Calcium channel blockers and dementia

Degenerative dementia is mainly caused by Alzheimer''s disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer''s disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available.     

钙通道阻滞药与心肌顿抑

心肌顿抑是指短暂缺血后可逆性心肌收缩功能异常 ,是再灌注损伤的一种形式 ,临床上常出现该现象。钙通道阻滞药是心血管疾病常用药物 ,目前大量研究证明可以抑制心肌顿抑。本文综述了钙通道阻滞药治疗心肌顿抑的实验证据、理论基础以及在临床心肌顿抑中的应用等问题     

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.     

Calcium channel blockers in cerebral ischaemia

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

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.     

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.     

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.     

Effect of calcium channel blockers on baroreceptor reflex in anaesthetized cats.

The baroreflex-induced changes in heart rate in chloralose anaesthetized and artificially ventilated cats (2.5-4.0 kg) before and after pretreatment with calcium channel blockers (CCBs) were compared. Baroreflex mediated changes in heart rate (HR) were elicited by raising and lowering the systemic blood pressure with intravenous injections of phenylephrine and sodium nitroprusside, respectively. The effects of three CCBs, verapamil, diltiazem and nifedipine administered either intravenously (i.v.) or intracisternally (i.c.) were studied. Verapamil administration markedly inhibited the reflex bradycardia as well as the tachycardia following either i.v. or i.c. administration. Intracisternally, a relatively smaller dose of verapamil produced an effect comparable in magnitude and duration, to a higher i.v. dose. The reflex bradycardia was inhibited following i.v., but not i.c. administration of nifedipine while the reflex tachycardia was not affected significantly by either i.v. or i.c. nifedipine. Intravenous diltiazem did not appear to affect the reflex bradycardia or tachycardia significantly. It is suggested that verapamil administration interacts with central cardiovascular integrating mechanisms to reduce the gain of the baroreflex function. Nifedipine and diltiazem are relatively free from this effect.     

Calcium channel blockers: effect on morphine-induced hypermotility

Acute morphine treatment has been shown to cause a uniform calcium depletion in various brain regions and to evoke hypermotility in mice. On the other hand, it has been reported previously that calcium channel blockers reduce the behavioral stimulation induced by different methods in mice, and it is known that these drugs increase the morphine analgesia and reduce the abstinence syndrome. The effect of calcium channel blockers, nifedipine and diltiazem, on the morphine- and amphetamine-induced hypermotility were evaluated. Mice activity was measured with photocell motility meters. The results show that neither nifedipine nor diltiazem decrease significantly the motility in control and amphetamine-treated mice; however, when they were administered to morphine-treated mice the hypermotility was significantly reduced. The mechanism responsible for this interference is still unknown.     

Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room

Calcium channel blockers and beta-blockers intoxications account for up to 65% of deaths for cardiovascular drugs, causing severe clinical symptoms refractory to standard medications. The most serious poisonings are those resulting from verapamil and propanolol ingestion. Both support and antidotic therapy are necessary for these potentially unstable patients. Supportive measures and the use of digoxin-specific antibody fragments are first line treatment for digitalis glycoside poisoning.     

Calcium channel blockers in affective illness: role of sodium-calcium exchange

Available evidence suggests that verapamil and perhaps other calcium channel blockers are effective in treating mania but not unipolar depression. This article briefly reviews the clinical experience and reexamines potential mechanisms. It is proposed that antimanic efficacy is primarily related to inhibition of sodium-calcium counterexchange rather than calcium channel blockade.     

Calcium channel blockers verapamil and diltiazem impaired rubratoxin B-caused toxicity in HL60 cells

The effects of calcium channel blockers (CCBs) verapamil and diltiazem on the toxicity of rubratoxin B in HL60 cells were investigated. Treatment of rubratoxin B caused a considerable rate of blebbing, fragmentation and condensation of cells. The rate of this morphological change was much lower in the concomitant rubratoxin B and CCBs-treated cells than in the cells treated only with rubratoxin B. Cell viability was determined by measuring mitochondrial succinic dehydrogenase activity and the rate of cell proliferation. The results of these assays were of the same tendency as that of the morphological study. CCBs attenuated rubratoxin B's toxicity on cell viability because of their protective action. Rubratoxin B induced apoptosis in the presence of internucleosomal fragmentation. In contrast, concomitant rubratoxin B and CCBs treatment did not. Taken together, the above results indicated that CCBs impaired the toxicity including morphological change, cell viability and apoptosis caused by rubratoxin B.