RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.

Research advances in the relationship between iron deficiency and neurodevelopment in preterm infants / 中国当代儿科杂志

Iron deficiency (ID) is the most common micronutrient deficiency in children. Due to insufficient iron storage at birth and rapid catch-up growth after birth, preterm infants tend to have a high incidence rate of ID. During the critical period of brain development, ID alters iron-dependent neurometabolism, neurochemistry, neuroanatomy, and gene/protein profiles. This affects the central nervous system and causes the change in neurocognitive and behavioral development. Iron supplementation in infancy cannot reverse neurodevelopmental impairment caused by perinatal ID. The influence of ID on neurodevelopment is time- and region-specific, and in the high-risk population, early diagnosis and optimal iron treatment may help with the recovery of brain function and improve quality of life and long-term prognosis in preterm infants.

Protection of hypothermic preserved isolated rat hearts by resveratrol and its underlying mechanism / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate whether resveratrol (RES) plays a protective role in hypothermic preserved isolated rat hearts and whether it is mediated by regulation of silent information regulator protein-1 (Sirt-1) expression.</p><p><b>METHODS</b>The Langendorff model of isolated rat heart was used. After stored in different Celsior solution at 4 degrees C for 9 h, SD rat hearts were randomly divided into 7 groups: blank control group;9 h group (soley hypothermic preservation for 9 h); RES group (3, 10, 30 micromol/L RES treatment plus hypothermic preservation for 9 h ), niacinamide (NAM) group (40 micromol/L NAM added in Celsior solution plus hypothermic preservation for 9 h), RES + NAM group (30 micromol/L RES and 40 micromol/L NAM were added in Celsior solution plus hypothermic preservation for 9 h). The morphological changes of cardiomyocytes were detected by the HE staining with the light microscope. The mRNA and protein expression levels of Sirt-1 were detected by Real-Time PCR and Western blot respectively.</p><p><b>RESULTS</b>(1) Compared with the blank control group, myocardiocytes were injured remarkably in the 9 h group and the Sirt-1 mRNA and protein expression levels were decreased significantly (P < 0.01); (2) Compared with the 9 h group, rat myocardial injury was alleviated gradually in 3, 10, 30 micromol/L RES group and the Sirt-1 mRNA and protein expression levels were increased in a dose-dependent manner (P < 0.05); (3) The above protective effects of RES were attenuated by Sirt-1 inhibitor NAM.</p><p><b>CONCLUSION</b>RES can protect myocardiocytes from injury caused by long range hypothermic preservation and this protective effect maybe mediated by upregulation of Sirt-1 expression.</p>

Effect of total flavonoids from Chrysanthemun morifolium on learning and memory in aging mice / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the effect of total fiavonoids from Chrysanthemun morifolium (TFCM) on learning and memory, and cholinergic system function in aging mice.</p><p><b>METHODS</b>The aging mice model was established by subcutaneous injection of D-galactose. ICR mice were divided into five groups (n=10): contrA group, model group, and TFCM groups. Mice in TFCM groups were given TFCM (50,100 or 150 mg/kg) by gastric irrigation once a day. Learning and memory ability were evaluated by Morris water maze test. The MDA content, SOD and Ach E activity were also measured.</p><p><b>RESULTS</b>Compared with control group, learning and memory ability declined in the D-galactose-induced aging mice; meanwhile MDA content and AchE activity increased, SOD activity decreased. Treatment with TFCM (100, 150 mg/kg) ameliorated the decrease in learning and memory ability of aging mice. Compared with model group, TFCM (100, 150 mg/kg) could also decrease MDA content and Ach E activity, and increase SOD activity in aging mice.</p><p><b>CONCLUSION</b>TFCM may improve the learning and memory ability of aging mice. The mechanism is involved in its antioxidative characteristic and improvement of central cholinergic system function.</p>

