Dopamine Induces Postischemic Cardiomyocyte Apoptosis In Vivo: An Effect Ameliorated by Propofol

Abstract

Dopamine is commonly used to improve postischemic myocardial contractile function. However, there is evidence that dopamine augments apoptosis after ischemia through increased intracellular calcium and opening of the mitochondrial permeability transition pore. Propofol (2,6-diisopropylphenol) is an anesthetic that has been shown to prevent mitochondrial permeability transition pore opening. We evaluated the effects of propofol given during reperfusion on dopamine-mediated apoptosis. Hearts from 8-week-old inbred New Zealand White rabbit siblings were subjected to 2 hours of cold cardioplegic ischemia and 6 hours of reperfusion in a heterotopic transplant model. Controls consisted of the recipient rabbit's nonischemic heart. The ischemia-reperfusion (IR) group consisted of postischemic hearts reperfused with no drugs; the IR plus dopamine (IR+D) group received dopamine (20 microg x kg(-1) x min(-1)) continuously; the IR+D plus propofol (IR+D+P) group received dopamine (20 microg x kg(-1) x min(-1)) plus propofol (500 to 600 microg x kg(-1) x min(-1)); and the IR plus propofol (IR+P) group received propofol only (500 to 600 microg x kg(-1) x min(-1)) throughout reperfusion (n = 7 to 9 in each group). Myocardial function was measured using a left ventricular balloon; terminal nick-end labeling (TUNEL) staining, DNA electrophoresis, and immunoblotting for caspase-3 cleavage were performed at the end of reperfusion. Dopamine increased the number of TUNEL-positive nuclei significantly (14.0 +/- 2.0/1,000 for IR+D versus 6.7 +/- 2.0/1,000 for IR, p = 0.01). Propofol (IR+D+P) reduced the total number of apoptotic cells in hearts receiving dopamine (7.1 +/- 1.8/1,000, p = 0.01 versus IR+D) to the extent seen in IR alone. DNA laddering and caspase-3 cleavage were observed at greater frequency in the IR+D group compared with the IR and IR+D+P groups. Propofol had no effect on dopamine-mediated increased systolic function, but improved diastolic function after ischemia. Dopamine infusion has a positive inotropic effect on the postischemic heart at the expense of increased cardiomyocyte apoptosis. The addition of propofol prevents dopamine-induced apoptosis after ischemia while maintaining positive inotropy.