Effects of ambroxol combined with low-dose heparin on TNF-alpha and IL-1beta in rabbits with acute lung injury / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the intervention and mechanism of ambroxol combined with low-dose heparin on oxidative stress, TNF-alpha and IL-1beta in rabbits with acute lung injury (ALI).</p><p><b>METHODS</b>Twenty-four healthy Japanese rabbits were randomly divided into three groups: (1) Normal saline control group (NC), (2) Oleic acid injury group (OA), (3) Ambroxol + low-dose heparin therapy group (AH). After the success of ALI model, AH group was injected ambroxol + low-dose heparin, while the NC group and OA group were injected the same dose of normal saline by the same method. Arterial oxygen tension (PaO2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) at different time points were determined. The pathological manifestation of both side lungs was observed at the end of expeiment. The activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), xanthine oxidase (XO) and the content of malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) and lung tissue homogenate were tested. The apoptosis index was detected. The lung wet/dry (W/D) ratio was calculated. The pathological changes in lung tissue were observed by light microscopy, and the ultrastructural changes of lung tissue were observed by electron microscopy.</p><p><b>RESULTS</b>(1) The instructive injury induced by ALI observed under electron microscope and light microscope and W/D was decreased significantly in AH group. (2) PaO2 was improved significantly in AH group, compared with that in OA group (P < 0.01). (3) The activity of GSH-Px and SOD in AH group increased significantly (P < 0.01 or P < 0.05) but the activity of XO and the content of MDA decreased significantly (P < 0.01), compared with those in OA group. (4) Except the content of IL-1beta in serum before treatment, the content of IL-1beta and TNF-alpha in serum, BALF, lung tissue homogenate of OA group increased significantly (P < 0.01), and those were obviously improved in AH group. (5) Apoptosis index (AI) in AH group decreased significantly (P < 0.01) compared with that in OA group.</p><p><b>CONCLUSION</b>In ALI induced by OA, IL-1beta and TNF-alpha increases significantly and involved in the occurrence and development of ALI. Ambroxol combined with low-dose heparin can reduce lung cells oxidative stress to inhibit the release of IL-1beta and TNF-alpha, which play a role in the treatment of ALI.</p>

Involvement of potassium channel in hemin-induced cardioprotection in rat hearts / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effects of heme oxygenase 1 inducer hemin on protection of ischemia-reperfusion injury in rats and its mechanisms.</p><p><b>METHODS</b>The Langendorff model of isolated rat heart was used; the left anterior descending coronary artery was occluded for 30 min and subsequently reperfused for 2 h. Then the ventricular function and infarct size were measured.</p><p><b>RESULT</b>Hemin preconditioning prevented the increase in LVEDP, decrease in LVDP and +/- dp/dt(max) in the isolated ischemia-reperfusion rat hearts. The leakage of LDH and CK in the coronary effluent was significantly declined in hemin-treated rat hearts. And the infarct size was also reduced. Administration of a blocker of mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) 5-HD (5 mg/kg) before hemin preconditioning increased the LVEDP, and reduced the LVDP and +/- dp/dt(max). The leakage of LDH and CK in the coronary effluent and the infarct size were also increased compared with only hemin-treated rat hearts. Pretreatment of the rats with a blocker of sarcolemmal ATP-sensitive potassium channel (sarcK(ATP)) HMR-1098 (6 mg/kg) before hemin preconditioning also abolished the protective effect. Infusion of paxilline (1 micromol/L), a blocker of calcium activated potassium channel (K(Ca)) for 10 min before ischemia/reperfusion led to larger infarct size and poorer myocardial performance as compared with the hemin group. The leakage of LDH and CK in the coronary effluent was also increased.</p><p><b>CONCLUSION</b>Both mitoK(ATP)and sarcK(ATP)channels activation are required for the delayed cardioprotection induced by hemin. The opening of K(Ca) channels-dependent mechanism may be involved in the protection.</p>

COX-2 and HO-1 are involved in the delayed preconditioning elicited by bradykinin in rat hearts / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate whether cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) are involved in the bradykinin-induced delayed protection.</p><p><b>METHODS</b>Cardiac contractility, lactate dehydrogenase (LDH) and infarct area were analyzed in isolated rat hearts undergoing ischemia-reperfusion injury induced by Langendorff method.</p><p><b>RESULT</b>Conscious rats received bradykinin (40 microg/kg), and the isolated hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion 24 h later. Bradykinin pretreatment would improve post-ischemic performance, and reduced the release of LDH and infarct size. COX-2 inhibitor celecoxib (3 mg/kg) abolished bradykinin-induced protection, leading to poorer myocardial performance, release of more LDH and larger infarct sizes. Administration of HO-1 inhibitor ZnPP IX(20 microg/kg) before bradykinin partially abrogated the delayed protection. Pretreatment with the mitochondrial ATP sensitive potassium channel(mitoK(ATP) antagonist 5-HD before or 24 h after bradykinin administration also abolished the effect of protection.</p><p><b>CONCLUSION</b>The results indicate that activation of HO-1 and COX-2 might be involved in the delayed cardioprotection evoked by bradykinin, and mitoK(ATP) channel may serve as both a trigger and a mediator in the cardioprotection.</p>

