Bepridil, myocardial accumulation kinetics and dynamic effects in the isolated rabbit heart.
Both myocardial uptake and disposition of bepridil in the isolated rabbit heart showed two-compartment characteristics which possibly reflects the existence of superficial and deep binding sites. Terminal accumulation and disposition half-lives were 218 and 196 min., respectively. The half-times of the initial distributory processes were about 33 min. At a drug concentration in the perfusion liquid of 0.54 micrograms ml-1 (1.27 microM) the average concentration of bepridil in the myocardium at steady state was about 489 micrograms g-1 (1161 microM) with 43% referable to the deepest, presumably intracellular compartment. Increasing bepridil concentrations from 3 to 2333 ng ml-1 (7-5542 nM) in the perfusion liquid caused a terminal decrease in coronary flowrate to 58% of the mean control flowrate. Amplitude and velocity of myocardial contraction both decreased in a biphasic way to about 28.6 and 13.6%, respectively. Apparent dynamic steady states developed within about 20 min. Inhibitory Em-values related to the first phase were 39.8 and 53.2%, and to the second phase 97.7 and 98.5%, respectively. Heart beating frequency also decreased biphasically to 53.9% and showed inhibitory Em-values of 17.2 and 47.5% related to the two phases. Myocardial oxygen consumption decreased to 55.6%. The electrocardiographic PQ- and QRS-intervals increased to 147 and 133%, respectively. The frequency-corrected QT-interval also increased significantly from 100 to 123%. Our findings demonstrate a slow and very pronounced accumulation of bepridil in the rabbit heart. Biphasic and very marked negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption developed much faster.(ABSTRACT TRUNCATED AT 250 WORDS)
Nielsen-Kudsk
F
F
Institute of Pharmacology, University of Aarhus, Denmark.
Askholt
J
J
Jakobsen
P
P
D000818:Animals; D015764:Bepridil; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits
D002121:Calcium Channel Blockers; D011759:Pyrrolidines; D015764:Bepridil