In advanced
sepsis, hemodynamic support is often complicated by a tachyphylaxis against exogenous
catecholamines. Although activation of
adenosine triphosphate (
ATP)-sensitive
potassium (K(
ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory
shock, previous studies demonstrated only a transient increase in mean arterial pressure (MAP) after bolus administration of K(
ATP) channel inhibitors. We hypothesized that a continuous infusion of the sulfonylurea
glipizide, a K(
ATP) channel inhibitor, may reverse cardiovascular dysfunctions in
sepsis permanently. Eighteen adult sheep were instrumented for chronic study. After a baseline measurement in healthy ewes,
endotoxin (Salmonella typhosa, 10 ng kg(-1) min(-1)) was continuously infused for 19 h. After 16 h of
endotoxemia, the surviving sheep (n = 14) were randomly assigned to be treated with either
glipizide (5 mg/kg, followed by a continuous infusion of 8 mg kg(-1) h(-1)) or placebo (
normal saline; each n = 7). Measurements of cardiopulmonary hemodynamics, global
oxygen transport,
acid-base status, and urine output were performed in the healthy state, after 16 h of
endotoxemia, and during 3 h of
glipizide infusion. Continuous infusion of
glipizide reversed the
endotoxin-induced hyperdynamic circulation, as indicated by significant increases in MAP and systemic vascular resistance index, as well as decreases in cardiac index and heart rate (P < 0.001 each). In addition,
glipizide increased urine output as compared with untreated controls (P < 0.001). The anticipated decrease in
glucose plasma levels was prevented by infusion of
glucose 5%. From these results, we conclude that continuous
glipizide infusion may represent a useful therapeutic option in the treatment of arterial
hypotension related to
sepsis and
systemic inflammatory response syndrome.