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Actions of the anti‐oestrogen agent clomiphene on outward K + currents in rat ventricular myocytes
Author(s) -
Borg John J,
Hancox Jules C,
Hogg Dayle S,
James Andrew F,
Kozlowski Roland Z
Publication year - 2004
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2004.03956.x
Subject(s) - extracellular , medicine , chemistry , intracellular , endocrinology , myocyte , patch clamp , voltage clamp , pulse (music) , electrophysiology , steady state (chemistry) , biophysics , biology , physics , voltage , biochemistry , quantum mechanics
Summary 1. The effects of clomiphene (CLM) on cardiac outward K + current components from rat isolated ventricular myocytes were investigated using the whole‐cell patch‐clamp technique. Clomiphene (10 µmol/L) significantly inhibited both peak (I peak ) and end‐pulse (I late ) outward currents (elicited by a 500 msec voltage step from −40 to +50 mV in the presence of K + ‐containing intracellular and extracellular solutions) by approximately 37% ( n = 6; P < 0.01) and 49% ( n = 6; P < 0.01), respectively. In contrast, CLM had no effect on outward currents when K + ‐free solutions were used. 2. A double‐pulse protocol and Boltzmann fitting were used to separate individual K + current components on the basis of their voltage‐dependent inactivation properties. At potentials positive to −80 mV, two inactivating transient outward components (I to ) and (I Kx ) and a non‐inactivating steady state component (I ss ) could be distinguished. 3. Clomiphene inhibited both I to and I ss . The maximal block of I to and I ss induced by CLM (100 µmol/L) was approximately 61% ( n = 5) and 43% ( n = 5) with IC 50 values of 1.54 ± 0.39 and 2.2 ± 0.4 µmol/L, respectively. In contrast, the peak magnitude of I Kx was unaltered by CLM, although its time‐course of inactivation was accelerated. 4. Further experiments whereby myocytes were superfused with the vasoactive peptide endothelin (ET)‐1 (20 nmol/L) revealed that CLM (10 µmol/L) completely abolished the ET‐1‐sensitive component of I ss . 5. Our findings demonstrate, for the first time, the effects of CLM on distinct cardiac K + current components and show that CLM modulates the voltage‐gated K + current components I to and I Kx and inhibits the steady state outward current I ss in rat ventricular myocytes.