Inhibitory effects of the antiestrogen agent clomiphene on cardiac sarcolemmal anionic and cationic currents.
The aim of this study was to determine the effects of the antiestrogen agent clomiphene on cardiac anionic and cationic sarcolemmal ion channels. Whole-cell recordings were made from rat and guinea pig ventricular myocytes. Clomiphene inhibited the volume-regulated chloride current [I(Cl,vol), activated by cell swelling after hypotonic shock (approximately 145 mOsM)] with an IC(50) value of approximately 9.4 microM. In contrast, at concentrations up to 100 microM, clomiphene failed to inhibit both the chloride current activated by cyclic AMP (I(Cl,cAMP)) and the anionic background current (I(AB)). At 10 microM, clomiphene blocked the voltage-gated fast sodium current and the L-type calcium current (I(Ca,L)) in both species. The voltage-independent fractional block of I(Ca,L) induced by clomiphene (10 microM) was approximately 82%, this concentration also inhibited the inwardly rectifying K(+) current with a fractional current block of approximately 26% at -90 mV. Fractional block of outward current at +70 mV in rat was approximately 25%, implying that delayed rectifying K(+) channels were also affected by clomiphene. We conclude that clomiphene shows selectivity for I(Cl,vol) over I(Cl,cAMP) and I(AB) and therefore represents a useful tool for studying chloride conductances in isolated ventricular myocytes with interfering currents blocked. However, due to its effects on cation conductances it would be of little value in this regard for other types of in vitro or in vivo experiments.
Borg
John J
JJ
Department of Pharmacology, School of Medical Sciences, University of Bristol, United Kingdom.
Yuill
Kathryn H
KH
Hancox
Jules C
JC
Spencer
Ian C
IC
Kozlowski
Roland Z
RZ
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D002996:Clomiphene / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology
D018118:Chloride Channels; D020847:Estrogen Receptor Modulators; D007473:Ion Channels; D015221:Potassium Channels; D015222:Sodium Channels; D002996:Clomiphene