Contribution of hepatic adenosine A1 receptors to renal dysfunction associated with acute liver injury in rats

✍ Scribed by Zhi Ming; Yi-Jun Fan; Xi Yang; W. Wayne Lautt

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 530 KB
• Volume: 44
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.21336

✦ Synopsis

Acute liver injury is associated with renal insufficiency, whose mechanism may be related to activation of the hepatorenal reflex. We previously showed that intrahepatic adenosine is involved in activation of the hepatorenal reflex to restrict urine production in both healthy rats and in rats with cirrhosis. The aim of the present study was to test the hypothesis that activation of intrahepatic adenosine receptors is involved in the pathogenesis of the renal insufficiency seen in acute liver injury. Acute liver injury was induced by intraperitoneal injection of thioacetamide (TAA, 500 mg/kg) in rats. The animals were instrumented 24 hours later to monitor systemic, hepatic, and renal circulation and urine production. Severe liver injury developed following TAA insult, which was associated with renal insufficiency, as demonstrated by decreased (ϳ25%) renal arterial blood flow, a lower (ϳ30%) glomerular filtration rate, and decreased urine production. Further, the increase in urine production following volume expansion challenge was inhibited. Intraportal, but not intravenous, administration of a nonselective adenosine receptor antagonist, 8-phenyltheophylline, improved urine production. To specify receptor subtype, the effects of 8-cyclopentyl-1,3dipropylxanthine (DPCPX, an adenosine A 1 receptor antagonist) and 3,7-dimethyl-1propargylxanthine (DMPX, an adenosine A 2 receptor antagonist) were compared. Intraportal but not intravenous administration of DPCPX greatly improved impaired renal function induced by acute liver injury, and this beneficial effect was blunted in rats with liver denervation. In contrast, neither intraportal nor intravenous administration of DMPX showed significant improvement in renal function. In conclusion, an activated hepatorenal reflex, triggered by intrahepatic adenosine A 1 receptors, contributed to the pathogenesis of the water and sodium retention associated with acute liver injury.(HEPATOLOGY 2006;44: 813-822.) S evere acute liver injury is associated with the development of renal dysfunction. [1][2][3][4] There are disorders of sodium and water excretion even in the early stage of the disease, when a normal renal blood supply and glomerular filtration rate can be maintained. As liver injury progresses, functional renal failure (hepatorenal syndrome) develops with avid sodium and water retention, associated with a decrease in renal blood flow and an increase in plasma creatinine without significant morphological changes in the kidneys. In the end stage of the disease, acute tubular necrosis may occur because of extremely deteriorated renal circulation and the development of endotoxemia. 3,5,6 The pathophysiological processes characteristic of renal dysfunction associated with acute liver injury, although less studied, have been suggested to resemble those observed in cirrhosis but progressing more rapidly. 3 Various mechanisms have been suggested for the pathogenesis of renal insufficiency secondary to acute liver injury including peripheral arterial vasodilation secondary to overproduction of vasodilator substances in splanchnic circulation, leading to splanchnic pooling and decreased effective systemic arterial