PITUITARY-ADRENOCORTICAL STIMULATION AND ANTI-INFLAMMATORY ACTIONS OF 4-ETHOXY-2-METHYL-5-MORPHOLINO-3 (2H)-PYRIDAZINONE (M73101)

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We investigated the mechanism of the elevation of serum corticosterone level by 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M73101) and its participation in the anti-inflammatory action. M73101 when given to rats intraperitoneally at doses of 50-200 mg/kg, caused an increase in serum and adrenal corticosterone in a dose-dependent manner. Oral administration of 200 mg/kg of M73101 also elevated the serum corticosterone level. Such action of M73101 was completely abolished by adrenalectomy, hypophysectomy, or the pretreatment with pentobarbital and morphine. In vitro experiment demonstrated that M73101 had no direct effect on adrenocortical function. These results indicate that the response to M73101 must be mediated through the release of ACTH from the adenohypophysis, which is probably due to the secretion of corticotropin releasing factor from the hypothalamus. M73101 at an oral dose of 200 mg/kg significantly decreased the volume of exudative fluid and the number of leucocytes in carrageenin-induced pleurisy of intact rats. However, the inhibitory action of this drug on cell mobilization decreased by adrenalectomy but not on exudative fluid, indicating that anti-inflammatory actions of M73101 may be due in part to pituitary-adrenocortical stimulation.
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