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

Abstract

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.

Role of mammalian cytosolic molybdenum Fe–S flavin hydroxylases in hepatic injury

“…A variety of industrial chemicals and drugs such as carbontetrachloride (CCl 4 ) (Wang et al, 2007;Wu et al, 2007), chloroform (CHCl 3 ) (Lind and Gandolfi, 1999;Begay and Gandolfi, 2003), thioacetamide (TAA) (Murayama et al, 2007;Ming et al, 2006;Fitzhugh and Nelson 1948), acetaminophen (AAP) (Cover et al, 2006;Sener et al, 2006) and bromobenzene (BB) (Heijne et al, 2004;Delnomdedieu et al, 1998;Lind and Gandolfi, 1999) have been reported to produce experimental animal models of hepatic injury. Occupational and accidental exposure of human to these compounds is not uncommon.…”

Regulatory processes interacting to maintain hepatic blood flow constancy: Vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction

“…In contrast, intravenous administration of the antagonist was only effective at higher doses, thereby confirming that the adenosine receptor antagonist was acting on the liver and not directly on the kidney. The adenosine A 2 agonist was without impact on the renal function 51 …”

“…We have recently suggested that a hepatic blood flow‐dependent hepatorenal reflex is the primary pathophysiological mechanism for renal dysfunction in liver disease. This reflex is activated by adenosine in the space of Mall that is regulated by hepatic blood flow 48–51 …”

Metabolic syndrome and the hepatorenal reflex

“…[101156157158159160] The compounding effect of RAS stimulation caused by renal ischemia in response to rSNA is well established, with elevated Ang II resulting in broad activation of sympathetic outflow capable of generalized overdrive. [55152163]…”

“…[18] Further, extracellular ATP is exclusively metabolized to adenosine by ecto-5’ nucleotidase. [277] Regardless of the dominant pathway, adenosine A1 receptors have been shown to be responsible for the activation of the hepatorenal reflex[101157158159160] and AMP,[207] inosine[11170] and adenosine[138] all activate A1 receptors.…”