Nitric oxide/heme oxygenase-1 mediates the antioxidant effect of ACEI in rat aortic rings / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To examine the effect of angiotensin-converting enzyme inhibitor (ACEI) on hydrogen peroxide (H(2)O(2))-induced decrease in contraction of isolated rataortic rings, and to investigate its mechanisms.</p><p><b>METHODS</b>The thoracic aortic rings with endothelium of male Sprague-Dawley rats were mounted on a bath system. Isometric contractions of aortic rings were measured.</p><p><b>RESULT</b>(1) After incubation with captopril (an ACEI with sulfhydryl groups) or perindoprilate (an ACEI without sulfhydryl groups), the decrease in contraction response to PE was prevented in arteries which were pretreated with 300 micromol/L H(2)O(2). (2) Captopril enhanced the HO-1 activity of thoracic aorta. After inhibition of HO-1 activity by ZnPP IX, the protection effect of captopril was abrogated. Hemin (an inducer of HO-1) and bilirubin (a product of HO-1) could mimic the antioxidative effect of captopril. (3) Both L-NAME (an inhibitor of NOS) and methylene blue (an inhibitor of GC) could abolish the protective effect of captopril. (4) SNAP could protect aortic rings against H(2)O(2) attack, and ZnPP IX could cancel the effect of SNAP.</p><p><b>CONCLUSION</b>Both ACEI with or without sulfhydryl groups could prevent the H(2)O(2) induced decrease in contraction responses to PE in intact aortic rings. The increase of NO and activation of HO-1 might be involved in the mechanism.</p>

Cardioprotective effects of NOS and PKC under hemin induced ischemia/reperfusion injury in rat hearts / 中国应用生理学杂志

<p><b>AIM</b>Whether hemin, a heme oxygenase 1 (HO-1) inducer, reduces ischemia/reperfusion injury and whether NO synthase (NOS) and PKC are involved in the cardioprotective effects were investigated in the present study.</p><p><b>METHODS</b>The Langendorff model of isolated rat heart was used. The ventricular function, infarct size, LDH and CK during ischemia/reperfusion period were also observed.</p><p><b>RESULTS</b>(1) After intraperitoneal injection of hemin (50 mg/kg) for 24 h, COHb concentration in rat blood enhanced. He-min preconditioning prevented the increase in LVEDP, decrease in LVDP and +/- dP/dt(max) in the isolated ischemia/reperfusion (ischemia for 30 main and subsequent reperfusion for 2 h) rat hearts. The leakage of LDH and CK in the coronary effluent was significantly declined in hemin-treated rat hearts. And the infarct size was als reduced. (2) By using an inhibitor of NOS NG-nitro-L-arginine methyl ester before the administration of hemin could inhibit the protection induced by hemin. (3) Administration of an inhibitor of protein kinase C chelerythrine (1 mg/kg) before hemin preconditioning could also abolish the cardioprotection induced by hemin.</p><p><b>CONCLUSION</b>These data suggest that the involvement of NO synthase and protein kinase C have been implicated in hemin-induced delayed cardioprotection in isolated rat hearts.</p>

Effect of heme oxygenase-1 on hydrogen peroxide induced hypo-responses in vascular contraction / 中国应用生理学杂志

<p><b>AIM</b>To examine the effect of HO-1 inducer hemin on hydrogen peroxide (H2O2) caused decrease in contraction of isolated rat aortic rings, and to elucidate the underlying mechanism.</p><p><b>METHODS</b>The thoracic aortic rings with endothelium of male Sprague-Dawley rats were mounted on a bath system. Isometric contractions of aortic rings were measured.</p><p><b>RESULTS</b>(1) After intraperitoneal injection of HO-1 inducer hemin, HO-1 activity of thoracic aorta and COHb concentration in rat blood enhanced. And it also prevented the decrease in contraction responses to PE which pretreatment of arteries with 300 micromol/L H2O2. (2) Pretreatment of ATP-sensitive potassium channel inhibitor glibenclamide, but not GC inhibitor methylene blue, could partly abolish the protection of hemin in arteries with H2O2 exposure. (3) Hemin could not influence the shift of concentration-response curve to [Ca2+]o in arteries with H2O2 exposure. (4) In Ca(2+) -free K-H solution, exposure of H2O2 reduced caffeine and PE-induced constriction in the rat aortic rings. After pretreatment of hemin, could prevent the decrease in contraction responses to caffeine and PE.</p><p><b>CONCLUSION</b>Increase in HO-1 activity could prevent the H2O2 induced decrease in contraction responses to PE in intact aortic rings. The mechanism might be involved in activation of ATP-sensitive potassium channel and mobilization of intracellular calcium stores, but had no relationship with the GC pathway.</p>