Prostaglandin F2α and the thromboxane A2 analogue ONO-11113 stimulate Ca2+ fluxes and other physiological responses in rat liver. Further evidence that prostanoids may be involved in the action of arachidonic acid and platelet-activating factor

Abstract

The administration of prostaglandin F2 alpha (PGF2 alpha) and the thromboxane A2 analogue, ONO-11113, to rat livers perfused with media containing either 1.3 mM- or 10 microM-Ca2+ was followed by a stimulation of Ca2+ efflux, changes in O2 uptake and glucose output, and increase in portal pressure. The responses elicited by 5 microM-PGF2 alpha were similar to those induced by the alpha-adrenergic agonist phenylephrine. At both 1.3 mM and 10 microM extracellular Ca2+, PGF2 alpha induced Ca2+ efflux (70-90 nmol/g of liver), probably from the same source as that released by phenylephrine. Prostaglandin D2 (5 microM) and prostaglandin E2 (5 microM) also induced responses, but these were generally much smaller (less than 30%) than those induced by PGF2 alpha. Similarly to vasopressin and other Ca2+-mobilizing hormones, PGF2 alpha also interacted synergistically with glucagon (and cyclic AMP) in stimulating Ca2+ influx both in the perfused liver and in isolated hepatocytes. By comparison with phenylephrine and PGF2 alpha, ONO-11113 was much more potent in inducing vasoconstriction, and, at concentrations of 10-200 nM, induced a different pattern of changes in Ca2+ flux, respiration and glycogenolysis. There was first a rapid efflux of Ca2+ (45-60 nmol/g of liver), followed by a smaller Ca2+ influx, and a further release of Ca2+ (approx. 90 nmol/g of liver) when ONO-11113 was removed. Respiration was first stimulated but then markedly inhibited. At concentrations less than 5 nM, ONO-11113 induced a sustained stimulation of O2 uptake and a more prolonged efflux of Ca2+, with less Ca2+ efflux occurring upon the removal of the agent. Glycogenolysis followed a pattern which was similar to the Ca2+ response. Co-administration of glucagon did not potentiate Ca2+ influx by ONO-11113, but the action of ONO-11113 was inhibited (50%) by a few minutes' prior administration of 10 nM-vasopressin. The vasoconstrictive action of ONO-11113 was synergistically potentiated by the co-administration of phenylephrine. Since the actions of arachidonic acid, platelet-activating factor and lysophosphatidylcholine in liver were recently found to be cyclo-oxygenase-sensitive, the results provide strong evidence that at least PGF2 alpha and thromboxane A2 may be involved in mediating the action of these agents.