Bjerring Peter Nissen, Dale Nicholas, Larsen Fin Stolze
Department of Hepatology, Rigshospitalet, 2100, Copenhagen, Denmark,
Neurochem Res. 2015 Feb;40(2):258-64. doi: 10.1007/s11064-014-1357-4. Epub 2014 Jun 13.
Acute liver failure (ALF) can lead to brain edema, cerebral hyperperfusion and intracranial hypertension. These complications are thought to be mediated by hyperammonemia and inflammation leading to altered brain metabolism. As increased levels of adenosine degradation products have been found in brain tissue of patients with ALF we investigated whether hyperammonemia could induce adenosine release in brain tissue. Since adenosine is a potent vasodilator and modulator of cerebral metabolism we furthermore studied the effect of adenosine receptor ligands on intracranial pressure (ICP) and cerebral blood flow (CBF). We measured the adenosine concentration with biosensors in rat brain slices exposed to ammonia and in a rat model with hyperammonemia and systemic inflammation. Exposure to ammonia in concentrations from 0.15-10 mM led to increases in the cortical adenosine concentration up to 18 µM in brain slices. In vivo recordings showed a tendency towards increased adenosine levels in rats with hyperammonemia and systemic inflammation compared to a control group (3.7 ± 0.7 vs. 0.8 ± 0.2 µM, P = 0.06). This was associated with a significant increase in ICP and CBF. Intervention with the non-selective adenosine receptor antagonist theophyllamine, the A2A receptor antagonist ZM241385, or the A1 receptor agonist N6-Cyclopentyladenosine did not reduce ICP or CBF. In conclusion, our results show that the adenosine concentration in cortex increases during exposure to ammonia, and is associated with a rise in intracranial pressure and cerebral perfusion. However adenosine receptor antagonism/agonism did not reduce the ICP or CBF which indicates that adenosine may not be of direct importance for these cerebral complications in ALF.
急性肝衰竭（ALF）可导致脑水肿、脑血流灌注过多和颅内高压。这些并发症被认为是由高氨血症和炎症介导的，进而导致脑代谢改变。由于在ALF患者的脑组织中发现腺苷降解产物水平升高，我们研究了高氨血症是否会诱导脑组织中腺苷释放。鉴于腺苷是一种强效血管舒张剂和脑代谢调节剂，我们还研究了腺苷受体配体对颅内压（ICP）和脑血流量（CBF）的影响。我们使用生物传感器测量了暴露于氨的大鼠脑片以及高氨血症和全身炎症大鼠模型中的腺苷浓度。暴露于浓度为0.15 - 10 mM的氨会导致脑片中皮质腺苷浓度升高至18 μM。体内记录显示，与对照组相比，高氨血症和全身炎症大鼠的腺苷水平有升高趋势（3.7 ± 0.7 vs. 0.8 ± 0.2 μM，P = 0.06）。这与ICP和CBF的显著增加相关。使用非选择性腺苷受体拮抗剂茶碱、A2A受体拮抗剂ZM241385或A1受体激动剂N6 - 环戊基腺苷进行干预并未降低ICP或CBF。总之，我们的结果表明，暴露于氨期间皮质中的腺苷浓度会升高，并与颅内压升高和脑灌注增加相关。然而，腺苷受体拮抗/激动并未降低ICP或CBF，这表明腺苷可能对ALF中的这些脑部并发症没有直接重要性。
