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 smo oth muscle cells of major cerebral arteries and arterioles. Current in tensity through L-type Ca2+ channels is higher in cerebral than in per ipheral arteries, which points to a greater dependence on extracellula r Ca2+ of contractile responses in cerebral arteries. The increase in cytosolic Ca2+ concentration is the key event leading both to maintena nce of basal cerebrovascular tone and to contraction of cerebral arter ies in response to depolarization and agonist-receptor interaction. Su ch an increase results from increased transmembrane influx of Ca2+ thr ough L-type Ca2+ channels, as well as from the release of Ca2+ from in tracellular Ca2+ stores. Ca2+ entry modulators (dihydropyridines, phen ylalkylamines, benzothiazepines, and diphenylpiperazines) bind to allo sterically coupled sites in the Ca2+ channel, thus inhibiting (Ca2+ en try blockers) or stimulating (Ca2+ entry activators) Ca2+ influx and, therefore, contractile responses of the cerebral arteries. In vivo, Ca 2+ entry blockers increase pial vascular caliber and cerebral blood fl ow by their direct action on the cerebroarterial wall. However, such a n action also takes place on several peripheral vascular beds, which l eads to hypotension. Therefore, the brain cannot be considered a ''pri vileged'' organ when the vasodilatatory action of Ca2+ entry blockers is considered. Since increased cytosolic Ca2+ concentration (and, ther efore, activation of Ca2+ channels) plays a crucial role in the pathog enesis of ischemic brain damage (e.g., acute stroke and subarachnoid h emorrhage), Ca2+ entry blockers could be useful cytoprotective drugs. However, with the exception of nimodipine in the management of subarac hnoid hemorrhage, clinical trials have yielded results that are not so promising as one could expect from those obtained in experimental res earch.