THE DEVELOPMENT OF RESISTANCE TO A POTENT LIPOLYSIS INHIBITOR, 3-METHYLISOXAZOLE-5-CARBOXYLIC ACID

¹ Medical Research Laboratories, Chas. Pfizer & Co., Inc., Groton, Connecticut

3-Methylisoxazole-5-carboxylic acid (MIC) was a potent inhibitor of lipolysis in vitro and produced marked decreases in plasma free fatty acids (FFA) in fasted dogs and rats. When MIC was administered repeatedly to dogs and rats for several days, a challenge dose of MIC was without effect on plasma FFA. The onset of this resistance required 2 days in the rat and resistant animals regained the response to MIC after a 3-day rest period. Nicotinic acid, another potent antilipolytic agent, did not induce resistance but was ineffective in reducing plasma FFA levels in rats rendered resistant to MIC. Endocrine ablation studies in rats established the requirement for an intact pituitary-adrenal system in the induction of resistance. An increased basal release of FFA from adipose tissue taken from resistant rats was observed and is consistent with a role of adrenal cortical hormones and pituitary growth hormone in the induction of resistance. A reduced sensitivity to the antilipolytic effects of MIC and nicotinic acid was observed in adipose tissue taken from MIC-resistant rats.