which considers being one possible cellular mechanism underlying learning and memory. The long-term effect of VDCCs of hippocampal dentate gyrus (DG) so far on synaptic plasticity has not received much attention. In this study, the effect of chronic (60 days) oral administration of L-type calcium channel blocker verapamil on learning and memory and synaptic plasticity of hippocampal dentate gyrus in rats has been investigated. L-type calcium channel antagonist, verapamil chronically and orally at different doses (10, 20 and 50 mg/kg) was used to investigate learning and memory by passive avoidance learning. LTP in perforant-DG synapses was assessed (by either 200 or 400 Hz tetanization) in order to investigate long-term effect of verapamil on synaptic plasticity. In this case, field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. Our behavioral study has shown that chronic oral treatment of verapamil has no effect on learning whereas verapamil (50 mg/kg) decreased memory retrieval. Verapamil (20 and 50 mg/kg) inhibited EPSP-LTP induction at 400 Hz but not at 200 Hz tetanization. Furthermore, only verapamil (50mg/kg) decreased PS-LTP with respect to control group. These data suggest that 400 Hz LTP is required for activation of L-type VDCCs and it seems that verapamil is more effective on L-type calcium channels of DG dendrites than their soma.

Administration, Oral↗
PubMed1991

Calcium channel blocker and calmodulin antagonists affect the gradient of free calcium ions in lily pollen tubes.

The distribution of intracellular free calcium ions ([Ca2+]i) was measured in pollen tubes of Lilium longiflorum using video imaging microscopy and the calcium sensitive indicators fura-2 and quin-2. The mean [Ca2+]i in growing pollen tubes measured with fura-2 shows a maximum of 1.7 to 2.6 microM in the tube tip and decreases almost exponentially to 60 to 100 nM at 100 microns behind the tip. Using quin-2, the maximum [Ca2+]i was also found in the tube tip but with a lower Ca2+ concentration, namely 1 microM. Addition of the calcium channel blocker La3+ caused a decrease of the [Ca2+]i maximum in the tube tip, indicating a heterogeneous distribution of Ca2+ channels along the plasma membrane of pollen tubes. The [Ca2+]i increased after addition of vanadate or compound 48/80. This suggests an involvement of a calmodulin-dependent Ca2+ pump in generation of the Ca2+ gradient in lily pollen tubes. The high [Ca2+]i found in the tube tip with fura-2 seems to indicate the real Ca2+ concentration and is probably responsible for vesicle fusion, fragmentation of actin filaments, and inhibition of cytoplasmic streaming.

Aminoquinolines↗
PubMed1991

Calcium-channel blockers for treatment of diabetic nephropathy.

The use of calcium-channel blockers (CCBs) to reduce proteinuria associated with nephropathy in patients with diabetes mellitus is discussed. Metabolically induced damage to the nephrons in diabetic nephropathy decreases the filtration rate and increases the glomerular plasma flow rate and transcapillary hydraulic pressure. Microalbuminuria, which is predictive of nephropathy in patients with insulin-dependent diabetes mellitus, is associated with the development of clinical proteinuria and increased mortality. Micro-albuminuria should be evaluated periodically in diabetic patients, and antihypertensive therapy should be initiated when proteinuria is present or blood pressure control is needed. CCBs lower blood pressure because they prevent the action of angiotensin II by blocking the entry of calcium into renal vascular smooth muscle. Some CCBs, such as diltiazem and nicardipine, decrease glomerular pressure by increasing efferent arteriolar dilation. Others, such as nifedipine, may dilate both the afferent and efferent arterioles, thus causing increased excretion of protein. Studies in patients with diabetic nephropathy have shown that individual CCBs vary in their effects on proteinuria; this variation is attributable to their different sites of action and different effects on intrarenal activity. The choice of a CCB or an angiotensin-converting-enzyme inhibitor should be based on concomitant disease states and adverse-effect profiles. For control of hypertension in patients with diabetic nephropathy, diltiazem should be considered initially. Nicardipine is effective for short-term use but has not been tested in long-term studies; it should be considered a reasonable alternative.

Calcium Channel Blockers↗
PubMed1990

Calcium channel blockers versus angiotensin-converting enzyme inhibitors: renal effects.

Angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are two classes of antihypertensive agents with novel effects on renal function. In both experimental and clinical studies, calcium channel blockers tend to increase renal blood flow, glomerular filtration rate, and urinary sodium excretion in essential hypertension. ACE inhibitors have similar effects on renal blood flow and glomerular filtration rate in essential hypertension, but they tend to cause sodium retention. ACE inhibitors can cause marked reductions in glomerular filtration rate in renovascular hypertension, making them a problematic choice for the treatment of this form of hypertension. In chronic, progressive renal diseases, ACE inhibitors have been shown to decrease protein excretion and morphologic evidence of glomerulosclerosis. The relationship of the decrease in protein excretion to the progression of renal disease has not yet been established.

Acute Kidney Injury↗