Effect and mechanism of puerarin on high glucose-induced hypo-responses in vascular contraction / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To examine the effect of puerarin on high glucose-induced decrease in contraction of isolated rat aortic rings, and to elucidate its underlying mechanism.</p><p><b>METHODS</b>The thoracic aortic rings with or without endothelium of male Sprague-Dawley rats were mounted on a bath system. Isometric contractions of aortic rings were measured. The activity of heme oxygenase-1 (HO-1) was also measured.</p><p><b>RESULTS</b>(1) After incubation with 44 mmol/L of glucose (high glucose) for 4 h, the vascular contraction responses to phenylephrine (PE) decreased in an endothelium-dependent manner, when compared with the control group (containing 11 mmol/L of glucose). (2) After coincubation with puerarin ( 10(-10) - 10(-8) mol/L) and high glucose, the decrease in contraction responses to PE of arteries was partly inhibited in a dose-dependent manner. (3) After incubation with puerarin for 4 h, the HO-1 activity of thoracic aorta increased; ZnPP, an inhibitor of HO-1, abrogated the protection effect of puerarin.</p><p><b>CONCLUSION</b>Puerarin could prevent the high glucose-induced decrease in contraction responses to PE in intact aortic rings. The mechanism might be involved in the activation of HO-1.</p>

Effects of diazoxide on the mitochondrial ultrastructure and permeability in donor rat myocardium / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the effect of diazoxide (DE) on the myocardial ultrastructure and opening of maitochondrial permeability transition pore (MPTP) in donor rat heart suffered from long-term hypothermic preservation.</p><p><b>METHODS</b>The Langendorff model of isolated rat heart was used. The hearts were stored in 4 degrees C Celsior solution containing different concentration of DE (15, 30, or 45 micromol/L) for 9 h followed by 60 min of reperfusion. The recovery of rate-pressure product (RPP) was observed. The opening of MPTP and myocardial mitochondria ultrastructure were also evaluated.</p><p><b>RESULTS</b>(1) As compared with the celsior solution preserved group, DE (30 micromol/L) increased recovery of RPP during reperfusion and inhibited the opening of MPTP. DE also alleviated the myocardial mitochondrial ultrastucture damage induced by long-term hypothermic preservation. (2) The above effects of DE were attenuated by a mitoK(ATP) channel inhibitor 5-hydroxydecanoate and a MPTP opener atractyloside.</p><p><b>CONCLUSION</b>In the donor rat heart, DE protects myocardial mitochondria ultrastructure against long-term hypothermic preservation injury via inhibiting the opening of MPIP.</p>

Dynamic changes of Smac/DIABLO protein expression in rat donor myocardium suffered from hypothermic preservation / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effect of different duration of hypothermic preservation on the expression of Smac/DIABLO protein in rat hearts.</p><p><b>METHODS</b>The Langendorff model of isolated rat heart was used. After stored in 4 degrees C Celsior solution for different time (0, 3, 6, 9 or 12 h), the activity of SOD and the content of MDA in heart mitochondria were measured. Cell apoptosis was detected by TUNEL technique. The expression of Smac/DIABLO protein was also analyzed by Western blotting.</p><p><b>RESULTS</b>(1) After hypothermic preservation, the activity of SOD was decreased and the content of MDA was increased in rat hearts in a time-dependent manner. (2) Prolonged the hypothermic preservation, the percentage of apoptotic cell also enhanced. (3) After long-term of cold preservation, the expression of Smac/DIABLO protein increased at 3-6 h of preservation but decreased after 9 h.</p><p><b>CONCLUSION</b>Prolonged the hypothermic preservation might lead to the expression of Smac/DIABLO protein and induce cardiomyocytes apoptosis, which may in turn result in malfunction of cardiomyocytes.</p>

Effects of diazoxide on Fas/FasL protein expressions in rat myocardium suffered from long-term hypothermic preservation / 生理学报

