Role of aspirin in modulating myocardial ischemic reperfusion injury

The role of low-dose aspirin (3 mg/kg, i.v.) in attenuating ischemic reperfusion injury was studied in a canine model. Regional ischemia for 40 min was produced by temporary occlusion of the left anterior descending coronary artery and thereafter reperfusion instituted for 3 h. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LV dP/dt _max and negative (–) LV dP/dt _max were monitored alongwith myocardial adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate. Following reperfusion, there was a significant fall in (i) MAP, (ii) (+) LV dP/dt _max and (iii) (–) LV dP/dt _max. LVEDP was corrected after about 2h of reperfusion. Replenishment of only myocardial CP occurred, without any change in ATP and glycogen, although lactate accumulation was corrected.Aspirin administered 15 min before reperfusion (posttreatment) caused normalisation of LVEDP within 15 min and prevented any deterioration in (–) LV dP/dt _max, although it had no effect on MAP and (+) LV dP/dt _max. After 3h of reperfusion (post-treatment), myocardial ATP, CP, glycogen and lactate contents became normal. The number of premature ventricular complexes was significantly reduced after aspirin treatment. The present study indicates that low-dose aspirin post-treatment can ameliorate at least some of the deleterious consequences of reperfusion injury of the myocardium.     

Glutathione deficiency intensifies ischaemia‐reperfusion induced cardiac dysfunction and oxidative stress

The efficacy of glutathione (GSH) in protecting ischaemia‐reperfusion (I‐R) induced cardiac dysfunction and myocardial oxidative stress was studied in open‐chest, stunned rat heart model. Female Sprague–Dawley rats were randomly divided into three experimental groups: (1) GSH‐depletion, by injection of buthionine sulphoxamine (BSO, 4 mmol kg^–1, i.p.) 24 h prior to I‐R, (2) BSO injection (4 mmol kg^–1, i.p.) in conjunction with acivicin (AT125, 0.05 mmol kg^–1, i.v.) infusion 1 h prior to I‐R, and (3) control (C), receiving saline treatment. Each group was further divided into I‐R, with surgical occlusion of the main left coronary artery (LCA) for 30 min followed by 20 min reperfusion, and sham. Myocardial GSH content and GSH : glutathione disulphide (GSSG) ratio were decreased by ?50% (P < 0.01) in both BSO and BSO + AT125 vs. C. Ischaemia‐reperfusion suppressed GSH in both left and right ventricles of C (P < 0.01) and left ventricles of BSO and BSO + AT125 (P < 0.05). Contractility (+dP/dt and –dP/dt) in C heart decreased 55% (P < 0.01) after I and recovered 90% after I‐R, whereas ±dP/dt in BSO decreased 57% (P < 0.01) with ischaemia and recovered 76 and 84% (P < 0.05), respectively, after I‐R. For BSO + AT125, ±dP/dt were 64 and 76% (P < 0.01) lower after ischaemia, and recovered only 67 and 61% (P < 0.01) after I‐R. Left ventricular systolic pressure in C, BSO and BSO + AT125 reached 95 (P > 0.05) 87 and 82% (P < 0.05) of their respective sham values after I‐R. Rate‐pressure double product was 11% (P > 0.05) and 25% (P < 0.05) lower in BSO and BSO + AT125, compared with Saline, respectively. BSO and BSO + AT125 rats demonstrated significantly lower liver GSH and heart Mn superoxide dismutase activity than C rats after I‐R. These data indicate that GSH depletion by inhibition of its synthesis and transport can exacerbate cardiac dysfunction inflicted by in vivo I‐R. Part of the aetiology may involve impaired myocardial antioxidant defenses and whole‐body GSH homeostasis.     

