title: Inhibition by 5-N-(4-chlorobenzyl)-2',4'-dimethylbenzamil of Na+/Ca2+ exchange and L-type Ca2+ channels in isolated cardiomyocytes.
abstract: The inhibitory effect of the amiloride derivative 5-N-(4-chlorobenzyl)-2',4'-dimethylbenzamil (CBDMB) on calcium (Ca2+) uptake via sarcolemmal sodium-calcium (Na+/Ca2+) exchange and L-type Ca2+ channels was investigated in isolated adult rat ventricular cardiomyocytes under depolarizing conditions in cells preincubated with 1 mM ouabain or 137 mM lithium (Li+), respectively. Fifteen or 120 min. preincubation with CBDMB inhibited Ca2+ uptake via Na+/ Ca2+ exchange in Na(+)-loaded depolarized cells completely at 100 microM with an IC50 of 21 microM. After 120 min. preincubation, CBDMB inhibited Ca2+ uptake via L-type Ca2+ channels by 75.1 +/- 8.1% (mean and S.E.M.) and IC50 of 4 microM, whereas no significant inhibition was observed after 15 min. preincubation. (+)-Isradipine (10 microM) inhibited high potassium (K+) induced Ca2+ uptake via L-type Ca2+ channels by 35% after 15 min. and by 70% after 120 min. preincubation. Inhibition by CBDMB of specific (+)-[3H]isradipine binding to L-type Ca2+ channels showed similar concentration dependency as inhibition of Ca2+ uptake via L-type Ca2+ channels. In conclusion, CBDMB inhibits sarcolemmal Na+/Ca2+ exchange in rat ventricular cardiomyocytes rapidly. However, after longer preincubation periods, L-type Ca2+ channels are inhibited as well and with higher potency than Na+/Ca2+ exchange.
authors.affiliation: Clinical Chemistry Department, Ullevål University Hospital, Oslo, Norway.
authors.forename: M N
authors.initials: MN
authors.lastname: Sharikabad
authors.forename: E J
authors.initials: EJ
authors.lastname: Cragoe
authors.forename: O
authors.initials: O
authors.lastname: Brørs
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects; D017275:Isradipine / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D019831:Sodium-Calcium Exchanger; D014316:Tritium
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D014316:Tritium; C054391:5-(N-4-chlorobenzyl)-N-(2',4'-dimethyl)benzamil; D000584:Amiloride; D002118:Calcium; D017275:Isradipine