Potassium channel blockade restores the attenuated noradrenaline sensitivity in human endotoxemia

Introduction

Vasodilatory shock is a major problem in intensive care medicine. It is recently recognized that activation of vascular potassium (K) channels may play an important role in sepsis-induced vasodilation and attenuated sensitivity to noradrenaline. Pharmacological K-channel blockade restores blood pressure and improves mortality in animal models of sepsis. Human data are lacking. We examined whether endotoxin administration to healthy volunteers resulted in an attenuated noradrenaline sensitivity and whether this effect could be restored by the K-channel blocker tetra-ethyl ammonium (TEA).

Methods

Human volunteers received 2 ng/kg Escherichia coli endotoxin. The brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured using venous occlusion plethysmography. Noradrenaline was administrated intra-arterially at 1, 3, 10, 30 ng/min/dl and the vasoconstrictive response to noradrenaline was determined before endotoxin was administrated. Four hours after endotoxin administration the noradrenaline dose–response curve was repeated to determine the effects of endotoxin. One hour later the K-channel blocker TEA was administrated intra-arterially (1 mg/min/dl), after which the noradrenaline dose response curve was determined again. During the experiments continuous monitoring of heart rate and mean arterial pressure was performed and blood samples were taken to determine effects on standard laboratory values. Data are expressed as mean ± standard error of the mean. Differences were tested by analysis of variance repeated measures or Student t test, as appropriate. P < 0.05 was considered to indicate significance.

Results

Endotoxin administration induced the expected flu-like symptoms and fever (maximum temperature 38.3 ± 0.1°C, P < 0.001). Mean arterial pressure decreased from 93 ± 2 to 79 ± 2 mmHg (P < 0.001) and the heart rate increased from 60 ± 2 to 95 ± 2 bpm (P < 0.001). After the administration of endotoxin, leucocytes increased to 14.2 ± 0.6 × 10⁹/l (P < 0.001) and C-reactive protein increased to 36.0 ± 2.7 mg/l (P < 0.001). Intra-arterial noradrenaline infusion decreased forearm blood flow: percentage of baseline ratio (infused/noninfused arm), 100 ± 0%, 84 ± 4%, 70 ± 4%, 55 ± 4%, 38 ± 4%. Following endotoxin administration, the noradrenaline-induced vasoconstriction was attenuated: 100 ± 0%, 101 ± 4%, 92 ± 4%, 83 ± 6%, 56 ± 7% (P < 0.001, pooled data, n = 25). Time control experiments (n = 6) demonstrated excellent repeatability of the attenuated noradrenaline response after the administration of endotoxin (see Fig. 1, top). Intra-arterial infusion of the K-channel blocker TEA almost completely restored the vasoconstrictive effect of noradrenaline (see Fig. 1, bottom; n = 6, P = 0.045).

Figure 1

(abstract P79)

Conclusions

In experimental human endotoxemia, noradrenaline sensitivity is decreased. K-channel blocker TEA almost completely restores the vasoconstrictive effects of noradrenaline. Our study demonstrates that endotoxin-induced vascular K-channel activation plays a major role in the observed attenuated sensitivity to noradrenaline during human endotoxemia.