Activation of glycogenolysis by methotrexate: Influence of calcium and inhibitors of hormone action

Abstract

The influence of Ca 2+ and the possible action of hormone blockers on the activation of glycogenolysis by methotrexate were investigated. Methotrexate was inactive on glycogenolysis and oxygen uptake when the liver, depleted of intracellular Ca 2+, was perfused with Ca 2+-free medium. The action of methotrexate in calcium-depleted hepatocytes could be restored by the addition of extracellular Ca 2+. When Ca 2+ was absent in the extracellular medium, but the intracellular stores were not depleted, methotrexate produced transient and progressively attenuated increases in glycogenolysis and oxygen uptake. Like many agonists, methotrexate produced transient increases in Ca 2+ efflux. The action of methotrexate was not blocked by the antagonists of norepinephrine, phenylephrine, isoproterenol, vasopressin and angiotensin II. It was concluded that methotrexate acts through a Ca 2+-dependent mechanism, which is similar to that of the Ca 2+-dependent agonists. This action, however, seems not to be receptor mediated.