Ca2+-agonistic effect of a T-type Ca-channel blocker mibefradil (Ro 40-5967).
Here we report that a Ca2+ antagonist mibefradil (Ro 40-5967) which has been shown to be a selective inhibitor of T-type calcium channels increases free calcium concentration ([Ca2+]i) in the cytoplasm of cultured smooth muscle cells isolated from porcine coronary artery. Smooth muscle cells were loaded with Fura 2 and a videoimage system was used to follow the [Ca2+]i responses. It was shown that at a concentration of 1 nM mibefradil induced a transient [Ca2+]i elevation in individual cells and at a concentration of 100 nM this compound stimulated almost all the cells in monolayer. The [Ca2+]i response did not change with the further increase of the mibefradil concentration up to 10 microM. The half-maximal effect was observed at 10 nM. The increase in [Ca2+]i strongly depended on the presence of Ca in the extracellular medium. Calcium antagonists belonging to three different classes--verapamil (phenylalkylamines), diltiazem (benzothiazepines) and amlodipin (dihydropyridines) neither suppressed the mibefradil effect nor mimicked it. These data indicate that mibefradil increased [Ca2+]i acting via a distinct receptor site. We suggest that these receptors are coupled to calcium channels of plasma membrane.
Avdonin
P V
PV
Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow. avdonin@orc.ru
Buhler
F R
FR
Tkachuk
V A
VA
D017311:Amlodipine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000819:agonists / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000502:physiology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D004110:Diltiazem / Q000378:metabolism / Q000494:pharmacology; D020748:Mibefradil / Q000378:metabolism* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D013552:Swine; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D017311:Amlodipine; D020748:Mibefradil; D014700:Verapamil; D004110:Diltiazem; D002118:Calcium