Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157

J Cardiovasc Pharmacol. 1993 Apr;21(4):595-9. doi: 10.1097/00005344-199304000-00013.


The objective was to determine if the benzothiazepine compound CGP-37157 selectively inhibits the Na(+)-Ca2+ exchanger of cardiac mitochondria without affecting the L-type voltage-dependent calcium channel, the Na(+)-Ca2+ exchanger, or the Na(+)-K(+)-ATPase of the cardiac sarcolemma, or the Ca(2+)-ATPase of the cardiac sarcoplasmic reticulum. Mitochondrial Na(+)-Ca2+ exchange activity was determined by monitoring intramitochondrial free [Ca2+] in isolated heart mitochondria loaded with the Ca(2+)-sensitive fluorophore fura-2. CGP-37157 inhibited the activity of mitochondrial Na(+)-Ca2+ exchange in a dose-dependent manner (IC50 0.36 microM). Calcium currents were recorded by whole-cell voltage clamp in isolated neonatal ventricular myocytes. Diltiazem was able to block the recorded current completely, thus confirming the current to be exclusively L-type. CGP-37157 had no effect on the calcium current recorded under identical conditions. CGP-37157, at concentrations < or = 10 microM, had no effect on the activities of the Na(+)-Ca2+ exchanger and Na(+)-K(+)-ATPase in isolated cardiac sarcolemmal vesicles or on activity of the Ca(2+)-ATPase in isolated cardiac sarcoplasmic reticulum vesicles. The data suggest that CGP-37157 is a potent, selective, and specific inhibitor of mitochondrial Na(+)-Ca2+ exchange at concentrations < or = 10 microM.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Clonazepam / analogs & derivatives*
  • Clonazepam / pharmacology
  • Diltiazem / pharmacology
  • Male
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Rabbits
  • Sodium / metabolism*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Thiazepines / pharmacology*


  • Thiazepines
  • Clonazepam
  • CGP 37157
  • Sodium
  • Sodium-Potassium-Exchanging ATPase
  • Diltiazem
  • Calcium