Isradipine dynamics and pharmacokinetics in the isolated rabbit heart.
The cardiac effects of increasing concentrations of isradipine (racemic) from 1.64 pM to 232 nM were studied in isolated spontaneously beating rabbit hearts. Inhibitory responses with regard to contraction amplitude, contraction velocity and oxygen consumption exhibited a biphasic progressive course at increasing drug exposure. Computer derived inhibitory Emax-values of the second phase were 104, 103 and 87% (IC50: 7.1, 6.3 and 28.7 nM), respectively, whereas those of the initial phase were 24.7, 25.9 and 19.5% (IC50: 0.012, 0.038 and 0.026 nM). A progressive inhibition of frequency reached a maximum of only 21%. The ECG-derived PQ-interval showed a rapid increase (maximum 46%) at drug concentrations above 1 nM. Complete AV-block and ventricular asystolia occurred in half of the hearts at the second highest (99 nM) and in all except one at the highest concentration. SA-node activity was retained in 9 of 10 hearts at the second highest and in 3 at the highest drug exposure. The QRS-and the frequency-corrected QT-interval did not increase significantly. Coronary flow-rate showed no initial increase, but a decrease to 70% of control at the highest concentration. Supplementary in vitro studies on rabbit coronary artery ring-preparations contracted with 124 mM K+ showed, however, an relaxant Emax-value for isradipine of about 100% and an inhibitory EC50-value of 0.63 nM with a 'Hill' coefficient of 1.1. At toxic concentrations isradipine showed a kinetic monophasic accumulation in the rabbit heart of about 44-fold with a half-time of 10.6 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Mellemkjaer
S
S
Institute of Pharmacology, University of Aarhus, Denmark.
Bang
L
L
Nielsen-Kudsk
F
F
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D017275:Isradipine