Role of ATP-sensitive K<Superscript>+</Superscript>-channels in antiarrhythmic and cardioprotective action of adaptation to intermittent hypobaric hypoxia

Mature Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 30 sessions). This mode of adaptation enhanced heart tolerance to the arrhythmogenic action of 45-min coronary occlusion, but does not affect the infarction size/risk area ratio. In some series, the rats were exposed to more severe intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) followed by 20-min coronary occlusion and 3-h reperfusion one day after the last hypoxia session. In this case, adaptation reduced the infarction size/risk area ratio and enhanced cardiac tolerance to the arrhythmogenic effect of reperfusion, but had no effect on the incidence of ventricular arrhythmia during ischemia. We found that the cardioprotective and antiarrhythmic effects of adaptation to an altitude of 7000 m and the antiarrhythmic effect of 5000-m adaptation were mediated via activation of K_ATP channels. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 395–398, April, 2008     

Repeated normoxic hyperbaric exposures induce haemodynamic and myocardial changes in rats

Summary The effect of repeated exposure to ambient pressures of 5 bar (500 kPa), in atmospheres comprising normal partial pressures of oxygen [0.2 bar (20 kPa)] and nitrogen [0.8 bar (80 kPa)] and 4 bar (400 kPa) helium, on cardiac function and morphology was assessed in conscious rats. Ten test rats underwent chamber dives daily for 40 consecutive days, and ten control rats were exposed in the same chamber for an equal period of time, but in air at 1 bar (100 kPa). Cardiac output (Q_c) and myocardial blood flow (Q_myocardial) were determined by the microsphere method. After 40 days, the body mass was 7% greater in the control than in the test rats (P<0.05), although they were given exactly the same amount of standard food. The test rats had a significantly higher (7% absolute, 12% ventricular mass to body mass, P<0.05) heart mass (left ventricular myocardium, including the ventricular septum) than the control rats. The percentage tissue dry mass of the right and left ventricles was equal in the two groups. Microscopic examination revealed a number of small focal necroses in the left ventricle of the test rats but none in the control rats. The left ventricular pressure (LVP) and the maximum velocity of LVP increase (contractility) and decrease were significantly increased (25%–96%, P<0.001) in the pre-exposed compared to the control rats at 1 bar (100 kPa). The systolic arterial pressure, heart rate and respiratory frequency were similar in the two groups at 1 bar (100 kPa). The LVP and + dP/dt increased linearly and in parallel in both groups during compression, although at 5 bar (500 kPa) the test rats had reached a significantly higher LVP and + dP/dt level. However, the heart rate was unchanged in both groups. The pre-exposed rats had a higher left Q_myocardial [1 bar (100 kPa)=33%, P<0.05; and 5 bar (500 kPa)=maximum 40%, P<0.05] than the control rats. The systolic arterial blood pressure also increased during compression to its maximum after 20 min at 5 bar (500 kPa) in both groups. The mean arterial pressure, respiratory frequency, end-diastolic pressure and Q_c were unchanged throughout the experiments. A pressure drop of 42 mmHg (5.6 kPa) between the left ventricle and the arteries would suggest stenosis in the aortic valve region in the test rats. In conclusion, the cardiac function as well as myocardial mass and morphology were changed after 40 consecutive exposures to 5 bar (500 kPa) in conscious rats.     

Organ blood flow and cardiac contractility in anaesthetized cats at 5 bar (500 kPa) ambient pressure

Summary Previous in vivo and in vitro experiments have demonstrated increased cardiac contractility and increased total myocardial blood flow ( ) when rats were exposed to normoxic 5-bar (500 kPa) ambient pressure. In the present study, regional blood flow was measured using the microsphere method on nine anaesthetized cats at surface and normoxic 5-bar (500 kPa) ambient pressure. Left ventricular pressure (LVP) and cadiac contractility, measured as peak left ventricular +dP/dt and –dP/dt were measured in six of the cats. Arterial pressure, heart rate and cardiac output remained unchanged after compression, but total increased by 29% (P<0.01) and cerebral blood flow increased by 66% (P<0.05). At the same time +dP/dt and –dP/dt was increased by 83% and 102%, respectively (P<0.01), while LVP was enhanced by 14% (P<0.05). Except for a moderate decrease in partial pressure of oxygen, acid base status in arterial blood remained unchanged. The results indicate that the effects of increased ambient pressure on the heart are general physiological phenomena, which are not only limited to the laboratory rat.     

