title: Myocardial accumulation kinetics and pharmacodynamics in the isolated rabbit heart of a new inhibitor of dopamine reuptake, GBR 12909.
abstract: Myocardial accumulation of GBR 12909 showed monophasic exponential kinetics with a half-life of 93 min. The disposition followed a three-phasic exponential time-course with half-lives of 1.1, 17 and 98 min., respectively, which was interpreted as three-compartment kinetics. The drug accumulated 430 times in the myocardium at steady-state with 8, 30 and 61% of the drug amount referable to a central, superficial and two deeper myocardial drug pools. GBR 12909 produced concentration dependent (range 0.01 to 12400 nM) biphasic negative inotropic and chronotropic effects. The inhibitory Em-values with regard to contraction velocity were 42 and 105% with corresponding EC50-values of 29 and 688 nM and the related Hill-exponents were 0.6 and 1.1, respectively. Frequency and contraction amplitude related inhibitory Em-values were of similar size. Apparent dynamic steady states developed within about 17 min. Very marked monophasic negative dromotropic effects were observed with computer-derived inhibitory Em-values related to the electrocardiographic PQ- and QRS-intervals exceeding 100%. The frequency-corrected QTc-interval showed an initial increase of 10% but decreased to about 20% below control level at the highest two drug concentrations. Coronary flow-rate increased about 30% and then gradually decreased to near the control value. Oxygen consumption only decreased at the three highest concentrations. Our findings seem compatible with the view that GBR 12909 may possibly act in the myocardium as a membrane-stabilizer which causes inhibition of Na(+)- and Ca+(+)-influx over sarcolemma. Intracellular inhibition of Ca+(+)-liberation from organelles and other calcium depots also seems possible.
authors: Institute of Pharmacology, University of Aarhus, Denmark.
authors: F
authors: F
authors: Nielsen-Kudsk
authors: C
authors: C
authors: Siggaard
authors: C B
authors: CB
authors: Nielsen
authors: S
authors: S
authors: Mellemkjaer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D004562:Electrocardiography; D005260:Female; D006207:Half-Life; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D012044:Regression Analysis; D012964:Sodium / Q000378:metabolism
chemical_list: D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine; D012964:Sodium; D002118:Calcium