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

Abstract

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 84Ϯ4%, 70Ϯ4%, 55Ϯ4%, and 38Ϯ4% (meanϮSEM) of its baseline value. After endotoxin administration, norepinephrine-induced vasoconstriction was attenuated (FBF ratio, 101Ϯ4%, 92Ϯ4%, 83Ϯ6%, and 56Ϯ7%; nϭ30; Pϭ0.0018; pooled data). Intrabrachial infusion of the K-channel blocker tetraethylammonium (TEA) completely restored the vasoconstrictor response to norepinephrine from 104Ϯ5%, 93Ϯ7%, 93Ϯ12%, and 69Ϯ12% to 89Ϯ9%, 73Ϯ4%, 59Ϯ5%, and 46Ϯ8% (nϭ6; Pϭ0.045). Other K-channel blockers did not affect the response to norepinephrine. The NO synthase inhibitor N

Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans

“…12 In a previous phase 1 study, constant concentration increases of hepcidin after increasing doses of lexaptepid from 0.3 to 4.8 mg/kg indicated that the administration of lexaptepid did not induce hepcidin production by itself. 14 In addition, hepcidin production may have been influenced by the major changes in serum iron as observed throughout the experiment.…”

“…In a first-in-human trial, lexaptepid was well tolerated and effective in elevating serum iron. 14 The primary aim was to investigate the effectiveness of lexaptepid in preventing the serum iron decrease observed during systemic inflammation in healthy volunteers. The secondary objective was to assess the effects of lexaptepid on the innate immune response.…”

Mass Spectrometry–Based Hepcidin Measurements in Serum and Urine: Analytical Aspects and Clinical Implications

“…The patients were recruited by their physicians during outpatient clinic visits (all in Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, except for the thalassemia major patients, who were in Ospedale Sant'Eugenio, Rome, Italy). Endotoxemia samples from volunteers injected with lipopolysaccharide were selected from a human endotoxemia project (10 ). Written informed consent was obtained from all study participants, according to the Declaration of Helsinki.…”

“…We collected samples randomly between December 2005 and June 2006, at no specified time of day, except from the endotoxemia patients, from whom samples were collected according to a tight time schedule (10,13 ). Urine and blood samples were centrifuged immediately after collection, divided into aliquots to avoid multiple freezethaw cycles, and stored at Ϫ80°C.…”

Selective, Direct Activation of High-Conductance, Calcium-Activated Potassium Channels Causes Smooth Muscle Relaxation

“…Maxi-K channel dysfunction caused either by genetic ablation of either channel subunit or by the use of selective channel inhibitors leads to increased tone in vascular, corpus cavernosum, and detrusor smooth muscles (Suarez-Kurtz et al, 1991;DeFarias et al, 1996;Brenner et al, 2000;Garcia and Kaczorowski, 2001;Meredith et al, 2004;Thorneloe et al, 2005;Werner et al, 2005Werner et al, , 2008Brown et al, 2008), and Maxi-K channel knockout mice display hypertension (Brenner et al, 2000;Plü ger et al, 2000;Sausbier et al, 2005), erectile dysfunction (Werner et al, 2005), and overactive bladder/incontinence (Meredith et al, 2004). Maxi-K channels appear to mediate indirectly the relaxant effects of a number of vasodilators, including nitric oxide, and recent data suggest that attenuated vasoconstrictor response to norepinephrine during experimental human endotoxemia is due to nitric oxide-mediated activation of Maxi-K channels in the vascular wall (Pickkers et al, 2006). Maxi-K channels are major modulators of bladder function by regulating spontaneous and nerve-evoked contractions, and overactivity of urinary bladder smooth muscle causes urge incontinence (Herrera et al, 2005;Thorneloe et al, 2005).…”