Aims: Cardiac arrest and cardiopulmonary resuscitation (CPR) can lead to intestinal ischemia/reperfusion (I/R) injury. Increasing studies have indicated that hydrogen sulfide (H2S) is in favor of a variety of tissue I/R injury. The purpose of this study was to explore whether sodium hydrosulfide (NaHS), a H2S donor, can protect intestinal mucosa after CPR and its potential mechanisms. Main methods: Male Sprague-Dawley rats were subjected to 6 min cardiac arrest induced by transcutaneous electrical epicardium stimulation and then resuscitated successfully. A bolus of either NaHS (0.5 mg/kg) or placebo (NaCl0.9%) was blindly injected 1 min before the start of CPR intravenously, followed by a continuous injection of NaHS (2 mg/kg/h) or placebo for 3 h. Intestinal and plasma samples were collected for assessments 24 h after CPR. Key findings: We found that NaHS can markedly alleviate cardiac arrest induced intestinal mucosal injury. Rats treated with NaHS showed a lower malondialdehyde content, higher superoxide dismutase activity and glutathione content in intestine after CPR. Increased intestinal myeloperoxidase activity was significantly decreased by NaHS after CPR. Moreover, a reduced intestinal apoptotic cells after CPR were evident when pretreated with NaHS. Further studies indicated that NaHS enhances the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in intestine after CPR. Significance: Our data demonstrated that NaHS treatment before CPR induces intestinal mucosal protection 24 h post-resuscitation. The protective effects may be through oxidative stress reduction, inflammation alleviation, apoptosis inhibition and HIF-1 alpha activation. (C) 2013 Elsevier Inc. All rights reserved.