Inhibition of L-type Ca2+ channel by mitochondrial Na+-Ca2+ exchange inhibitor CGP-37157 in rat atrial myocytes.
7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepine-2(3H)-one (CGP-37157) inhibits mitochondrial Na(+)-Ca(2+) exchange. It is often used as an experimental tool for studying the role of the mitochondrial Na(+)-Ca(2+) exchanger in Ca(2+) signaling. Because the selectivity of CGP-37157 in adult cardiomyocytes has not been confirmed, we tested whether CGP-37157 affects the L-type Ca(2+) channel using a whole-cell patch-clamp in adult rat atrial myocytes. We found that CGP-37157 suppressed L-type Ca(2+) current (I(Ca)) with IC(50) of approximately 0.27 microM, without altering the voltage dependence of the current-voltage relationships. CGP-37157 inhibited the Ba(2+) current (I(Ba)) through the Ca(2+) channel with a similar dose-response. The inhibitory effects of CGP-37157 on I(Ca) or I(Ba) were resistant to the intracellular Ca(2+) buffering. Intracellular application of CGP-37157 did not significantly alter I(Ca). The combination of CGP-37157 with known Ca(2+) channel inhibitor diltiazem yielded antagonism consistent with additivity of response. Our data suggest that CGP-37157 directly suppresses the L-type Ca(2+) channel in intact adult cardiomyocytes.
Thu
Le Thi
le T
College of Pharmacy, Chungnam National University, 220 Gungdong, Yuseong-Gu, Daejeon, 305-764, South Korea. shwoo@cnu.ac.kr
Ahn
Joung Real
JR
Woo
Sun-Hee
SH
D000818:Animals; D001464:Barium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D006325:Heart Atria / Q000166:cytology; D007473:Ion Channels / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D001464:Barium; D004533:Egtazic Acid; D002998:Clonazepam; C079032:CGP 37157; D004110:Diltiazem