The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated. DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10(-7) and 3 X 10(-6) mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 mumol/l respectively. In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 mumol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but Vmax was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer. DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecula septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 dit not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria. In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.
I Guinea-pig ileum suspended in Krebs solution showed a continuous increase of tone which was lost by changing the bath fluid. Prostaglandin E2 was released from the ileum during incubation, and its concentration in the bath fluid appeared to correlate with the increase in tone.2 Supramaximal field stimulation (10 Hz) resulted in increased release of prostaglandin E2 from the ileum. At lower rates of stimulation, the increase in the release of E2 compared with the resting output was not significant. 3 Indomethacin (1 and 10 ,g/ml) produced a significant, dose-related reduction of the amount of prostaglandin E2 measured in the bath fluid at rest and with field stimulation. Indomethacin inhibited the contraction of the ileum during incubation in Krebs solution. 4 Indomethacin (10 and 20,ug/ml) had no significant effect on the release of acetylcholine during field stimulation, but reduced the resting output of acetylcholine-from guinea-pig ileum in some experiments.
5The results are discussed in the context of the role ascribed to prostaglandins as physiological modulators in transmitter release. No evidence for a prostaglandin-mediated negative feedback mechanism on acetylcholine release was obtained.
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