Death calcium antagonists

Calcium plays a vital role ia excitation—contraction coupling, and failure to maintain iatraceUular calcium homeostasis results ia ceU death. The avaUabUity of the calcium antagonists also provides a powerful tool for basic studies of excitation—contraction coupling, stimulus—excretion coupling, and other specific physiological functions. 

Calcium antagonists can cause serious toxicity or death with relatively small overdoses. These channel blockers depress sinus node automaticity and slow AV node conduction (see Chapter 12). They also reduce cardiac output and blood pressure. Serious hypotension is mainly seen with nifedipine and related dihydropyridines, but in severe overdose all of the listed cardiovascular effects can occur with any of the calcium channel blockers. 

Nimodipine is a calcium antagonist. In this pharmacological class, di-hydropyridines are blockers of voltage-dependent L-type calcium channels. These ion channels facilitate Ca" " ion movement through cell membranes. The channels are found throughout the organism, occur in several types, can interact [122] and are involved in cell death [123], neurocytotoxicity [124] and in the consequences of cell phenomena due to hypoxia/ischaemia, particularly in the brain [125-127]. 

Thus the neurotransmitter role of ATP is well established in the periphary and also in sensory systems but its importance in the CNS remains to be elucidated (see Burnstock 1996). That requires the development of more specific antagonists and methods of mapping its location. The strong linkage of its P2x receptors to calcium currents may also provide a role for ATP in more long-term effects such as plasticity and neuronal development and death. 

Chizh BA, Headley PM, Tzschentke TM (2001) NMDA receptor antagonists as analgesics focus on the NR2B subtype. Trends Pharmacol Sci 22 636-642 Choi DW (1995) Calcium stiU center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 18 58-60... 

Acute intoxication with amphetamine is associated with tremor, confusion, irritability, hallucinations and paranoid behaviour, hypertension, sweating and occasionally cardiac arrhythmias convulsions and death may occur. The cardiovascular effects of the stimulants may be treated by beta-blockers, or by the combined alpha- and beta-blocker labetalol calcium channel antagonists such as nifedipine may correct the arrhythmias, while intravenous diazepam is of value in attenuating seizures. 

Of note, there have also been links between glutamate receptor stimulation and pathology. Excessive stimulation of glutamate receptors can cause seizure and it is hypothesized that NMDA overstimulation can cause neuronal cell death from an excessive influx of calcium. This has led to the development of NMDA antagonists like memantine to treat Alzheimer s Disease. 

I Ca antagonists nimodipine. Final common pathway in cell death is increase in intracellular calcium. Potential use in small vessel dementia. 

Ionotropic glutamate receptors also promote perturbations in ionic homeostasis that play a critical role in cerebral ischemia. For example, L, P/Q, and N-type calcium channel receptors mediate excessive calcium influx, and Ca " channel antagonists reduce ischemic brain injury in preclinical studies [12-14]. Zinc is stored in vesicles of excitatory neurons and coreleased upon depolarization after focal cerebral ischemia, resulting in neuronal death [15, 16]. Recently, imbalances in potassium have also been implicated in ischemic cell death. Compounds that selectively modulate a class of calcium-sensitive high conduc-tance potassium (maxi-K) channels protect brain against stroke in animal models [17]. 

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