CGMP STIMULATES BILE ACID-INDEPENDENT BILE FORMATION AND BILIARY BICARBONATE EXCRETION

The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on hepatic b ile formation was studied in isolated perfused rat livers and rat hepa tocytes. Studies in isolated perfused rat livers showed that infusion of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 3 mu mol/min or 100 mu M) 1) increased bile flow without affecting biliary excreti on of simultaneously infused taurocholate, 2) increased biliary concen tration and excretion of HCO3- but did not affect biliary excretion of glutathione, and 3) increased net perfusate H+ efflux without affecti ng hepatic O-2 uptake. Studies in isolated rat hepatocytes showed that 1) 8-BrcGMP increased intracellular pH in the presence (but not in th e absence) of extracellular HCO3-, an effect inhibited by 4,4'-diisoth iocyanostilbene-2,2'-disulfonic acid and Na+ replacement, 2) 8-BrcGMP did not affect taurocholate uptake and intracellular [Ca3+], and 3) bi le acids, like ursodeoxycholate and cholate, did not increase cellular cGMP. Taken together, these results indicate that cGMP stimulates bil e acid-independent bile formation, in part by stimulating biliary HCO3 - excretion. cGMP may increase HCO3- excretion by stimulating sinusoid al Na+-HCO3- cotransport, but not Na+/H+ exchange. cGMP, unlike adenos ine 3',5'-cyclic monophosphate, may not regulate hepatic taurocholate transport, and bile acid-induced HCO3--rich choleresis may not be medi ated via cGMP.