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

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 alpha(1)-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 N-G-nitro-L-arginine (L-NNA), indomethacin cyclooxygenase (COX) inhibitor, L-NNA + indomethacin, or the thromboxane (TX) A(2) receptor blocker SQ29,548. TXA(2) production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA(2) synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA(2) synthase as well as with increased production of TXA(2). 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 TXA(2), play a major role in regulating the response of cirrhotic livers to methoxamine.