ACUTE AND CHRONIC EFFECTS OF TROGLITAZONE (CS-045) ON ISOLATED RAT VENTRICULAR CARDIOMYOCYTES

Freshly isolated and primary cultured adult rat cardiomyocytes were us ed to elucidate the mechanism of action of the new oral antidiabetic a gent (+/-)-5-[4-(6-hydroxy-2, 5, 7, chroman-2-yl-methoxy)benzyl]-2,4-t hiazolidinedione (troglitazone) on the heart. Interaction with protein kinase C (PKC) and regulation of glucose transport were evaluated as possible sites of drug action. Acute treatment (30 min) of cardiomyocy tes with troglitazone did not affect the phorbolester-induced membrane association of PKC-delta and PKC-epsilon, which represent the major i soforms present in these cells. However, under these conditions the ph orbolester-mediated increase in membrane associated PKC activity was i nhibited by 43 +/- 4 % (n = 4) without affecting the basal distributio n of PKC activity. In contrast to these findings, troglitazone had no acute effect on basal or insulin-stimulated glucose transport in fresh ly isolated cardiomyocytes; even after 120 min treatment an unaltered release of lactate was determined in the presence of the drug. After 2 0 h in serum-free culture troglitazone induced a dose-dependent increa se in 2-deoxyglucose uptake reaching a 40-fold stimulation at 5 mu mol /l. This was paralleled by a dose-dependent increase of glucose transp orter-1 (GLUT1) and GLUT4 protein expression to 320 +/- 80 and 156 +/- 15 % of control, respectively. In addition, chronic exposure to trogl itazone increased the GLUT4 abundance in a plasma membrane fraction ab out twofold. These data show that troglitazone exerts multiple effects on cardiomyocytes involving inhibition of PKC and regulation of gluco se transporter expression and distribution. We suggest that an increas ed glucose supply may be beneficial for the diabetic heart and that mo dulation of PKC-activity could be relevant for improving insulin actio n in muscle tissue.