INOTROPIC AND ELECTROPHYSIOLOGICAL EFFECTS OF BDF-9148, A CONGENER OF DPI-201-106, IN GUINEA-PIG ATRIA AND PAPILLARY-MUSCLES

1 BDF 9148 is a newly synthesized congener of DPI 201-106 in which the piperazidinyl moiety has been replaced by an azetidine-3-oxy-moiety. The inotropic effect of both drugs was studied as well as their influence on the action potential, by use of standard microelectrode techniques. 2 BDF 9148 increased the contractile force of guinea-pig atria and papillary muscles. The EC50 was 1.32 x 10(-7) mol l-1 and 0.7 x 10(-6) mol l-1 respectively. DPI 201-106 was effective in a similar concentration-range, the EC50 being 2.6 x 10(-7) mol l-1 for atria and 2.8 x 10(-7) mol l-1 for papillary muscles. 3 Both drugs caused a concentration-dependent prolongation of the relaxation time of the isometric contraction curve. With 10(-6) mol l-1 BDF 9148, the mean increase was 39.1 +/- 4.4 ms in atria and 39.4 +/- 7.5 ms in papillary muscles while 10(-6) mol l-1 DPI 201-106 caused increases of 56.7 +/- 2.5 ms and 79.3 +/- 11.7 ms, respectively. The effect of BDF 9148 was not prevented by propranolol, but was reversed by 3 x 10(-6) mol l-1 tetrodotoxin. Pretreatment of atria with 3 x 10(-8) mol l-1 BDF shifted the concentration-response curve of ouabain to the left and reduced the EC50 of the glycoside from 3.21 x 10(-7) mol l-1 to 2 x 10(-7) mol l-1. 4 BDF 9148 and DPI 201-106 concentration-dependently increased the action potential duration of papillary muscles and their functional refractory period. The drugs did not modify the resting potential, the action potential amplitude or the maximum depolarization velocity. 5 All effects of BDF 9148 persisted after washout. The lipophilic drug accumulated in the tissues and the tissue drug concentration was little reduced by washout of BDF 9148 from the organ bath. 6 In contrast to DPI 201-106, which had a prominent negative chronotropic effect in right atria, BDF 9148 caused only a slight reduction of the beating frequency with the largest (3 x 10(-5) mol l-1) concentration. 7 The results are consistent with BDF 9148 being a sodium channel activator with much weaker influence on the beating frequency than the parent compound DPI 201-106.