There are several subtypes of voltage-dependent blockers of calcium influx which modulate the L-type channel, i.e. one with relatively long (L) opening times. These subtypes include the widely recognized phenylalkylamines typified by verapamil, the benzothiazepines typified by diltiazem, the diphenylpiperazines typified by flunarizine, and the 1,4-dihydropyridines typified by nifedipine, nimodipine, isradipine, amlodipine, nicardipine, and nitrendipine. Remarkably, even though these agents all potently bind to this voltage-dependent calcium channel and act to inhibit calcium influx, their biochemical and physiological effects are very different ( Table 1.).
Verapamil and the phenylalkylamines are charged and gain access to the inside of the calcium channel less readily than most of the dihydropyridines which are uncharged (except amlodipine). These different membrane properties and binding characteristics result in a profile of effects for the dihydropyridines compared with the phenylalkylamines, including the following: increased lipid solubility; anticonvulsant effects on kindling and hyperfusion models and clinical seizures; the ability to block cocaine hyperactivity; behavioural sensitization, and its associated dopamine overflow in the nucleus accumbens (whereas verapamil is inactive); positive effects in two animal models of depression (including the forced swim test and learned helplessness model); decreased glycine inhibition of 3H-5,7-dichlorokynurenic acid binding similar to that of other antidepressant modalities; and, possibly, a different effectiveness on mood in some bipolar patients.
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