Background: Activation of NO-synthase and vascular potassium (K) channels may play a role in the sepsis-induced attenuated sensitivity to norepinephrine. We examined whether various K channel blockers and NO-synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia.

Methods and Results: Volunteers received 2ng/kg E. coli endotoxin. The brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured using venous occlusion plethysmography. Intrabrachial norepinephrine infusion (1-3-10-30ng/min/dl) decreased FBF to 84±4, 70±4, 55±4, and 38±4% of baseline ratio, mean±SEM). Following endotoxin administration, norepinephrine-induced vasoconstriction was attenuated: 101±4, 92±4, 83±6, and 56±7% (P=0.0018, pooled data, n=30). Intrabrachial infusion of the K channel blocker tetra-ethyl ammonium (TEA) completely restored the vasoconstrictive effect of norepinephrine: from 104±5, 93±7, 93±12, and 69±12% to 89±9, 73±4, 59±5, and 46±8% (n=6, P=0.045), whereas other K channel blockers had no effect. NO-synthase inhibitor L-NMMA (0.2mg/min/dl) also restored the norepinephrine sensitivity (from 92±5, 85±4, 68±11, and 43±13% after endotoxin to 71±3, 66±7, 48±11, and 21±3% in the presence of L-NMMA, n=6, P=0.009). Furthermore, in the presence of L-NMMA, TEA did not have an additional effect on the norepinephrine-induced vasoconstriction (n=6, P =0.9).

Conclusions: The K channel blocker TEA completely restores the attenuated vasoconstrictive effects of norepinephrine during experimental human endotoxemia. Co-administration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on K channels. In the absence of an effect of the selective KATP channel blocker tolbutamide we conclude that endotoxin-induced vasorelaxation is the result of NO-mediated activation of KCa channels.