The existence of a hepatorenal link is suggested by several pathophysi
ological observations (indirect actions of glucagon on the kidney, hep
atorenal syndrome), but the nature of this link; remains unidentified.
We propose that extracellular circulating cyclic AMP could be this li
nk. Cyclic AMP (cAMP) is the intracellular second messenger of glucago
n (G) action in the liver, and this organ is known to release cAMP in
the blood in relatively large amounts after G administration. On thr o
ther hand, the proximal tubule (mainly the pars rectal is known to tak
e up cAMP through,ugh the organic acid transport system. We observed t
hat the glucagon-induced rise in phosphate excretion, which requires s
upraphysiologic concentration of tr, was significantly correlated with
the simultaneous rise in plasma cAMP and could be mimicked by i.v. in
fusion of cAMP alone. Moreover, we showed that a significant hyperfilt
ration (similar to that induced by supraphysiologic G) can be observed
if cAMP (mimicking G-induced hepatic release) is coinfused with a muc
h lower. physiologic, amount of G. Taken together, these observations
suggest that: (1) cAMP is a hepatorenal link and that plasma cAMP perm
anently influences the intensity of reabsorption in the pars recta of
the proximal tubule; and (2) that cAMP participates, in conjunction wi
th G, to control GFR. Insulin is known to exert an inhibitory influenc
e on G-induced cAMP release by the liver and will thus weaken the indi
rect (cAMP-mediated) influence of G on renal function. This ''pancreat
o-hepatorenal cascade'' may explain the natriuretic effects of G and a
ntinatriuretic effects of insulin, and probably contributes to disturb
ances observed in some pathophysiological situations such as the edema
of liver cirrhosis or hyperfiltration of diabetes.