DIHYDRAPYRIDINES, PHENYLALKYLAMINES AND BENZOTHIAZEPINES BLOCK N-TYPE, P/Q-TYPE AND R-TYPE CALCIUM CURRENTS

We compared the effects of representative members of three major classes of cardiac L-type channel antagonists, i.e. dihydropyridines (DHPs), phenylalkylamines (PAAs) and benzothiazepines (BTZs) on high-voltage-activated (HVA) Ca2+ channel currents recorded from a holding potential of -100 mV in rat ventricular cells, mouse sensory neurons and rat motoneurons. Nimodipine (DHP), verapamil (PAA) and diltiazem (BTZ) block the cardiac L-type Ca2+ channel current (EC(50): 1 mu M, 4 mu M and 40 mu M, respectively). At these concentrations, the drugs could also inhibit HVA Ca2+ channel currents in both sensory and motor neurons. Large blocking effects (> 50%) could be observed at 2-10 times these concentrations. The toconotoxin-GVIA-sensitive (omega-CTx-GVIA. N-type), omega-agatoxin-IVA-sensitive (omega-Aga-IVA, P- and Q-types) and non-L-type omega-CTx-GVIA-, omega-Aga-IVA-insensitive (R-types) currents accounted for more than 90%, of the global current. Furthermore, our data showed that (CTx-GVIA and omega-Aga-IVA spare L-type currents and have only additive blocking effects on neuronal HVA currents. We conclude that DHPs, PAAs and BTZs have substantial inhibitory effects on neuronal non-L-type Ca2+ channels. Inhibitions occur at concentrations that are not maximally active on cardiac L-type Ca2+ channels.