The inotropic agents DPI 201-106 and BDF 9148 differentially affect potassium currents of guinea-pig ventricular myocytes.
The inotropic agents DPI 201-106 and BDF 9148 increase action potential duration (APD) of heart muscle. This effect can be explained by inhibition of inactivation of sodium current, which is affected by both agents to a similar extent (Ravens et al. 1991, Br J Pharmacol 104:1019-1023). However, as DPI 201-106 prolongs APD of guinea-pig ventricle to a larger extent than BDF 9148, other currents may also be involved. The aim of the present study was to measure the effects of DPI 201-106 and BDF 9148 on the inward rectifier IK1, and the two components of the delayed rectifier, IKs and IKr. The methyl-for-carbonitrile-substituted derivative BDF 8784 was included to study structure-activity relationships. Single-electrode whole-cell voltage-clamp technique was used to measure membrane currents of guinea-pig ventricular myocytes. Only DPI 201-106 reduced IK1 at potentials both negative and positive to the reversal potential. Three microM of DPI 201-106 reduced IKs, whereas 1 microM of BDF 9148 had no effect on this current. These concentrations were equieffective with respect to positive inotropic action (Ravens et al. 1991, Br J Pharmacol 104:1019-1023). BDF 9148 did however block IKs at higher concentrations, as did BDF 8784. It is concluded that block of outward current by DPI 201-106, but insignificant effects of BDF 9148, are responsible for the differential effects of these compounds on APD at equieffective concentrations with respect to inotropy.
Amos
G J
GJ
Institut für Pharmakologie, Universitätsklinikum Essen, Germany.
Ravens
U
U
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001384:Azetidines; D002316:Cardiotonic Agents; D007211:Indoles; D010879:Piperazines; C071117:BDF 9148; C060322:BDF 8784; C046261:DPI 201-106; D011188:Potassium