ABSTRACT
Objective To investigate the effects of A3 adenosine receptor ( A3AR) agonist on lung injury after cardiopulmonary bypass ( CPB) in rabbits. Methods Twenty-four rabbits were randomly divided into 3 groups, with 8 in each group. Rabbits in control group only received CPB, those in agonist group were given selective A3AR agonist IB-MECA intravenously 15 min before aorta clamp, and those in agonist + antagonist group were managed with selective A3AR receptor antagonist MRS-1191 intravenously before IB-MECA infusion. After CPB, serum concentrations of tumor necrosis factor-α ( TNF-α) and interleukin-8 ( IL-8), concentrations of malondialdehyde ( MDA) and myeloperoxidase ( MPO) in lung tissues, lung wet/dry weight ratio ( W/D), lung function related indexes of PaO_2/FiO_2, airway pressure (AWP) and pulmonary vascular resistance ( PVR), and histological changes of lung tissues were observed. Results Concentrations of serum TNF-a and IL-8 were significantly lower in agonist group than in control group and agonist + antagonist group (P <0.05). Compared with control group and agonist + antagonist group, W/D was much smaller, and concentrations of MDA and MPO were significantly lower in agonist group after CPB (P <0.05). PaO_2/FiO_2 was significantly higher, while AWP and PVR were significantly lower in agonist group than in control group and agonist + antagonist group (P <0.05). It was revealed by histological examinations that the pathological changes were less severe in agonist group than in control group and agonist + antagonist group. Conclusion A3AR agonist IB-MECA can reduce lung injury after CPB.
ABSTRACT
A brief period of cerebral ischemia produces neuronal damage in the vulnerable regions of the brain, such as the CA1 area of the hippocampus. However, mild ischemic episodes may limit damage from subsequent ischemic insults, the phenomenon known as ischemic tolerance or preconditioning. We used hippocampal slices as an experimental model to investigate the possible utilization of ischemic tolerance, and to determine the effects of various drugs acting on glutamate and adenosine receptors following a conditioned ischemic insult. Preconditioning ischemic insult was induced in hippocampal slices of 450nm thickness for 60-70 seconds. Glutamate and adenosine receptors were pretreated 1 hour later with D,L-2-amino-5-phosphonovaleric acid(AP-5, 50nM), propentofylline(PPF, 200nM), 6-cyano-7-nitroquinoxaline-2,3-dione(CNQX, 10nM), 8-cyclopentyl-3,7-dihydro-1,3-dipropyl-1H-purine-2,6-dione(DPCPX, 1, 10nM) and 2-chloro-N6-cyclopentyl-adenosine (CCPA, 1, 10, 50nM). The slices were reoxygenated for 3 hours, after then a second ischemic insult was induced by substituting 95% O2, 5% CO2 and glucose for 95% N2, 5% CO2 and sucrose for 10 minutes. Population spikes(PS) were estimated from extracellular electrophysiological recordings of the hippocampal CA3-CA1 synaptic conduction 1 hour following the second ischemic insult. The PS(mV) was 2.69+/-0.06 in the normal hippocampal slice, while it was reduced to 1.21+/-0.05 in the hippocampal slice induced with 10 minutes of ischemia. The effects of the A1 selective agonist CPPA revealed a reduction of PS to 0.98+/-0.06 with low concentration(1nM), similar PS as the control group with a concentration of 10nM, and an increase in ischemic tolerance of 1.78+/-0.05 at a higher concentration(50nM). The selective A1 antagonist DPCPX(1nM) showed minimal reduction in PS of 1.10+/-0.04, while the NMDA antagonist AP-5(5nM) had a more profound weakening effect(1.05+/-0.04). The adenosine uptake inhibitor profentophylline(200nM) augmented the PS to 1.56+/-0.06; this effect was not influenced by 1nM DPCPX(1.60+/-0.07), but was abolished by a higher concentration of 10nM(1.36+/-0.05). These results confirmed ischemic tolerance in the hippocampal experimental model. We conclude that adenosine plays an important role in ischemic tolerance as activation of adenosine receptors or adenosine uptake inhibition enhances ischemic tolerance.