{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:24:09Z","timestamp":1773660249052,"version":"3.50.1"},"reference-count":78,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2017,11,1]]},"abstract":"<jats:p> Activation of large-conductance Ca<jats:sup>2+<\/jats:sup>-activated K<jats:sup>+<\/jats:sup> (BK<jats:sub>Ca<\/jats:sub>) channels evokes cell survival programs that mitigate intestinal ischemia and reperfusion (I\/R) inflammation and injury 24 h later. The goal of the present study was to determine the roles of reactive oxygen species (ROS) and heme oxygenase (HO)-1 in delayed acquisition of tolerance to I\/R induced by pretreatment with the BK<jats:sub>Ca<\/jats:sub> channel opener NS-1619. Superior mesentery arteries were occluded for 45 min followed by reperfusion for 70 min in wild-type (WT) or HO-1-null (HO-1<jats:sup>\u2212\/\u2212<\/jats:sup>) mice that were pretreated with NS-1619 or saline vehicle 24 h earlier. Intravital microscopy was used to quantify the numbers of rolling and adherent leukocytes. Mucosal permeability, tumor necrosis factor-\u03b1 (TNF-\u03b1) levels, and HO-1 activity and expression in jejunum were also determined. I\/R induced leukocyte rolling and adhesion, increased intestinal TNF-\u03b1 levels, and enhanced mucosal permeability in WT mice, effects that were largely abolished by pretreatment with NS-1619. The anti-inflammatory and mucosal permeability-sparing effects of NS-1619 were prevented by coincident treatment with the HO-1 inhibitor tin protoporphyrin-IX or a cell-permeant SOD mimetic, Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), in WT mice. NS-1619 also increased jejunal HO-1 activity in WT animals, an effect that was attenuated by treatment with the BK<jats:sub>Ca<\/jats:sub> channel antagonist paxilline or MnTBAP. I\/R also increased postischemic leukocyte rolling and adhesion and intestinal TNF-\u03b1 levels in HO-1<jats:sup>\u2212\/\u2212<\/jats:sup> mice to levels comparable to those noted in WT animals. However, NS-1619 was ineffective in preventing these effects in HO-1-deficient mice. In summary, our data indicate that NS-1619 induces the development of an anti-inflammatory phenotype and mitigates postischemic mucosal barrier disruption in the small intestine by a mechanism that may involve ROS-dependent HO-1 activity. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY Antecedent treatment with the large-conductance Ca<jats:sup>2+<\/jats:sup>-activated K<jats:sup>+<\/jats:sup> channel opener NS-1619 24 h before ischemia-reperfusion limits postischemic tissue injury by an oxidant-dependent mechanism. The present study shows that NS-1619-induced oxidant production prevents ischemia-reperfusion-induced inflammation and mucosal barrier disruption in the small intestine by provoking increases in heme oxygenase-1 activity. <\/jats:p>","DOI":"10.1152\/ajpheart.00620.2016","type":"journal-article","created":{"date-parts":[[2017,8,20]],"date-time":"2017-08-20T00:30:25Z","timestamp":1503189025000},"page":"H988-H999","source":"Crossref","is-referenced-by-count":21,"title":["Preconditioning with the BK<sub>Ca<\/sub> channel activator NS-1619 prevents ischemia-reperfusion-induced inflammation and mucosal barrier dysfunction: roles for ROS and heme oxygenase-1"],"prefix":"10.1152","volume":"313","author":[{"given":"Hongyan","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, 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