thioacetamide and 8-phenyltheophylline

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 (approximately 25%) renal arterial blood flow, a lower (approximately 30%) 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-1,3-dipropylxanthine (DPCPX, an adenosine A(1) receptor antagonist) and 3,7-dimethyl-1-propargylxanthine (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.

Topics: Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Animals; Chemical and Drug Induced Liver Injury; Denervation; Disease Models, Animal; Liver; Liver Diseases; Male; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Receptors, Adenosine A2; Renal Insufficiency; Sodium; Theobromine; Theophylline; Thioacetamide; Urine; Xanthines

In healthy rats, we recently showed that reduced intrahepatic portal blood flow leads to activation of hepatic adenosine receptors and a nerve-induced decrease in urine production. We hypothesize that the impaired urine excretion in liver cirrhosis is related to an increase in intrahepatic adenosine.. Anesthetized normal and thioacetamide-induced cirrhotic rats were instrumented for the measurement of urine flow, hepatic portal venous blood flow, and renal arterial blood flow. 8-Phenyltheophylline was used to block adenosine receptors.. Compared to normal rats, cirrhotic rats had a lower baseline urine flow (P<0.05). In both normal and cirrhotic rats, intraportal but not intravenous administration of 8-phenyltheophylline increased urine flow. Saline overload in normal rats increased urine flow (from 6.8+/-0.6 to 42.2+/-4.6 microlmin(-1)) and this ability was impaired in cirrhotic rats (from 3.9+/-0.4 to 6.2+/-0.9 microlmin(-1)). Intraportal, but not intravenous, administration of 8-phenyltheophylline partially restored the renal ability to excrete the saline load.. Impaired renal ability to excrete urine in liver cirrhosis is related to the activation of intrahepatic adenosine receptors, and this is consistent with our previous data showing renal regulation through a hepatorenal neural mechanism activated by intrahepatic adenosine.

Topics: Adenosine; Animals; Female; Injections, Intravenous; Kidney; Liver; Liver Circulation; Liver Cirrhosis; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Sodium; Theophylline; Thioacetamide; Urine