Propofol Modulates Na+–Ca2+Exchange Activity via Activation of Protein Kinase C in Diabetic Cardiomyocytes

Abstract

The authors' objective was to identify the role of the Na+-Ca2+ exchanger (NCX) in mediating the contractile dysfunction observed in diabetic cardiomyocytes before and after exposure to propofol. Freshly isolated ventricular myocytes were obtained from normal and diabetic rat hearts. Intracellular concentration of Ca2+ and cell shortening were simultaneously measured in electrically stimulated, ventricular myocytes using fura-2 and video-edge detection, respectively. Postrest potentiation (PRP) and sarcoplasmic reticulum Ca2+ load were used to assess propofol-induced changes in the activity of the NCX. Propofol (10 microM) increased PRP in diabetic cardiomyocytes but had no effect on PRP in normal cardiomyocytes. Removal of sodium enhanced and KB-R7943 (reverse mode NCX inhibitor) blocked PRP in both normal and diabetic cardiomyocytes. In the absence of sodium, propofol enhanced PRP in diabetic cardiomyocytes but had no additional effect in normal cardiomyocytes. KB-R7943 completely blocked propofol-induced potentiation of peak intracellular concentration of Ca2+ and shortening in both cell types. Propofol increased sarcoplasmic reticulum Ca2+ load and prolonged removal of cytosolic Ca2+ in diabetic cardiomyocytes, but not in normal cardiomyocytes. Removal of sodium enhanced propofol-induced increases in sarcoplasmic reticulum Ca2+ load and further prolonged removal of cytosolic Ca2+, whereas KB-R7943 completely blocked propofol-induced increase in sarcoplasmic reticulum Ca2+ load. Protein kinase C inhibition with bisindolylmaleimide I prevented the propofol-induced increase in PRP and prolongation in Ca2+ removal. These data suggest that propofol enhances PRP via activation of reverse mode NCX, but attenuates Ca2+ removal from the cytosol via inhibition of forward mode NCX in diabetic cardiomyocytes. The actions of propofol are mediated via a protein kinase C-dependent pathway.