Published Online
on July 24, 2006

A more recent version of this article appeared on August 1, 2006

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Submitted on September 22, 2005
Revised on May 5, 2006
Accepted on May 26, 2006

In Vivo Evidence for Nitric Oxide-Mediated Calcium-Activated Potassium-Channel Activation During Human Endotoxemia

Peter Pickkers MD, PhD^*, Mirrin J. Dorresteijn MSc, Martijn P.W.J.M. Bouw , Johannes G. van der Hoeven MD, PhD, and Paul Smits MD, PhD

From the Departments of Intensive Care Medicine (P.P., M.J.D., M.P.W.J.M.B., J.G.v.d.H.) and Pharmacology-Toxicology (P.S.), Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

^* To whom correspondence should be addressed. E-mail: p.pickkers{at}ic.umcn.nl.

Background--During septic shock, the vasoconstrictor response to norepinephrine is seriously blunted. Animal experiments suggest that hyperpolarization of smooth muscle cells by opening of potassium (K) channels underlies this phenomenon. In the present study, we examined whether K-channel blockers and/or nitric oxide (NO) synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia.

Methods and Results--Volunteers received 2 ng/kg Escherichia coli endotoxin intravenously. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Infusion of 4 dose steps of norepinephrine into the brachial artery decreased the FBF ratio (ratio of FBF in the experimental arm to FBF in the control arm) to 84±4%, 70±4%, 55±4%, and 38±4% (mean±SEM) of its baseline value. After endotoxin administration, norepinephrine-induced vasoconstriction was attenuated (FBF ratio, 101±4%, 92±4%, 83±6%, and 56±7%; n=30; P=0.0018; pooled data). Intrabrachial infusion of the K-channel blocker tetraethylammonium (TEA) completely restored the vasoconstrictor response to 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). Other K-channel blockers did not affect the response to norepinephrine. The NO synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA; 0.2 mg · min^-1 · dL^-1 intra-arterially) also restored the norepinephrine sensitivity. 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 restores the attenuated vasoconstrictor response to norepinephrine during experimental human endotoxemia. Coadministration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on vascular K channels. In the absence of an effect of the selective adenosine triphosphate-dependent K-channel blocker tolbutamide, we conclude that the blunting effect of endotoxin on norepinephrine-induced vasoconstriction is caused by NO-mediated activation of calcium-activated K channels in the vascular wall.

Key words: inflammation • ion channels • nitric oxide synthase • pharmacology • regional blood flow • vasoconstriction

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