Preferential inhibition of Ikr by MCI-154, a putative cardiotonic Ca2+ sensitizer, in guinea pig atrial cells.
OBJECTIVE
To define the electrophysiologic mechanism(s) by which MCI-154, a putative Ca2+ sensitizer, produces a positive inotropic response without a positive chronotropic response, we examined effects of MCI-154 on the action potential of atrial preparations and the membrane currents of atrial myocytes.


METHODS
The action potentias were recorded from left atrial and sinoatrial node preparations of guinea pigs by the use of standard microelectrode techniques. The whole-cell membrane currents were recorded from enzymatically-dissociated guinea pig atrial myocytes using conventional patch clamp techniques.


RESULTS
In isolated left atria, MCI-154 increased the developed tension in a concentration-dependent manner. MCI-154 at concentrations of 10 and 100 microM increased the action potential duration (APD) in left atria stimulated at 0.5 Hz. In sinoatrial node preparations MCI-154 at a concentration of 100 microM produced a negative chronotropic response and prolonged APD. In single right atrial myocytes, MCI-154 at concentrations of 10 and 100 microM failed to increase the inward L-type Ca2+ current, but decreased the delayed rectifier K+ current (IK) in a concentration-dependent manner. MCI-154 decreased IK elicited by short depolarizing pulses more markedly than that induced by long depolarizing pulses. In addition, MCI-154 produced only a little inhibition of IK in the presence of E-4031, a specific blocker of rapidly activating component of IK (IKr).


CONCLUSIONS
MCI-154 preferentially blocks IKr and the inhibitory action on IKr may be partly involved in the negative chronotropic and positive inotropic responses in atrial preparations.
Eto
K
K
Department of Pharmacology, Yamanashi Medical University, Japan.
Hashimoto
K
K
Nakaya
H
H
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D008839:Microelectrodes; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects
D002316:Cardiotonic Agents; D015221:Potassium Channels; D011724:Pyridazines; C052228:MCI 154