This Article Full Text Full Text (PDF) All Versions of this Article: 114/5/414    most recent CIRCULATIONAHA.105.590232v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pickkers, P. Articles by Smits, P. Search for Related Content PubMed PubMed Citation Articles by Pickkers, P. Articles by Smits, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information E. Coli Infections Hazardous Substances DB NITRIC OXIDE TOLBUTAMIDE Related Collections Cardiovascular Pharmacology Other Vascular biology

(Circulation. 2006;114:414-421.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to P. Pickkers, Department of Intensive Care Medicine (551), Radboud University Nijmegen Medical Centre, GeertGrooteplein 10, PO Box 9101, 6500HB, Nijmegen, Netherlands. E-mail p.pickkers{at}ic.umcn.nl

Received September 22, 2005; revision received May 5, 2006; accepted May 26, 2006.

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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				L. H. Clapp and N. N. Orie Stoking Up BKCa Channels in Hemorrhagic Shock: Which Channel Subunit Is Really Fueling the Fire? Circ. Res., August 31, 2007; 101(5): 436 - 438. [Full Text] [PDF]

				E. H.J.M. Kemna, H. Tjalsma, V. N. Podust, and D. W. Swinkels Mass Spectrometry-Based Hepcidin Measurements in Serum and Urine: Analytical Aspects and Clinical Implications Clin. Chem., April 1, 2007; 53(4): 620 - 628. [Abstract] [Full Text] [PDF]