| Objective: Experimental researches showed that chronic intermittent hypobaric hypoxia (CIHH) conferred a protective effect on heart, such as enhancement of cardiac resistance against ishchemia/reperfusion injury, relief of cardiac function decrease induced by ishchemia/reperfusion and anti- arrhythmia. The mechanism for cardioprotection of CIHH has not been well elucidated yet. The adenosine and adenosine receptors play an important role in the cardioprotection induced by ischemia or hypoxia preconditioning. But the role of adenosine and adenosine receptors in the protective effects of CIHH has not been reported. The aim of the present study was to explore the protective effect of CIHH against ischemia/reperfusion in adult rat hearts and the adenosine mechanisms involved in the cardioprotection of CIHH.Methods: Adult male Sprague-Dawley rats (n=54) were randomly divided into nine groups: ischemia/reperfusion control (Con-I/R, n=6) group, caffeine injection control (Con-caf, n=6) group, adenosine perfusion control (Con-ado-p, n=6) group, CIHH ischemia/reperfusion (CIHH-I/R, n=6) group, CIHH caffeine injection (CIHH-caf, n=6) group, CIHH caffeine perfusion (CIHH-caf-p, n=6) group, CIHH-A1receptor block (CIHH-dpc-p, n=6) group, CIHH-A2A receptor block (CIHH-sch-p, n=6) group, and CIHH-A2B receptor block(CIHH-mrs-p, n=6 ) group.CIHH rats were put into hypobaric chamber to get 28 days CIHH mimicking 5000m altitude (PB=404 mmHg, PO2=84 mmHg), 6 hrs per day. The isolated rat hearts in Con-I/R group underwent a 30-min global ischemia followed by 60-min reperfusion with K-H solution;the rats in Con-caf group accepted intraperitoneal injection caffeine (10mg/kg), a non-specificity adenosine receptor blocker, for 28-day, and the isolated hearts underwent a 30-min global ischemia followed by 60-min reperfusion with K-H solution; the isolated rat hearts in Con-ado-p group accepted 20-min reperfusion with K-H solution containing Adenosion(100uM) during 60-min reperfusion; the isolated rat hearts in CIHH-I/R underwent a 30-min global ischemia followed by 60-min reperfusion with K-H solution; the rats in CIHH-caf group accepted 28-day intraperitoneal injection caffeine (10mg/kg) before CIHH, and the isolated hearts underwent a 30-min global ischemia followed by 60-min reperfusion with K-H solution; the isoloated hearts in CIHH-caf-p group accepted 20-min reperfusion with K-H solution containing caffeine (100uM) during 60-min reperfusion; the isolated hearts in CIHH-dpc-p, CIHH-sch-p and CIHH-mrs-p groups accepted 20-min reperfusion with K-H solution containing DPCPX(100nM), a specific adenosine A1 receptor blocker, SCH58261(200nM), a specific adenosine A2A receptor blocker, and MRS1754(75nM), a specific adenosine A2B receptor blocker, during 60-min reperfusion, respe ctively.The animals were anesthetized with sodium pentobarbital (60 mg/kg, ip). The chest was opened and heart was quickly excised and mounted on a Langendorff apparatus for a retrograde perfusion with Krebs–Henseleit solution (K-H solution) undergoing 30-min global ischemia followed with 60-min reperfusion. The cardiac function including left ventricular develop pressure (LVDP), left ventricular end-diastolic pressure( LVEDP), the peak rate of pressure develop (±dp/dtmax) and coronary flow (CF) were, recorded at 5 min before ischemia and 10, 20, 30, 60 min during reperfusion, respectively. Lactate dehydrogenase (LDH) quantity and infarct area were measured, respectively.Results: (1) there was no significant difference between those groups. (2) The basic coronary flow (CF) in CIHH rats was significant higher than that in CON rats (P<0.05), while other parameters of cardiac function were not significant different among groups (P>0.05). (3) The cardiac function was damaged during hypoxia/reperfusion, but there was a significant different between CIHH-I/R and CON-I/R rats. The recovery of cardiac function in CIHH-I/R rats was much better than that in CON-I/R. The recovery of LVDP,±LVdP/dtmax and CF were 37.5±6.7%, 36.5±6.1%, 36.6±2.6% and 34.3± 5.0%,significant higher than 14.8±2.6%, 10.9±1.2%, 15.1±1.2% and 24.1±5.8% in CON-I/R rats,respectively (P<0.05). The LVEDP was 68.8±6.3mmHg,significant lower than 79.9±5.5mmHg in CON-I/R rats (P<0.05). The recovery of cardiac function in Con-ado-p rats was much better than that in CON-I/R. The recovery of LVDP,±LVdP/dtmax and CF were 27.9±8.2%, 24.6±7.0%, 26.3±7.3% and 44.0±6.5%,much higher than 14.8±2.6%, 10.9±1.2%, 15.1±1.2% and 24.1±5.8% in CON-I/R rats,respectively (P<0.05). The LVEDP was 68.8±9.4mmHg,significant lower than 79.9±5.5mmHg in CON-I/R rats (P<0.05). The CF in Con-caf rats was 31.8±4.8% ,significant higher than 24.1±5.8% in CON-I/R rats, while other parameters of cardiac function were not different between the two groups (P>0.05). The recovery of cardiac function in CIHH-caf, CIHH-caf-p, CIHH-dpc-p, CIHH-sch-p and CIHH-mrs-p rats were much lower than those in CIHH-I/R rats (P<0.05). The recovery of LVDP,±LVdP/dtmax in CIHH-caf, CIHH-caf-p, CIHH-dpc-p, CIHH-sch-p and CIHH-mrs-p rats were lower than those in CIHH-I/R rats (P<0.05). The recovery of CF in CIHH-caf, CIHH-caf-p, CIHH-sch-p and CIHH-mrs-p rats were lower than that in CIHH-I/R rats (P<0.05), and the CF was not different between CIHH-dpc-p and CIHH-I/R rats (P>0.05). The LVEDP in CIHH-caf-p, CIHH-dpc-p, CIHH-sch-p and CIHH-mrs-p was higher than that in CIHH-I/R rats (P<0.05), but the LVEDP was not different between CIHH-caf and CIHH-I/R rats (P>0.05). (4) The infarct size of CIHH-I/R rats was 45.9±5.1%,much smaller than 73.0±3.4% in Con-I/R rats (P<0.01). (5) The content of LDH in perfusate in Con-ado-p and CIHH-I/R rats was 43.8±5.1IU/L and 46.5±5.6IU/L, significant lower than 93.5±18.9IU/L in Con-I/R rats. The content of LDH in perfusate was not different between Con-caf and Con-I/R rats (P>0.05). The content of LDH in perfusate in CIHH-caf, CIHH-caf-p, IHH-dpc-p, CIHH-sch-p and CIHH-mrs-p rats were 103.9±37.2IU/L, 86.3±12.3IU/L, 89.0±19.8IU/L, 88.0±29.11U/L and 72.9±7.61U/L, higher than 46.5±5.6IU/L in CIHH-I/R rats, respectively (P<0.05).Conclusion: CIHH has a significant cardioprotection. CIHH can enhance resistance of myocardium against ischemia/reperfusion injury, promote the recovery of cardiac function, diminish the infarct size, and decrease the content of LDH. The activation of adenosine receptor might contribute to the cardioprotection afforded by CIHH and the protective effect of CIHH may be related with increasing in CF. |
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