DIFFERENTIAL EFFECTS OF SELECTIVE AND NONSELECTIVE POTASSIUM CHANNEL INHIBITORS IN OVINE ENDOTOXEMIC SHOCK (MACROCIRCULATION) AND IN A RAT MODEL OF SEPTIC SHOCK (MICROCIRCULATION)

Background: Potassium-(K+)-channel inhibitors may increase systemic vascular resistance in vasodilatory shock states. Objective: The purpose of the present study was to compare the macro-and microvascular effects of the adenosine triphosphate-sensitive K+-channel-(K(+)ATP)-inhibitor glipizide and the nonselective K+-channel inhibitor tetraethylammonium (TEA) in ovine endotoxemic shock and septic shock in rats. Design: Two randomized, controlled laboratory studies. Animals: Thirty female sheep and 40 male Sprague Dawley rats. Setting: Animal research facility Intervention: Systemic hemodynamics were analyzed in ovine endotoxemic shock with guideline-oriented supportive therapy. Sheep were allocated to three treatment groups for 12 h: glipizide 10mgkg(-1)-h(-1), TEA 8mgkg(-1)-h(-1), or 0.9% saline. The microvascular effects of each drug were evaluated in septic rats (cecal ligation and puncture model) receiving a 2-h infusion of each study drug: glipizide 20mgkg(-1)-h(-1); TEA 50mgkg(-1)-h(-1), or 0.9% saline, respectively, followed by intravital microscopy of villi microcirculation. Results: Compared with the control group, glipizide infusion increased systemic vascular resistance index and decreased cardiac index and heart rate (HR) in sheep (P<0.05), whereas TEA infusion decreased HR and resulted in a decreased survival time (P = 0.001). In rats, glipizide infusion resulted in an increase in mean arterial pressure and a decrease in HR compared with baseline measurement (P<0.05) without relevant effects on the villi microcirculation. TEA decreased HR and decreased capillary perfusion of the villi microcirculation compared with the sham group (P = 0.002). Conclusions: Selective inhibition of K+ ATP-channels in ovine endotoxemic shock with glipizide partially restored vasomotor tone without exerting harmful effects on intestinal microcirculation in septic shock in rats. On the contrary, nonselective K+-channel inhibition with TEA showed deleterious effects in both models, including impaired microcirculation and decreased survival time. Future research on glipizide in vasodilatory shock may be warranted.