Short-term exercise provides left ventricular myocardial protection against intermittent hypoxia-induced apoptosis in rats

We investigated whether exercise provides beneficial effects to attenuate intermittent hypoxia (IH)-induced myocardial apoptosis. Male Sprague-Dawley rats were randomly assigned to four groups: control (CON), IH, exercise (EXE) or IH interspersed with EXE (IHEXE). IH rats were exposed to repetitive hypoxia–reoxygenation cycles (30 s of 5% O₂; 45 s of 21% O₂, 6 h day⁻¹) during the light phase (1000–1600 h) for 12 consecutive days. EXE rats were habituated to treadmill running for 5 days, permitted 2 days of rest, followed by 5 exercise bouts (30 m min⁻¹ for 60 min on a 2% grade) on consecutive days during the dark phase (2000–2200 h). IHEXE rats were exposed to IH during the light phase interspersed with exercise programs during the dark phase on the same day. Apoptosis levels, cytochrome c (Cyt-c), cleaved caspase-3, oxidative stress and antioxidant capacity were determined in the left ventricular (LV) myocardium. IH rats showed higher myocardial levels of the apoptotic index, mitochondria-released Cyt-c, cleaved caspase-3 and oxidative stress and lower catalase activity levels than CON rats (p < 0.05, for all). These changes were not observed in EXE rats (p > 0.05, for all) except that catalase activity increased (p < 0.05). IHEXE rats showed lower myocardial levels of apoptotic index, mitochondria-released Cyt-c, cleaved caspase-3 and oxidative stress and higher catalase activity levels (p < 0.05, for all) than IH rats. We conclude that short-term exercise provides potent cardioprotective effects by attenuating IH-induced myocardial apoptosis.     

精胺减轻大鼠在体心肌缺血/再灌注损伤的作用及机制初探

目的: 观察低浓度外源性精胺对大鼠心肌缺血/再灌注损伤的影响。方法: Wistar大鼠随机分成假手术（Sham）组、缺血/再灌注损伤（I/R）组、盐水对照（NS）组和精胺干预（Sp）组（n=10）。结扎冠脉复制心肌缺血/再灌注损伤模型。Sp组缓慢静脉推注 0.5 mmol/L 精胺 2 mL/kg。观察指标：心电图，心功能参数，血清SOD、LDH、NO、MDA水平和心肌超微结构等。结果: I/R组心律失常发生率高达90％，心肌超微结构损伤严重，LVSP 和±dp/dtmax明显降低，血清中NO、MDA及LDH升高，SOD活性降低（P<0.05或P<0.01 vs Sham组）。Sp组与I/R组及NS组相比，上述指标均有显著差异（P<0.05或P<0.01）。结论: 低浓度外源性精胺能减轻大鼠心肌缺血/再灌注损伤，其机制可能与抗氧化和减轻氧自由基损伤有关。     

Hemodilution with liposome-encapsulated low-oxygen-affinity hemoglobin does not attenuate hypothermic cerebral ischemia in rats

Hypothermia decreases cerebral metabolism and increases hemoglobin oxygen affinity. A hypothesis that the reversal of increased oxygen affinity would further attenuate hypothermic cerebral ischemia was tested by evaluating the effects of liposome-encapsulated hemoglobin (LipoHb) with low oxygen affinity (P₅₀ = 40–50 mmHg) on hypothermic incomplete cerebral ischemia. Wistar rats were randomly assigned to one of the following two groups: (A) exchange transfusion with LipoHb solution (Hb = 6 g/dl) (LipoHb, n = 5), (B) no exchange transfusion (control, n = 5). After surface cooling to 22°C, forebrain ischemia was induced for 15 min by bilateral carotid artery occlusion combined with a decrease in the mean arterial pressure (MAP) to 40 mmHg. ³¹P-magnetic resonance spectroscopy was performed during ischemia and 45 min of reperfusion. After reperfusion, MAP was significantly higher in the control group than in the LipoHb group (P < 0.01), although there were no significant differences during ischemia. Intracellular pH and phosphocreatine (PCr) levels decreased during ischemia and returned to the preischemic level in both groups following reperfusion. The LipoHb group had a significantly larger decrease and smaller recovery in PCr than the control group (P < 0.0001). Althouth β-adenosine triphosphate decreased during ischemia in the LipoHb group, it increased in the control group (P < 0.0001). Inorganic phosphate (Pi) increased during ischemia and decreased to the normal value after reperfusion. The LipoHb group experienced a significantly larger production of Pi than the control group (P = 0.02). Hemodilution with high-P₅₀ LipoHb does not reduce ischemic energy depletion induced by hypothermic incomplete forebrain ischemia in rats.     

