Abstract:The myocardial accumulation of pinacidil showed one‐compartment characteristics with a half‐time of 1.11 min., whereas the disposition followed three‐compartment kinetics with half‐times for the relevant two redistributory and the terminal phases of 0.39, 1.51 and 5.44 min., respectively. At a steady‐state drug concentration in the perfusate of 6.12 nmol ml−1, the average concentration of pinacidil in the myocardium was 20.6 nmol g−1. The accumulated amount could predictically be referred with 57% to a central and 31 and 12% to two peripheral (deeper) drug pools. The pharmacodynamic effects of pinacidil in the isolated perfused rabbit heart were studied at stepwise increasing concentrations from 0.15 to 100 μM. Coronary flowrate increased initially up to 24.5% at 1.5 μM pinacidil and then gradually decreased. Amplitude and velocity of contraction were both inhibited in a biphasic way up to 92.7 and 94.1%, respectively. Apparent dynamic steady states developed within 13–15 min. The computer‐derived inhibitory Em‐values related to the first phase were 49.2 and 52.4% and those related to the second phase were 111.7 and 108.3%, respectively. Heart frequency decreased monophasically and exhibited an inhibitory Em‐value of 19.6%. Oxygen consumption decreased at pinacidil concentrations higher than 15 μM and the Em‐value was 69.7%. The frequency‐corrected QT‐interval decreased biphasically and the related inhibitory Em‐values were 8.6 and 58.7%. The QRS‐interval did not change and the PQ‐interval only showed a minor increase at the highest pinacidil concentration. Our findings are compatible with the concept of pinaci