The purpose of this study was to investigate the effect of a mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) opener, diazoxide (DE), on Fas/FasL protein expressions in rat heart suffered from long-term hypothermic preservation. The Langendorff isolated rat heart model was used. The hearts were stored in 4 °C Celsior solution with or without (control) DE for 8 h followed by 60 min of reperfusion. The recovery of rate-pressure product (RPP) was observed. Apoptotic cardiomyocytes were detected by TdT-mediated dUTP nick end labeling (TUNEL) technique. The expressions of Fas/FasL proteins were also analyzed by immunohistochemical method. The results showed that compared with the control group, DE (30 mmol/L) increased the recovery of RPP during reperfusion, reduced the percentage of apoptotic cells and the expressions of Fas and FasL proteins in rat hearts suffered from 8 h of hypothermic preservation. The above effects of DE were attenuated by a mitoK(ATP) channel inhibitor 5-hydroxydecanoate (5-HD). These results indicate that DE could alleviate rat myocardial injury induced by ischemia-reperfusion through reducing the expressions of Fas and FasL proteins via opening of mitoK(ATP)channel.

COX-2 inhibitor nimesulide protects rat heart against oxidative stress by improving endothelial function and enhancing NO production / 生理学报

Since a cyclooxygenase 2 (COX-2) inhibitor can reduce infarct size and improve contractility in ischemic myocardium, the aim of the present study was to explore whether COX-2 inhibitor nimesulide could protect myocardial function against oxidative stress injury in rat hearts, and to investigate the underlying mechanisms. The isolated rat hearts perfused by Langendorff method were exposed to 140 mumol/L of H2O2, and the cardiac contractility was measured. Then, the responses of coronary arteries, precontracted with U-46619, to the endothelium-dependent vasodilator serotonin (5-HT) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were evaluated. The results were as follows: (1) In hearts exposed to H2O2 for 20 min, the left ventricular developed pressure [LVDP, (54.8 +/- 4.0)%] and maximal rate of rise/fall of ventricular pressure [+/-dp/dt(max), (50.8 +/- 3.1)% and (46.2 +/- 2.9) %] were reduced compared with that in the control group (100%). After pretreatment with nimesulide (5 mumol/L) for 10 min before H2O2 perfusion, LVDP and +/-dp/dt(max) were enhanced to (79.9 +/- 2.8)%, (80.3 +/- 2.6)% and (81.4 +/- 2.6)%, respectively (P<0.01), and this was partially abolished by the nitric oxide synthase (NOS) inhibitor L-NAME [(60.2 +/- 2.1)%, (63.9 +/- 2.4)% and (63.1 +/- 2.9)%, respectively, P<0.01]. (2) The vasodilatation induced by 5-HT and SNP in H2O2-treated group was significantly less than that in the control group. Pretreatment with nimesulide for 10 min antagonized the decrease of endothelium-dependent vasodilatation in H2O2-treated group [(-22.2 +/- 4.2) % vs (-6.0 +/- 2.5) %, P<0.01], but had no effect on the decline of endothelium-independent vasodilatation [(-2.0 +/- 1.8)% vs (-7.0 +/- 3.5) %, P>0.05]. (3) Pretreatment with nimesulide for 10 min increased the NO production in H2O2-treated hearts [(2.63 +/- 0.40) vs (1.36 +/- 0.23) nmol/g protein, P<0.05], and this was inhibited by L-NAME. (4) Pretreatment with the selective COX-1 inhibitor piroxicam had no effect on LVDP and +/-dp/dt(max) in isolated hearts exposed to H2O2, but the left ventricular end diastolic pressure (LVEDP) was much higher than that in the group treated with H2O2 alone. Piroxicam did not influence the coronary resistance in H2O2-treated rat hearts. These data suggest that the COX-2 inhibitor nimesulide improves myocardial function in rat hearts suffering from oxidative stress, and this may be through an improvement in endothelium-dependent arterial relaxation and an enhancement of NO production in rat heart.

