Pharmacokinetics and dynamic effects of diltiazem in the isolated guinea-pig heart.
Myocardial pharmacokinetics of diltiazem showed two-compartment characteristics in the isolated, spontaneously beating guinea-pig heart. Half-times of initial and terminal drug accumulation phases were about 2.1 and 14.4 min., respectively. At 1 microgram ml-1 (2.4 microM) in the perfusion liquid the average concentration of diltiazem in the myocardium at steady state was about 16 micrograms g-1 (38.6 microM) with 17% referable to the deepest, possibly intracellular compartment. Increasing diltiazem concentrations from 13 to 889 ng ml-1 (31-2144 nM) produced a progressive increase in coronary flowrate from 100 to 174%. The computed Em- and EC50-values were 73.2% and 187 nM, respectively. Oxygen consumption decreased to 27.6% showing Em = 106% and IC50 = 1536 nM. Amplitude and velocity of myocardial contraction decreased to about 6% and 2%; Em = 101% and 104%, IC50 = 266 and 186 nM, respectively. Heart beating frequency decreased to 63% exhibiting Em = 58% and IC50 = 2015 nM. The PQ- and QRS-intervals increased to 133% and 112%, respectively. The frequency-corrected QT-interval decreased to 81.6%. Our findings demonstrate a relatively rapid and moderate accumulation of diltiazem in the guinea-pig heart accompanied by a marked increase in coronary flow, progressive and pronounced negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption.
Jensen
H K
HK
Institute of Pharmacology, University of Aarhus, Denmark.
Nielsen-Kudsk
F
F
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004110:Diltiazem / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects
D004110:Diltiazem