ENDOGENOUS CARBON-MONOXIDE SUPPRESSION STIMULATES BILE ACID-DEPENDENTBILIARY TRANSPORT IN PERFUSED-RAT-LIVER

This study aimed to investigate whether carbon monoxide (CO), a produc t of heme oxygenase that degrades protoheme IX serves as an endogenous modulator for biliary transport. To that end, effects of zinc protopo rphyrin IX (ZnPP), a heme oxygenase inhibitor, on the biliary transpor t were tested in perfused rat liver. Perfusion of 1 mu M ZnPP abolishe d detectable levels of CO in the venous perfusate and increased bile a cid-dependent bile output accompanying an increased secretion of bile salts. The ZnPP-induced choleresis coincided with a reduction of tissu e guanosine 3',5'-cyclic monophosphate (cGMP) levels and a decrease in vascular conductance. On administration of 2.5 mu M CO, ZnPP-elicited choleresis, decreases in vascular conductance, and cGMP levels were a ll attenuated. Treatment with 1 mu M 8-bromoguanosine 3',5'-cyclic mon ophosphate (8-BrcGMP) partly attenuated the ZnPP-induced choleresis in concert with repression of vascular conductance. Furthermore, treatme nt of the liver with methylene blue, a guanylate cyclase inhibitor, ev oked a choleresis similar to that induced by ZnPP. Thus endogenous CO suppression stimulates the biliary transport in part through a cGMP-de pendent mechanism.