digoxin and rilmakalim

The aim of this study was to examine the influence of pre-treatment with rimalkalim (formerly HOE 234), an activator of ATP-sensitive K+ channels (KATP), on the chronotropic, inotropic and electrophysiological effects of digoxin in the guinea pig heart. To study these effects we used spontaneously beating right atria and isolated papillary muscles from the guinea pig heart. The following parameters were measured: the heart rate (b.p.m.), force of contraction (Fc), rate of rise (+dF/dt) and rate of fall (-dF/dt) of force of contraction, time to peak contraction (ttp) and time to 10% of total amplitude of force (tt10), action potential (RP, APA, APD, Vmax) and effective refractory period (ERP). Apart from the positive inotropic effect, digoxin induced negative chronotropic action at the concentration of 30 microM. Digoxin also significantly decreased APD50 and APD90 duration and reduced APA and RP. Rimalkalim itself, has similar electrophysiological and chronotropic effects to digoxin, but opposite to digoxin, a negative inotropic action and hyperpolarisation of the isolated tissue. After pre-treatment with rimalkalim (1 microM), the significant potentiation of maximum positive inotropic effect (Emax) of digoxin has been observed, as well as a significant shortening of the duration of ttp, tt10 and ERP when compared with the values obtained with digoxin alone. Furthermore, a significant increase in Vmax occurred, compared to the value obtained with rimalkalim. Glibenclamide (1 microM), a selective inhibitor of ATP-sensitive K+ channels, added to rimalkalim, prevented the changes in digoxin action observed after pre-treatment with rimalkalim. The results demonstrate significant influence of pre-treatment with rimalkalim on digoxin-induced inotropic and electrophysiological effects in the guinea pig heart. An abolishing action of glibenclamide on this effect of rimalkalim suggests that an activation of ATP-sensitive K+ channels might cause these changes.

Topics: Animals; Cardiotonic Agents; Chromans; Digoxin; Drug Interactions; Female; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Potassium Channels; Pyrrolidines; Stimulation, Chemical