Stereospecific regulation of [3H]inositol monophosphate accumulation by calcium channel drugs from all three main chemical classes.

Depolarization of [3H]inositol-prelabelled rat cortical slices through the elevation of extracellular K+ levels leads to increased accumulation of [3H]inositol phosphates. In the presence of 18 mM K+, Ca2+ channel activators selectively stimulated the formation of [3H]inositol monophosphate ([3H]IP1) whereas Ca2+ channel blockers were inhibitory. Blockade of the Na+ channel by 1 microM tetrodotoxin had no effect but chelation of extracellular Ca2+ abolished the response. The enantiomers of the benzoxadiazol 1,4-dihydropyridine 202-791 showed opposite stereospecific regulation of [3H]IP1 formation: (+)-(S)-202-791 stimulated (252%; ED50: 88 nM), whereas (-)-(R)-202-791 inhibited (65% inhibition, ED50: 602 nM). The (-) enantiomer of Bay K 8644 was a potent [3H]IP1 stimulator (258%; ED50: 82 nM). While (+)-Bay K 8644 was inactive in the presence of 18 mM K+, it completely inhibited the (-)-Bay K 8644-induced stimulation with a Ki of 103 nM. Representatives of the other two main classes of Ca2+ channel blockers (phenylalkylamines and benzothiazepines) inhibited K+ depolarization-induced and (-)-Bay K 8644 enhanced [3H]IP1 formation in a dose-dependent, stereospecific manner. The results show that Ca2+ channel blockers are efficient modulators of depolarization-induced and Ca2+ channel activator-induced [3H]inositol monophosphate formation in brain, and demonstrate the functional coupling of three distinct drug receptor sites on neuronal Ca2+ channels.