Calcium channels in cerebral arteries.

Electrophysiological evidence shows the existence of voltage-operated Ca2+ channels of the L- and, in some cases, T- and B-, type in the smooth muscle cells of major cerebral arteries and arterioles. Current intensity through L-type Ca2+ channels is higher in cerebral than in peripheral arteries, which points to a greater dependence on extracellular Ca2+ of contractile responses in cerebral arteries. The increase in cytosolic Ca2+ concentration is the key event leading both to maintenance of basal cerebrovascular tone and to contraction of cerebral arteries in response to depolarization and agonist-receptor interaction. Such an increase results from increased transmembrane influx of Ca2+ through L-type Ca2+ channels, as well as from the release of Ca2+ from intracellular Ca2+ stores. Ca2+ entry modulators (dihydropyridines, phenylalkylamines, benzothiazepines, and diphenylpiperazines) bind to allosterically coupled sites in the Ca2+ channel, thus inhibiting (Ca2+ entry blockers) or stimulating (Ca2+ entry activators) Ca2+ influx and, therefore, contractile responses of the cerebral arteries. In vivo, Ca2+ entry blockers increase pial vascular caliber and cerebral blood flow by their direct action on the cerebroarterial wall. However, such an action also takes place on several peripheral vascular beds, which leads to hypotension. Therefore, the brain cannot be considered a "privileged" organ when the vasodilatatory action of Ca2+ entry blockers is considered. Since increased cytosolic Ca2+ concentration (and, therefore, activation of Ca2+ channels) plays a crucial role in the pathogenesis of ischemic brain damage (e.g., acute stroke and subarachnoid hemorrhage), Ca2+ entry blockers could be useful cytoprotective drugs. However, with the exception of nimodipine in the management of subarachnoid hemorrhage, clinical trials have yielded results that are not so promising as one could expect from those obtained in experimental research.