Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers

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Abstract
In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the α1-adrenergic vasoconstrictor methoxamine and the mechanisms involved in its regulation. A portal perfusion pressure dose-response curve to methoxamine was performed in control and cirrhotic rat livers preincubated with vehicle, the nitric oxide synthase blocker NG -nitro-l-arginine (l-NNA), indomethacin cyclooxygenase (COX) inhibitor, l-NNA + indomethacin, or the thromboxane (TX) A2 receptor blocker SQ 29,548. TXA2 production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA2 synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA2 synthase as well as with increased production of TXA2. The hyperresponse to methoxamine of cirrhotic livers disappeared by COX inhibition with indomethacin but not after NO inhibition. SQ 29,548 also corrected the hyperresponse of cirrhotic livers to methoxamine. In conclusion, COX-derived prostanoids, mainly TXA2, play a major role in regulating the response of cirrhotic livers to methoxamine.

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