Mechanisms of action of diazoxide.

Abstract

Abstract The mechanism of action of diazoxide vas investigated in dogs. Immunoreactive insulin, glucose, and free fatty acids were determined in treated and control dogs following intravenously administered glucose. The slower disappearance of glucose in the treated animals was associated with almost complete IRI suppression. Alpha adrenergic receptor blockade with phentolamine prevented the diabetogenic and insulin suppressive effects of diazoxide. Experiments in fasting dogs demonstrated that the elevation of FFA which follows diazoxide administration can be largely inhibited by beta adrenergic blockade with propranolol. The metabolic effects of diazoxide are therefore mediated either directly or indirectly through alpha and beta adrenergic receptors. Additional experiments indicated that the diazoxide effect on glucose tolerance and insulin secretion is not blocked by pretreatment with reserpine. Treatment with the massive doses of reserpine necessary to deplete tissue catecholamines caused a near-moribund state. However, the diazoxide effect could be demonstrated in the reserpinized animals that maintained the ability to secrete insulin normally in response to a glucose load. Our findings suggest that diazoxide stimulates alpha and beta adrenergic receptors directly.