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

The disposition and systemic vascular effects of bolus intravenous doses of diazoxide (3.75,7.5, and 15.0 mg/kg) were studied in anesthetized open-chest dogs. Blood flow (0) and right atrial pressure (P ra ) were independently controlled by a right heart bypass. The late phase disposition halflife (beta t Vt) of diazoxide averaged 3.4 0.5 hrs (x SEM) with an apparent volume of distribution at steady state of 1.3 0.1 liter/kg. There was a dose-related reduction in arterial pressure (P o ) with an excellent correlation between plasma diazoxide concentrations and the reduction in P. 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 0 &d P r .. Transient changes in blood volume following an acute decrease in P r . at constant 0 showed that blood was draining from two vascular compartments with different time constants: a fast time-constant compartment with a time constant of 0.052 minutes before and 0.048 minutes after diazoxide and a slow time-constant compartment with a time constant of 0.552 minutes before and 0.501 minutes after diazoxide. The major change in arterial resistance after all doses occurred in the slow time-constant compartment without a dear 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 rag/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 further 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 to 6 times more active on arterial resistance than on venous compliance. When the circulation was considered as consisting of two 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. (Hypertension 3: 225-232, 1981) KEY WORDS diazoxide pharmacokinetics concentration response resistance compliance capacitance circulation model anesthetized dog