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>

Mechanisms of cardioprotection induced by preconditioning after activation of MITOK(ATP) channel / 中国应用生理学杂志

<p><b>AIM</b>To determine mechanisms of cardioprotection induced by combination angiotensin-converting enzyme inhibitors (ACEI) with subthreshold preconditioning after activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel.</p><p><b>METHODS</b>The Langendorff model of isolated rat heart was used. The time of the onset of uncoupling, the activities of sarcolemmal Na+/K+ -ATPase and Ca2+/Mg2+ -ATPase were measured.</p><p><b>RESULTS</b>The subthreshold preconditioning (2 min of ischemia and 10 min reperfusion) or captopril (an ACEI) alone did not protect hearts against injury of sustained ischemia. However combination captopril with subthreshold preconditioning increased LVDP. Pretreatment hearts with mitoK(ATP) channel inhibitor 5-HD abolished the protection effect. Combination captopril with subthreshold preconditioning delayed the onset of uncoupling, and enhanced the activities of sarcolemmal Na+/K+ ATPase and Ca2+/Mg2+ -ATPase in ischemia/reperfusion hearts. But 5-HD cancelled these cardioprotection effects.</p><p><b>CONCLUSION</b>Combination ACEI with subthreshold preconditioning delays the onset of cellular uncoupling induced by acute ischemia, and promotes the stability of sarcolemmal ion channels, in which activation of the mitoK(ATP) channels may be involved.</p>

Experimental studies on antiarrhythmic effect of jumi extraction / 中国应用生理学杂志

<p><b>AIM</b>To investigate the antiarrhythmic effect of jumi (JM) extraction.</p><p><b>METHODS</b>The conventional antiarrhythmic methods were used.</p><p><b>RESULTS</b>Administration of JM extraction reduced the occurrence of ventricular fibrillation induced by chloroform in a dose-dependent manner in mice. Quinidine significantly decreased the number of ventricular premature beats and ventricular tachycardia, shortened the duration of arrhythmia in aconitine-treated rats. But JM extraction had no effect on aconitine-induced arrhythmia. Compared with control, arrhythmia score was lower in ischemia/reperfusion rats which pretreated with 2.0 g/kg of JM extraction.</p><p><b>CONCLUSION</b>JM extraction has obvious protection effects in chloroform- and ischemia-induced arrhythmia, but has no effect in aconitine-induced arrhythmia.</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>

Transfection with 5-lipoxygenase/green fluorescence protein for evaluating injury-induced 5-lipoxygenase translocation to the nuclear membrane in PC12 cells / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To evaluate the translocation of 5-lipoxygenase (5-LOX)) after injuries by transfection with green fluorescence protein (GFP)/5-LOX in PC12 cells.</p><p><b>METHODS</b>PC12 cells were stably transfected with pEGFP-C2/5-LOX (GFP/5-LOX) or pEGFP-C2 vectors (control). After treatment with oxygen-glucose deprivation (OGD), H(2)O(2) or NMDA, GFP/5-LOX localization in the cells was observed under a fluorescence microscope. Wild-type 5-LOX was determined by immunostaining after the treatment.</p><p><b>RESULT</b>In the GFP/5-LOX-transfected cells, GFP/5-LOX was primarily localized in the nucleus; while in the GFP-transfected cells, GFP was localized in both the cytoplasm and nucleus. After OGD and H(2)O(2) treatments, GFP/5-LOX was translocated to the nuclear membrane in 50.6 % and 57.7% cells respectively. However, after NMDA treatment or in GFP-transfected cells, no translocation was observed. Wild-type 5-LOX was distributed in the nuclei and cytoplasm, and all the 3 treatments induced 5-LOX translocation to the nuclear membrane.</p><p><b>CONCLUSION</b>In the PC12 cells stably transfected with GFP/5-LOX, GFP/5-LOX is primarily distributed in the nuclei; the OGD-, H(2)O(2)- and NMDA-induced 5-LOX translocation exhibits different properties.</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>