Relationship between ischaemic time and ischaemia/reperfusion injury in isolated Langendorff‐perfused mouse hearts

Myocardial functional recovery and creatine kinase (CK) release following various periods of ischaemia were investigated in isolated mouse hearts. The hearts were perfused in the Langendorff mode with pyruvate‐containing Krebs–Hensleit (KH) buffer under a constant perfusion pressure of 80 mmHg, and were subjected to either continuous perfusion or to 5, 15, 20, 25, 30, 45 or 60 min of global ischaemia followed by 45 min of reperfusion. In hearts subjected to ischaemic periods of 5, 15 or 20 min, there was a transient reduction in the left ventricular (LV) dP/dt max during the early phase of reperfusion, while the recovery at the end of reperfusion reached a level similar to that in hearts subjected to continuous perfusion. In hearts subjected to longer ischaemic periods, i.e. 25, 30, 45 or 60 min, the decrease in the cardiac performance was more pronounced and persistent, with significantly lower recovery in LV dP/dt max and higher LV end diastolic pressure (LVEDP) at the end of reperfusion than in the non‐ischaemic hearts. There were no significant differences in the recoveries in coronary flow or in heart rate (HR) between groups. Similarly to the functional recovery, the release of CK showed a clear ischaemic length‐related increase. In conclusion, the Langendorff‐perfused isolated mouse heart could be a valuable model for studies of myocardial ischaemia/reperfusion injury. Future studies using gene‐targeted mice would add valuable knowledge to the understanding of myocardial ischaemia/reperfusion injury.     

Intravenous administration of vascular endothelial growth factor improves cardiac performance and inhibits cardiomyocyte apoptosis

This study investigated the effects of vascular endothelial growth factor (VEGF) intravenous administration on cardiac performance and cardiomyocyte apoptosis in a rat model of acute myocardial infarction. Left coronary artery ligation produced extensive myocardial infarction in 48 rats and sham operated in 24 animals. Twenty-four hours after surgery, the rats were randomized to receive VEGF₁₆₅–heparin (treated group) or heparin–saline (control group) treatment. The sham-operated animals were also to receive VEGF₁₆₅–heparin (sham group) treatment. VEGF₁₆₅ (2 μg/ml) with heparin (50 U) or heparin–saline (50 U/ml) was administered daily via the tail vein for 7 and 14 days. Fifty-eight rats survived and included in the study. There were not significant effects of VEGF on hemodynamic parameters in sham animals. As compared with control animals at 9 days after ligation (with 10 rats for each group), rats treated with VEGF had significantly higher maximum rate of left ventricular pressure rise (+dP/dt_max) or fall ( ? dP/dt_max) and microvessel counts, and significantly lower left ventricular end-diastolic pressure (LVEDP) and infarct size. At 16 days after surgery (12, 7 and 9 rats in sham, control and treated groups; respectively), VEGF treatment significantly increased mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), ± dP/dt_max and microvessel counts, and significantly decreased LVEDP and infarct size. VEGF treatment significantly inhibited cardiomyocyte apoptosis and the expression of p53, Fas and Bax protein, and increased the expression of Bcl-2 protein in myocardium at 9 days after myocardial infarction.     

