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(Circulation Research. 2000;86:628.)
© 2000 American Heart Association, Inc.

Cellular Biology

T-Type and Tetrodotoxin-Sensitive Ca²⁺ Currents Coexist in Guinea Pig Ventricular Myocytes and Are Both Blocked by Mibefradil

Jürgen F. Heubach, Arndt Köhler, Erich Wettwer, Ursula Ravens

From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Correspondence to Prof Dr Ursula Ravens, Institut für Pharmakologie und Toxikologie, Universitätsklinikum der TU Dresden, Karl-Marx-Str. 3, D-01109 Dresden, Germany. E-mail ravens{at}rcs.urz.tu-dresden.de

Abstract—Under Na⁺-free conditions, low-voltage–activated Ca²⁺ currents in cardiomyocytes from various species have been described either as Ni²⁺-sensitive T-type Ca²⁺ current (I_Ca(T)) or as tetrodotoxin (TTX)-sensitive Ca²⁺ current (I_Ca(TTX)). So far, coexistence of the 2 currents within the same type of myocyte has never been reported. We describe experimental conditions under which I_Ca(T) and I_Ca(TTX) can be separated and studied in the same cell. Rat and guinea pig ventricular myocytes were investigated with the whole-cell voltage-clamp technique in Na⁺-free solutions. Whereas rat myocytes lack I_Ca(T) and exhibit I_Ca(TTX) only, guinea pig myocytes possess both of these low-voltage–activated Ca²⁺ currents, which are separated pharmacologically by superfusion with TTX or Ni²⁺. I_Ca(T) and I_Ca(TTX) were of similar amplitude but significantly differed in their electrophysiological properties: I_Ca(TTX) activated at more negative potentials than did I_Ca(T), the potential for half-maximum steady-state inactivation was more negative, and current deactivation and recovery from inactivation were faster. I_Ca(TTX) but not I_Ca(T) increased after membrane rupture ("run-up"). Isolation of I_Ca(TTX) by application of the bivalent cation Ni²⁺ is critical because of possible shifts in voltage dependence. Therefore, we investigated whether the T-type Ca²⁺ channel blocker mibefradil (10 µmol/L) is a suitable tool for the study of I_Ca(TTX). However, mibefradil not only blocked I_Ca(T) by 85±2% but also decreased I_Ca(TTX) by 48±8%. We conclude that under Na⁺-free conditions I_Ca(T) and I_Ca(TTX) coexist in guinea pig ventricular myocytes and that both currents are sensitive to mibefradil. Future investigations of I_Ca(T) will have to consider the TTX-sensitive current component to avoid possible interference.

Key Words: T-type Ca²⁺ currents • tetrodotoxin-sensitive Ca²⁺ currents • guinea pig ventricular myocytes • mibefradil

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