Dynamic effects and pharmacokinetics of lemakalim in the isolated guinea-pig heart

Myocardial effects of lemakalim were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation and disposition showed two-compartment characteristics with phasic half-times of about 0.27 and 2.1 min., respectively. Myocardial clearance was 6.8 ml min.-1, and myocardial drug accumulation was 5-fold. Dynamic parameters were studied during increasing lemakalim concentrations from 1.4 nM up to 10 microM. Dynamic steady-states developed within 3-4 min. Increase of coronary flowrate showed an Emax of 185% with an EC50 of 60 nM. Lemakalim produced biphasic inhibitory actions on contraction velocity and amplitude. Emax and EC50 for the two phases were: 48% and 47% and 100 nM and 65 nM, respectively, for the first phase and 100% in both cases and 1.7 microM and 1.6 microM for the second phase. Heart frequency increased to a maximum of 15% above baseline at 0.3 microM. Oxygen consumption increased progressively at concentrations above 7 nM and reached a maximum of 175% at 0.3 microM. The frequency-corrected QT-interval was biphasically shortened to a maximal extent of 30% at the highest concentration. Myocardial efficiency expressed as the ratio of amplitude times frequency to oxygen consumption exhibited a progressive decline to about 20% of control values. PQ- and QRS-intervals showed only minor or no changes, respectively. No arrythmogenic effects were observed. The study demonstrated a rapid and very moderate accumulation of lemakalim in the guinea-pig heart accompanied by a marked increase in coronary flowrate and a progressive negative inotropic effect followed by reduced myocardial efficiency.