Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues.
The mechanisms of the positive inotropic action of a new synthetic tetrahydroisoquinoline compound, SL-1, were investigated in isolated rat cardiac tissues and ventricular myocytes. SL-1 produced a rapidly developing, concentration-dependent positive inotropic response in both atrial and ventricular muscles and a negative chronotropic effect in spontaneously beating right atria. The positive inotropic effect was not prevented by pretreatment with reserpine (3 mg/kg) or the alpha-adrenoceptor antagonist prazosin (1 microM), but was suppressed by either the beta-adrenoceptor antagonist atenolol (3 microM) or the K+ channel blocker 4-aminopyridine (4AP, 1mM). In the whole-cell recording study, SL-1 increased the plateau level and prolonged the action potential duration in a concentration-dependent manner and decreased the maximum upstroke velocity (Vmax) and amplitude of the action potential in isolated rat ventricular myocytes stimulated at 1.0 Hz. On the other hand, SL-1 had little effect on the resting membrane potential, although it caused a slight decrease at higher concentrations. Voltage clamp experiments revealed that the increase of action potential plateau and prolongation of action potential duration were associated with an increase of Ca2+ inward current (ICa) via the activation of beta-adrenoceptors and a prominent inhibition of 4AP-sensitive transient outward K+ current (Ito) with an IC50 of 3.9 microM. Currents through the inward rectifier K+ channel (IK1) were also reduced. The inhibition of Ito is characterized by a reduction in peak amplitude and a marked acceleration of current decay but without changes on the voltage dependence of steady-state inactivation. In addition to the inhibition of K+ currents, SL-1 also inhibited the Na+ inward current (INa) with an IC50 of 5.4 microM, which was correlated with the decrease of Vmax. We conclude that the positive inotropic effect of SL-1 may be due to an increase in Ca2+ current mediated via partial activation of beta-adrenoceptors and an inhibition of K+ outward currents and the subsequent prolongation of action potentials.
Chang
G J
GJ
Pharmacological Institute, College of Medicine, National Taiwan University.
SU
M J
MJ
Lee
P H
PH
Lee
S S
SS
Liu
K C
KC
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D051381:Rats; D011921:Rats, Inbred WKY; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines
C102858:1-(3'-hydroxyphenyl)-6,7-dimethoxy-N-methyltetrahydroisoquinoline; D015220:Calcium Channels; D002316:Cardiotonic Agents; D007546:Isoquinolines; D015222:Sodium Channels; D044005:Tetrahydroisoquinolines