title: Short-term effects of glipizide (an adenosine triphosphate-sensitive potassium channel inhibitor) on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep.
abstract: In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific K(ATP) channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to elucidate the short-term effects of glipizide, a specific K(ATP) channel inhibitor, on cardiopulmonary hemodynamics and global oxygen transport in healthy sheep and sheep with endotoxemia. Ten adult ewes were anesthetized and operatively instrumented with a pulmonary artery, a femoral artery, and a foley catheter. After 24 h of recovery, healthy sheep received glipizide as a bolus infusion (4 mg/kg over 15 min). After 24 h of recovery, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng.kg.(-1)min) was started in the same sheep and administered for the next 17 h. After 16 h of endotoxemia, glipizide was given as described above. Administration of glipizide was followed by a transient, but significant, increase in mean arterial pressure in both healthy controls (95 +/- 3 mmHg vs. 101 +/- 2 mmHg, P < 0.05) and sheep with endotoxemia (86 +/- 3 mmHg vs. 93 +/- 3 mmHg, P < 0.05). However, the increase in mean arterial pressure was longer lasting in ewes with endotoxemia. Cardiac index, oxygen delivery index, arterial lactate concentrations, and arterial pH were not significantly affected by glipizide. Therefore, administration of glipizide may represent a beneficial therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome. Additional studies are required to determine the effects of continuous infusion of glipizide in the presence of systemic inflammation.
authors.affiliation: Department of Anesthesiology and Intensive Care, University of Muenster, 48161 Muenster, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: Hugo
authors.initials: H
authors.lastname: Van Aken
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.forename: Fritz
authors.initials: F
authors.lastname: Daudel
authors.forename: Katrin
authors.initials: K
authors.lastname: Bröking
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Salzman
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Bone
authors.forename: Martin
authors.initials: M
authors.lastname: Westphal
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D005260:Female; D005913:Glipizide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D015657:Respiratory Transport / Q000187:drug effects; D034561:Sheep, Domestic; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D010100:Oxygen; D005913:Glipizide