Dihydropyridines, phenylalkylamines and benzothiazepines block N-, P/Q- 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 (EC50: 1 microM, 4 microM and 40 microM, 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 omega -conotoxin-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 omega -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.
Diochot
S
S
Institut de Biologie, Boulevard Henri IV, F-34060 Montpellier Cedex, France.
Richard
S
S
Baldy-Moulinier
M
M
Nargeot
J
J
Valmier
J
J
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D020867:omega-Agatoxin IVA; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D010455:Peptides; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D009553:Nimodipine; D020866:omega-Conotoxin GVIA; D014700:Verapamil; D004110:Diltiazem; D006719:Homovanillic Acid