Synergism between prostaglandin E2 and isoproterenol in stimulating glucose oxidation in the heart.

Abstract

The increase in cardiac contractile function following adrenergic stimulation is accompanied by increased glucose metabolism. Since prostaglandin E2 (PGE2) can internalize beta-receptors, we determined what effects PGE2 and isoproterenol have on glycolysis and glucose oxidation in the isolated working rat heart. All hearts were perfused with Krebs-Henseleit buffer containing 11 mM [5-3H, 14C(U)]glucose, 100 microU/mL insulin, and 3% albumin. In the presence of 0.4 mM palmitate and 1.25 mM free Ca2+, isoproterenol (3 x 10(-8) M) increased the heart rate x peak systolic pressure product from 27 +/- 1 to 43 +/- 1 mmHg.beats.min-1.10(3) (1 mmHg = 133.3 Pa). This was accompanied by an increase in glycolytic rates from 3564 +/- 231 to 7775 +/- 475 nmol.g-1 dry weight min-1 and an increase in glucose oxidation from 930 +/- 72 to 2591 +/- 239 nmol.g-1 dry weight.min-1. Addition of PGE2 (10(-9) M) did not affect the isoproterenol stimulation of glycolysis, but caused a further increase in glucose oxidation (to 3863 +/- 495 nmol.g-1 dry weight.min-1). In the absence of isoproterenol, 10(-9) M PGE2 had no effect on either glycolysis or glucose oxidation. When perfusate [Ca2+] was raised to 2.5 mM, a significant increase in glycolysis was seen in control hearts (from 3564 +/- 231 to 5679 +/- 374 nmol.g-1 dry weight.min-1). The effects of isoproterenol and PGE2 on glucose metabolism remained, although the synergistic effects of PGE2 on glucose oxidation were less dramatic. When 1.2 mM palmitate was present in hearts perfused with 2.5 mM Ca2+, a decrease was seen in both glycolysis (from 5679 +/- 374 to 3027 +/- 346 nmol.g-1 dry weight.min-1) and glucose oxidation (from 1056 +/- 170 to 221 +/- 29 nmol.g-1 dry weight.min-1). Even at this high concentration of fatty acid, isoproterenol stimulated glucose oxidation (from 221 +/- 29 to 859 +/- 69 nmol.g-1 dry weight min-1), and addition of PGE2 resulted in a significant further increase (1021 +/- 139 nmol.g-1 dry weight.min-1). These data demonstrate that concentrations of PGE2 that bind to the high affinity cardiac PGE2 receptor have no effect on glucose metabolism in the absence of beta-agonists. In the presence of isoproterenol, which dramatically stimulates both glycolysis and glucose oxidation, PGE2 has a synergistic effect on glucose oxidation at lower fatty acid concentrations. These findings suggest that PGE2 receptors in the heart function to potentiate rather than decrease beta-adrenergic stimulation of glucose metabolism.