The role of sodium channels in the effects of the cardiotonic compound DPI 201-106 on contractility and membrane potentials in isolated mammalian heart preparations.
The novel compound DPI 201-106 (4-3-(4-diphenyl-methyl-1-piperazinyl)-2-hydroxypropoxy-1H-indole-carbon itrile) prolonged the action potential duration (APD) and enhanced force of contraction in isolated papillary muscles of the guinea-pig. The effective concentration range was 0.1-3 mumol/l. These effects persisted upon removal of the compound, even after extensive washings. Both prolongation of APD and the positive inotropic effect were readily reversed or prevented after exposure to tetrodotoxin, 3 mumol/l. Slow action potentials of partially depolarized preparations in high potassium solution were hardly influenced by DPI 201-106 (1 mumol/l) or were depressed (3 mumol/l). In isolated myocytes DPI 201-106 induced a slowly decaying net inward current, that disappeared again after exposure to tetrodotoxin. With the exception of the lack of reversibility by washing, these effects were similar to the ones reported previously for the Anemonia sulcata polypeptide ATX II. ATX II and DPI 201-106 did not affect the post-rest contraction. The biphasic response in APD after a transient interruption of stimulation was accentuated by ATX II and became monophasic with DPI 201-106. It is concluded that the effects of DPI 201-106 are also mediated by an interaction with the Na channels, but DPI 201-106 and ATX II probably affect the channels in a different manner.
Buggisch
D
D
Isenberg
G
G
Ravens
U
U
Scholtysik
G
G
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003064:Cnidarian Venoms / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*
D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D007473:Ion Channels; D010879:Piperazines; C028800:toxin II (Anemonia sulcata); C046261:DPI 201-106