ATP-dependent potassium channels and mitochondrial permeability transition pores play roles in the cardioprotection of theaflavin in young rat

Previous studies have confirmed that tea polyphenols possess a broad spectrum of biological functions such as anti-oxidative, anti-bacterial, anti-tumor, anti-inflammatory, anti-viral and cardiovascular protection activities, as well as anti-cerebral ischemia-reperfusion injury properties. But the effect of tea polyphenols on ischemia/reperfusion heart has not been well elucidated. The aim of this study was to investigate the protective effect of theaflavin (TF1) and its underlying mechanism. Young male Sprague-Dawley (SD) rats were randomly divided into five groups: (1) the control group; (2) TF1 group; (3) glibenclamide + TF1 group; (4) 5-hydroxydecanoate (5-HD) + TF1 group; and (5) atractyloside + TF1 group. The Langendorff technique was used to record cardiac function in isolated rat heart before and after 30 min of global ischemia followed by 60 min of reperfusion. The parameters of cardiac function, including left ventricular developing pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal differentials of LVDP (±LVdP/dt _max) and coronary flow (CF), were measured. The results showed: (1) compared with the control group, TF1 (10, 20, 40 μmol/l) displayed a better recovery of cardiac function after ischemia/reperfusion in a concentration-dependent manner. At 60 min of reperfusion, LVDP, ±LVdP/dt _max and CF in the TF1 group were much higher than those in the control group, whereas left ventricular end-diastolic pressure (LVEDP) in the TF1 group was lower than that in the control group (P < 0.01). (2) Pretreatment with glibenclamide (10 μmol/l), a K_ATP antagonist, completely abolished the cardioprotective effects of TF1 (20 μmol/l). Also, most of the effects of TF1 (20 μmol/l) on cardiac function after 60 min of reperfusion were reversed by 5-HD (100 μmol/l), a selective mitochondria K_ATP antagonist. (3) Atractyloside (20 μmol/l), a mitochondrial permeability transition pore (mPTP) opener, administered at the beginning of 15 min of reperfusion completely abolished the cardioprotection of TF1 (20 μmol/l). The results indicate that TF1 protects the rat heart against ischemia/reperfusion injury through the opening of K_ATP channels, particularly on the mitochondrial membrane, and inhibits mPTP opening.     

Antihypoxic effects of derivative on the EEG power spectra in rats with different susceptibility to oxygen deficiency

The succinate-containing hydroxypyridine derivative yancarb increases both the altitude tolerated by rats and their survival time at a high altitude, particularly in rats with low resistance to hypobaric hypoxia; it also prevents both phasic changes in the EEG characteristic of hypobaric hypoxia and hemispheric asymmetry and paroxysmal activity in the brain of highly resistant rats in the 5000–10,000 m range and in rats with low resistance in the 5000–11,000 m range. Antihypoxic effects of this substance are more pronounced in low-resistance rats and in the left hemisphere of both high- and low-resistant animals; in altitude range of 10,000–13,000 m these effects are weaker or absent. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 7, pp. 57–62, July, 1997     

Protein kinase C inhibitors block acetylcarnosine-induced contractions of ischemic myocardium

Protein kinase C inhibitors chelerythrine and Ro31-8220 blocked acetylcarnosine-induced myocardial contractions during subtotal ischemia, which was associated with an increase in ischemic and reperfusion myocardial contractures and a decrease in the developed pressure and cardiac contractility index during subsequent reperfusion. Neither chelerythrine nor Ro31-8220 decreased the membranoprotective effect of acetylcarnosine determined by its antioxidant properties. The results indicate the involvement of protein kinase C in acetylcarnosine stimulation of myocardial contractions in ischemia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 9, pp. 305–307, September, 1999     

绞股蓝总皂甙对大鼠心肌缺血再灌注损伤的保护作用

结扎大鼠冠状动脉40分钟,解除结扎恢复血流再灌注20分钟,复制大鼠心肌缺血/再灌注损伤模型,观察绞股蓝总皂甙(GP)对心肌缺血/再灌注损伤的影响。结果,GP明显提高心肌组织GSH-Px活性,降低心肌MDA含量,使降低的线粒体膜流动性恢复,减轻再灌注导致心肌超微结构损伤。提示,GP对大鼠心肌缺血/再灌注损伤有保护作用,作用机理与抗氧化作用有关。     

