Diazoxide disposition and effect on vascular resistance and compliance in dogs.

Abstract

The disposition and systemic vascular effects of bolus i.v. doses of diazoxide (3.75, 7.5 and 15.0 mg/kg) were studied in anesthetized open-chest dogs. Blood flow (.ovrhdot.Q) and right atrial pressure (Pra) were independently controlled by a right heart bypass. The late phase disposition half-life (.beta. t1/2) of diazoxide averaged 3.4 .+-. 0.5 h with an apparent volume of distribution at steady state of 1.3 .+-. 0.1 l/kg. There was a dose-related reduction in arterial pressure (Pa) with excellent correlation between plasma diazoxide concentrations and the reduction in Pa during the post drug-distribution phase. Diazoxide increased vascular capacitance (53 .+-. 16, 91 .+-. 10 and 134 .+-. 21 ml after 3.75, 7.5 and 15.0 mg/kg, respectively) as determined by volume changes (V) in the bypass reservoir at a constant .ovrhdot.Q and Pra. Transient changes in blood volume following an acute decrease in Pra at constant .ovrhdot.Q showed that blood drained from 2 vascular compartments with different time constants: a fast time-constant compartment with a time constant of 0.052 min before and 0.048 min after diazoxide and a slow time-constant compartment with a time constant of 0.552 min before and 0.501 min after diazoxide. The major change in arterial resistance after all doses occurred in the slow time-constant compartment without a clear dose response. Arterial resistance in the fast time-constant compartment was unchanged after diazoxide 3.75 mg/kg but was reduced by an extent similar to that in the slow compartment after 15.0 mg/kg (-42% .+-. 9% vs. -42% .+-. 4%). After diazoxide 3.75 mg/kg, venous compliance of both the slow and fast time-constant compartments was increased. Larger doses of diazoxide increased compliance of the slow time-constant compartment but reduced compliance of the fast compartment. When the circulation was considered as a single compartment, diazoxide was 4-6 times more active on arterial resistance than on venous compliance. When the circulation was considered as consisting of 2 compartments in parallel, the major effect of low doses of diazoxide was on both arterial and venous portions of vessels with a slow time constant for flow, presumably including the splanchnic circulation. Larger doses of diazoxide were required to reduce arterial resistance of vessels with a fast time constant for flow.