After the oral, intraperitoneal, or intravenous administration of an antihypertensive, antidiuretic benzothiadiazine, diazoxide, to dogs, rabbits, mice, and rats, rapid hyperglycemia is promptly elicited, but of short duration, and reversible. The hyperglycemia is accompanied by increased hepatic glycogenolysis, serum lactate and pyruvate, and blood urea nitrogen (BUN). The hyperglycemia is obtained in depancreatized dogs, alloxanized mice, propylthiouracil treated mice, and nephrectomized mice, suggesting that the pancreas, thyroid and kidneys are not the primary locus of action of diazoxide.

Modification of diazoxide hyperglycemia by hypophysectomy suggests that the pituitary plays a role in the hyperglycemic phenomenon. However, this view must be tempered by the realization that hypophysectomy causes partial inanition, perhaps sufficient to prevent hyperglycemia.

The partial suppression of diazoxide hyperglycemia by adrenalectomy and BW 61–43 (isopropyl methoxamine), a specific inhibitor of the metabolic effects of epinephrine, suggests that the metabolic effects of diazoxide are mediated, at least in part, by adrenergic hormones. Preliminary experiments wherein diazoxide hyperglycemia was markedly attenuated in adrenalectomized mice treated with a ganglionic blocking agent, chlorisondamine, tend to support this concept. However, some doubt is cast upon this concept since reserpine treated mice respond to diazoxide and differences were observed in the hyperglycemic responses to epinephrine and diazoxide in hypophysectomized mice.

Further work is underway to elucidate the mechanism(s) and locus of action of the metabolic effects of diazoxide.

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