低浓度11,12-EET预干预对大鼠心肌缺血/再灌注损伤的影响

目的:观察外源性低浓度 11,12-EET预干预对大鼠在体心肌缺血/再灌注损伤的影响。方法:雄性Wistar大鼠,开胸,结扎和松开冠状动脉左前降支,复制心肌缺血/再灌注模型;采用缺血 5min/再灌注 5min两次造成缺血预处置。实验分 3组:对照组;缺血预处置组;外源性 11,12-EET预干预组。每组再分为A、B 2小组:A组动物心肌缺血 10min/再灌注 10min,主要观察缺血/再灌注各时程之心律失常;B组动物缺血 6 0min/再灌注 30min,主要观察缺血期心律失常、心功能的变化及再灌注后心肌梗死范围。结果:缺血预处置和 11,12-EET(6 2 4× 10^-8mol/L)预干预均可减轻缺血/再灌注心律失常及心功能的变化,降低心肌梗死范围。结论:11,12-EET预干预具有类缺血预处置样的心肌保护作用.     

线粒体ATP敏感性钾通道参与超极化停搏的心肌保护作用

目的：探讨线粒体ATP敏感性钾通道（mitoKATP）开放在超极化停搏心肌保护中的作用机制。方法:将SD大鼠随机分为对照组（Control）、去极化停搏组（D）、超极化停搏组（H）、5-羟葵酸(5-HD) +去极化停搏组（5HD+D）、5-HD+超极化停搏组（5HD+H），每组8例。建立Langendorff灌注模型，平衡20 min，以不同方式停搏40 min，再灌注30 min，对比观察：(1)不同时间血流动力学变化；(2)再灌注末取心肌并分离、制备线粒体，电镜观察超微结构的变化。(3)平衡末、再灌注末线粒体活性氧的产生。结果: (1)各组再灌注末大鼠心脏功能明显低于平衡末, 心肌线粒体超微结构均遭受不同程度损伤，左室发展压（LVDP）、左室舒张末压（LVEDP）、率压双乘积（DP）、冠脉流量（CF）有显著差异（P<0.01）；（2）超极化停博组再灌注末心脏功能指标LVDP、LVEDP、DP、CF明显优于去极化停博组、5-HD+超极化停搏组、5-HD+去极化停搏组、对照组（P<0.01），电镜示：心肌、线粒体超微结构遭受的损伤较轻; (3)超极化停博组再灌注末心肌线粒体活性氧产生率低于对照组与其它3组（P<0.01）。结论:(1)超极化停搏能明显改善再灌注后心功能，保护心肌、线粒体超微结构，减少活性氧生成；(2)mitoKATP的早期开放参与超极化停搏，其作用可能通过保护再灌注后的线粒体呼吸功能，减轻线粒体的氧化损伤，为再灌注心肌提供较好的能量供应，从而使缺血再灌注后的心脏收缩功能得到一定恢复。     

Sleep structure and periodic breathing in Tibetans and Han at simulated altitude of 5000 m

Tibetans are the oldest population living permanently at high altitude. They possess several adaptations to low oxygen pressure that improve oxygen transport. We hypothesised that native Tibetans have mechanisms allowing them to maintain a better sleep structure and oxygenation during sleep at high altitude than newcomers from lower altitudes acclimatised to living at high altitude. We studied eight healthy young Tibetans, aged 26+/-7 years, and six healthy young Han aged 30.5+/-4 years. All subjects were living on the Tibetan plateau at an altitude of around 4000 m. Investigations were performed in Xining at an altitude of 2261 m, PB=581 mmHg. Two full polysomnographies (PSG) were performed in a hypobaric chamber, one at the ambient altitude, the second during acute exposure to the simulated altitude of 5000 m (PB=405 mmHg). Both PSG were done on the same night using split night design. At 2261 m no differences in sleep structure, breathing pattern during sleep or oxygenation were found, except a higher number of arousals and awakenings in Han (P<0.002). At 5000 m Tibetans had a longer sleep time (P=0.002), shorter stage 1 non-REM sleep (P<0.001) and longer stage 2 non-REM sleep than Han (P<0.001). Tibetans showed a trend to have more periodic breathing (PB) and higher mean arterial blood saturation than Han (NS). Our data suggest that Tibetans preserved better sleep structure and arterial blood oxygenation than Han during acute exposure to the simulated altitude of 5000 m.     

