Xiao-Zhou Yao
Dr.med.
Differential Effects of d,l-Sotalol and d-Sotalol on Isoproterenol-Increased Delayed
Rectifier Outward Potassium Current in Guinea Pig Single Ventricular Myocytes.
Influence of Temperature
Geboren am 17. Oktober 1962
Reifeprüfung am 07.-09. Juli 1980
Studiengang der Fachrichtung Medizin vom WS 1980 bis SS 1985
Klinisches Studium in Hebei, Volksrepublik China
Praktisches Jahr in Hebei, Volksrepublik China
Magisterarbeit vom September 1991 bis August 1993
Abschlußexamen am 06.-08. September 1993
Promotionsfach: Innere Medizin
Doktorvater: Professor Dr. med. Johannes Brachmann
In this study we compared the effects of d,l-sotalol and d-sotalol on the delayed rectifier
outward potassium current ( IK ) in the absence and presence of isoproterenol in isolated
guinea pig single ventricular myocytes. We also studied the modulation of the preventive
activities of d,l-sotalol on the isoproterenol-induced increase of IK by different temperatures.
Electrophysiological effects were studied using the whole-cell configuration of the patch-
clamp technique.
Time-dependent delayed rectifier K+ currents IK ( IKr and IKs ) were measured in response to
300 ms ( a time to mimic the cardiac action potential ) depolarizing pulses from a holding
potential of -40 mV in three experimental protocols [control, isoproterenol ( 10-9 -10-6 M ),
and isoproterenol ( 10-9-10-6 M ) plus either d,l-sotalol ( 10-4 M ) or d-sotalol ( 10-4 M )]. IK tail
currents were measured upon repolarization to -40 mV. The experiments were carried out at
approximately 37oC. To study the effect of temperature on IK , the temperature of the bath
solution was varied between 22oC and 37oC.
The magnitude of the IK current increased with the flow rate of the perfusion solution. Thus,
we chose a constant flow rate ( 1.5 ml/min ) during all the experiments. Isoproterenol
significantly increased IK and IK tail in a concentration- and temperature-dependent manner. At
37oC, IK was significantly amplified in the presence of isoproterenol ( 10-9 - 10-6 M ) plus d-
sotalol ( 10-4 M ). At 10-8 M isoproterenol, IK was increased by 92.7±17.1 % before and
54.3±13.4 % after d-sotalol ( P < 0.05 ). In contrast, d,l-sotalol strongly suppressed the effect
of isoproterenol on IK, and compared to control, IK was decreased by 35.6±8.1% at 10-8 M
isoproterenol ( P < 0.05 ). At 10-6 M isoproterenol, d,l-sotalol prevented partially the
isoproterenol-induced increase of IK. But at a temperature of 22oC, d,l-sotalol ( 10-4 M )
counteracted completely the increase of IK by 10-6 M isoproterenol and in comparison with the
control, IK was decreased by 30.6±6.7 % ( P < 0.05 ).
We conclude that the β-adrenergic blocking property of d,l-sotalol, but not of d-sotalol
maintains the delayed rectifier K+ outward current block in the presence of isoproterenol in
guinea pig myocytes. This may result in a superior antiarrhythmic efficacy compared to
d-sotalol. This effect of d,l-sotalol in the presence of isoproterenol results from its β-
adrenergic blocking properties, its contribution on IKs and its class III contribution on IKr. The
effect of isoproterenol on IK is also temperature-dependent. The temperature shifts the
preventive activities of d,l-sotalol on the isoproterenol-induced enhancement of IK toward low
values reducing its efficacy in patients with increased body temperature.
