Action of Diazoxide on Skeletal Muscle Vascular Resistance

Abstract

Controversy exists as to whether arteriolar dilation after diazoxide (DZ) administration is due to a prolonged vascular effect that outlasts the presence of circulating levels of DZ or to equilibrium of arteriolar sites with circulating DZ. To resolve this question, the direct effects of DZ on the vascular resistance (VR) of the isolated blood-perfused (constant-flow) gracilis muscle were evaluated in 44 anesthetized dogs. Intra-arterial infusions of DZ resulted in falls in vascular resistance (-35.9±5.5 SEM %) which returned to control levels after the infusions, thus indicating that irreversible binding to arterioles or a prolonged arteriolar effect independent of plasma levels of the drug did not obtain. Decreases (- 16% to -35%) in VR could also be achieved by premixing DZ in the blood perfusion reservoir at concentrations between 40 and 100 mg/L (which may be achieved clinically); thus albumin binding does not abolish the activity of DZ. Decreases in VR by DZ were not related to stimulation of beta-adrenergic receptors, alteration in Na⁺ or K⁺ balance, or changes in venous levels of glucose, lactate, pO₂, pCO₂, or pH. When norepinephrine and angiotensin II were infused during diazoxide infusions their vasoconstrictor response was attenuated. Thus DZ has a direct effect in lowering VR which is independent of measurable changes in gracilis muscle metabolism. Moreover, the VR effect of DZ is not dependent on a prolonged arteriolar effect independent of plasma concentrations of the drug.