COX-2 mediates U50488H-induced delayed cardioprotection in isolated rat heart / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To determine whether U50488H, a selective agonist of kappa-opioid receptor, could induce biphasic (early and late) cardioprotection against myocardial ischemia/reperfusion injury and to explore the underlying mechanisms.</p><p><b>METHODS</b>Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 120 min reperfusion and the cardiac function was evaluated.</p><p><b>RESULT</b>Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP) and maximal velocity of contraction and relaxation (+/-dP/dtmax) were improved when U50488H was administered 1 or 24 h before ischemia (P<0.05). Myocardial infarct size, activities of creatine kinase (CK) and lactate dehydrogenase (LDH) in the coronary effluent were lower in the U50488H pretreatment group than those in the control group. Administration of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib abolished the late phase of cardioprotection produced by administration of U50488H 24 h before ischemia. Activities of CK and LDH in the coronary effluent were higher in U50488H and celecoxib co-pretreatment group than those in U50488H group. However, administration of celecoxib did not block the early phase of cardioprotection by 1 h treatment of U50488H before ischemia.</p><p><b>CONCLUSION</b>The late (but not the early) phase of cardioprotection induced by kappa-opioid receptor agonist might be mediated by COX-2.</p>

Angiotensin-converting enzyme inhibitors potentiate subthreshold preconditioning through NO and mitoK(ATP) channel / 生理学报

The aim of the present study was to determine whether angiotensin-converting enzyme inhibitors (ACEI) could contribute to the protective effects of preconditioning, and to explore its underlying mechanism. The Langendorff model of isolated rat heart was used. Cardiac contractility and lactate dehydrogenase (LDH) in the coronary effluent were measured, and infarct area of hearts after 30 min of ischemia followed by 120 min of reperfusion was analyzed. We found that: (1) The subthreshold preconditioning (2 min of ischemia and 10 min of reperfusion), captopril (an ACEI with sulfhydryl groups) or perindoprilate (an ACEI without sulfhydryl groups) alone did not protect the hearts from being injured by 30 min of ischemia and 120 min of reperfusion. (2) However, the combination of captopril or perindoprilate with subthreshold preconditioning could decrease left ventricular end-diastolic pressure (LVEDP), increase left ventricular developed pressure (LVDP) and coronary flow compared with the subthreshold preconditioned group. The combination treatments also inhibited the release of LDH from ischemia/reperfusion hearts, and reduced the infarct area in ischemic heart after 2 h of reperfusion (P<0.05). (3) By using NOS inhibitor L-NAME (100 mumol/L) before combined administration of ACEI with subthreshold preconditioning, the protection effect triggered by the combination treatment was significantly reduced. Pretreatment of the hearts with mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel inhibitor 5-HD (100 mumol/L) also abolished the protection effect (P<0.05). (4) Subthreshold preconditioning, captopril or perindoprilate alone could enhance the NO content in coronary effluent (P<0.05), but the combination of captopril or perindoprilate with subthreshold preconditioning could further augment the NO content compared with the subthreshold preconditioned group (P<0.05). The results indicate that ACEIs with or without sulfhydryl groups may potentiate the subthreshold preconditioning to trigger cardiac protection effect against the ischemia/reperfusion injury. This protection effect in the heart is possibly mediated by the generation of NO and the activation of mitoK(ATP) channel.

Endogenous catecholamine participates in the action of interleukin-2 on the isolated rat heart / 中国应用生理学杂志

<p><b>AIM</b>To explore whether endogenous catecholamine participates in the effect of interleukin-2 on the isolated heart.</p><p><b>METHODS</b>The number of premature ventricular contraction (PVC), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure(LVEDP), heart rate (HR) and coronary flow(CF)were recorded in isolated Langendorff perfused rat hearts.</p><p><b>RESULTS</b>(1) 50 U/ml IL-2 increased the PVC number, LVDP LVEDP, HR and CF. (2) Pretreatment of reserpine or propranolol abolished the cardiac effect of IL-2 at 50 U/ml, while pretreatment with phentolamine did not change the effect of IL-2. (3) 200 U/ml IL-2 increased the number of PVC,but did not increase LVDP, LVEDP, HR and CF. (4) After pretreatment of reserpine or propranolol, IL-2 failed to increase the number of PVC, but caused decrease of LVDP, HR and CF, and elevation of LVEDP.</p><p><b>CONCLUSION</b>Endogenous catecholamine mediates the arrhythmogenic, positively chronotropic and inotropic effects of IL-2. IL-2 at 200 U/ml inhibits the cardiac function in the isolated rat heart.</p>