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.
Mellemkjaer
S
S
Department of Pharmacology, University of Aarhus, Denmark.
Nielsen-Kudsk
F
F
D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim; D003864:Depression, Chemical; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007551:Isotonic Contraction / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology*
D001578:Benzopyrans; D011758:Pyrroles; D019806:Cromakalim