Hydrogen sulfide preconditioning or neutrophil depletion attenuates ischemia-reperfusion-induced mitochondrial dysfunction in rat small intestine

Abstract

The objectives of this study were to determine whether neutrophil depletion with anti-neutrophil serum (ANS) or preconditioning with the hydrogen sulfide (H2S) donor NaHS (NaHS-PC) 24 h prior to ischemia-reperfusion (I/R) would prevent postischemic mitochondrial dysfunction in rat intestinal mucosa and, if so, whether calcium-activated, large conductance potassium (BKCa) channels were involved in this protective effect. I/R was induced by 45-min occlusion of the superior mesenteric artery followed by 60-min reperfusion in rats preconditioned with NaHS (NaHS-PC) or a BKCa channel activator (NS-1619-PC) 24 h earlier or treated with ANS. Mitochondrial function was assessed by measuring mitochondrial membrane potential, mitochondrial dehydrogenase function, and cytochrome c release. Mucosal myeloperoxidase (MPO) and TNF-α levels were also determined, as measures of postischemic inflammation. BKCa expression in intestinal mucosa was detected by immunohistochemistry and Western blotting. I/R induced mitochondrial dysfunction and increased tissue MPO and TNF-α levels. Although mitochondrial dysfunction was attenuated by NaHS-PC or NS-1619-PC, the postischemic increases in mucosal MPO and TNF-α levels were not. The protective effect of NaHS-PC or NS-1619-PC on postischemic mitochondrial function was abolished by coincident treatment with BKCa channel inhibitors. ANS prevented the I/R-induced increase in tissue MPO levels and reversed mitochondrial dysfunction. These data indicate that neutrophils play an essential role in I/R-induced mucosal mitochondrial dysfunction. In addition, NaHS-PC prevents postischemic mitochondrial dysfunction (but not inflammation) by a BKCa channel-dependent mechanism.

Ischemic preconditioning ameliorates intestinal injury induced by ischemia-reperfusion in rats

“…Activated neutrophils, which infiltrate the intestine during IR, produce inflammatory mediators, including TNF-a, ICAM-1, and VCAM-1, in the development of intestinal IR by releasing neutrophil proteases and reactive oxygen species, and sequestering polymorphonuclear neutrophils (PMNs) into ischemic intestinal tissue [20][21][22] . Depletion or inhibition of PMNs decreases intestinal tissue injury in IR [23] .…”

Hydrogen sulfide dilates rat mesenteric arteries by activating endothelial large-conductance Ca2+-activated K+ channels and smooth muscle Ca2+ sparks

“…As noted above, some studies suggest H 2 S activates the channel (7,15,17,28,34), whereas others find H 2 S inhibits BK Ca activity (13,30,31). Because the cell types in these two groups of studies do not overlap, it is possible that tissue-specific expression of subunits or other associated proteins modify the effect of H 2 S on BK Ca channels.…”

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

“…It enables H 2 S to suppress oxidative stress in the mitochondria (42). In rat models of ischemia and reperfusion (I/R) injury, it has been observed that preconditioning with H 2 S can prevent mitochondrial dysfunction in rat intestinal mucosa by a calcium-activated, large-conductance potassium channel-dependent mechanism (45). Under I/R conditions, production of ROS increases, which has a pivotal role in the pathogenesis of myocardial I/R injury.…”