Dopamine treatment of postischemic contractile dysfunction rapidly induces calcium-dependent pro-apoptotic signaling

Ischemia and adrenergic stimulation of cardiomyocyte cultures have been shown to induce apoptotic cell death. We hypothesized that in a model of contractile dysfunction following ischemia, a commonly used catecholamine such as dopamine augments cardiomyocyte apoptosis via activation of calcium-depen...

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Published in:Circulation (New York, N.Y.) N.Y.), 2002-09, Vol.106 (12 Suppl 1), p.I290-I298
Main Authors: Stamm, Christof, Friehs, Ingeborg, Cowan, Douglas B, Cao-Danh, Hung, Choi, Yeong-Hoon, Duebener, Lennart F, McGowan, Francis X, del Nido, Pedro J
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Ca(2+) Mg(2+)-ATPase - antagonists & inhibitors
Calcium - analysis
Calcium - physiology
Cardiotonic Agents - pharmacology
Diacetyl - analogs & derivatives
Diacetyl - pharmacology
Dopamine - pharmacology
Enzyme Inhibitors - pharmacology
Heart - anatomy & histology
Heart - physiology
In Vitro Techniques
Kinetics
Myocardial Contraction - drug effects
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - pathology
Myocardial Reperfusion Injury - physiopathology
Myocardium - chemistry
Myocardium - cytology
Myocardium - metabolism
Necrosis
Organic Chemicals
Rabbits
Signal Transduction - drug effects
Ventricular Pressure
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Summary:Ischemia and adrenergic stimulation of cardiomyocyte cultures have been shown to induce apoptotic cell death. We hypothesized that in a model of contractile dysfunction following ischemia, a commonly used catecholamine such as dopamine augments cardiomyocyte apoptosis via activation of calcium-dependent signaling cascades. Isolated perfused rabbit hearts were subjected to 45 minutes of normothermic ischemia with cardioplegic arrest. Hearts were reperfused for 120 minutes with unmodified perfusate (control), perfusate containing 20 nM dopamine, dopamine+2,3-butanedione monoxime (BDM), a MgATPase-inhibitor, or the calcium-sensitizing inotrope ORG 30029. Ischemia-reperfusion alone caused contractile dysfunction without significant myocardial necrosis (left ventricular pressure-volume curves; 1% triphenyltetrazolium chloride staining; creatine kinase release) or apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling [TUNEL] analysis; immunoblotting for poly(ADP-ribose) polymerase [PARP] cleavage; activation of caspases-3, -8, and -9; expression of Bax/Bcl-2). Intracellular calcium [Ca2+]i measured by rhod-2 spectrofluorometry was increased in dopamine-reperfused hearts. Although postischemic dopamine treatment improved contractility, the number of apoptotic cardiomyocytes was significantly higher than in untreated postischemic hearts (32.5+/-9 versus 5.5+/-1.6/1000 nuclei, P
ISSN:0009-7322
1524-4539
DOI:10.1161/01.cir.0000032896.55215.a0