Sepiapterin reduces postischemic injury in the rat heart

A reduced availability of tetrahydrobiopterin (BH4), an essential cofactor for NO-synthesis, is causally involved in the development of endothelial dysfunction associated with ischemia/reperfusion. We, therefore, investigated the effect of sepiapterin, a substrate for BH4 synthesis, on postischemic injury in myocardial infarction and myocardial stunning. In rats, myocardial stunning was induced by repetitive ischemia (5×10-min ligature of the left coronary artery, 5×20-min reperfusion) and myocardial infarction by 50-min ligature and 60-min reperfusion. Myocardial blood flow was determined by H₂-clearance, regional myocardial function by pulsed Doppler and infarct size by tetrazolium staining. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil extravasation. cGMP was determined in rat serum as an indicator of increased NO synthesis. In animals treated with sepiapterin, regional myocardial function was significantly improved in both myocardial stunning and infarction and infarct size was significantly reduced. MPO activity decreased with sepiapterin treatment in both models. The systemic level of cGMP was reduced both following myocardial stunning and myocardial infarction in the control group. Pretreatment with sepiapterin induced a significant increase of cGMP level at the end of the protocol in both models. Substitution of sepiapterin reduces postischemic injury both in myocardial stunning and infarction apparently by ameliorating the availability of NO, thereby attenuating the activation of neutrophils in ischemia/reperfusion.     

Role of cannabinoid receptors in the regulation of cardiac contractility during ischemia/reperfusion

We studied the effect of selective ligands of cannabinoid (CB) receptors on contractility of isolated Langendorff-perfused rat heart under conditions of 45-min total ischemia and 30-min reperfusion. Perfusion with a solution containing selective CB receptor agonist HU-210 for 10 min before ischemia increased the severity of reperfusion contractile dysfunction. This drug decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. The negative inotropic effect of the drug was transitory and disappeared after 5-min reperfusion. Pretreatment with selective CB1 receptor antagonist SR141716A and selective CB2 receptor antagonist SR144528 had no effect on heart rate and myocardial contractility during reperfusion. Our results indicate that stimulation of CB receptors can increase the degree of reperfusion-induced cardiac contractile dysfunction. However, endogenous cannabinoids are not involved in the development of myocardial contractile dysfunction during ischemia/reperfusion of the isolated heart. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 500–504, November, 2006     

The effect of 18 h of simulated high altitude on left ventricular function

High altitude produces increased pulmonary capillary pressure by hypoxia induced pulmonary vasoconstriction. It is also possible that hypoxia results in mildly elevated left ventricular (LV) filling pressures that may contribute to the elevated capillary pressures. This study investigates the impact of simulated high altitude on global and regional echocardiographic measures of LV performance and filling pressure. Seventeen healthy individuals underwent transthoracic echocardiography, including tissue Doppler of the septal mitral annulus and basal segments before and after an 18-h overnight stay in a high altitude simulation tent with a FiO₂ of 12%, simulating an altitude of approximately 4,000 m above sea level. In simulated high altitude, the ratio of early transmitral flow velocity to early myocardial relaxation velocity increased 22%, P < 0.001, and the Index of Myocardial Performance increased 30%, P < 0.01 due to an 58% increase in the isovolumic relaxation time (IVRT), P < 0.001. Simulated high altitude leads to a reduction in LV performance with an accompanying increase in markers of LV filling pressure. The significant changes in filling pattern and IVRT in the setting of normal and unchanged systolic function, indicates that hypoxia induces mild diastolic dysfunction in young healthy individuals.