Al. Gerbes et al., THE GUANYLATE CYCLASE-COUPLED NATRIURETIC PEPTIDE RECEPTOR - A NEW TARGET FOR PREVENTION OF COLD ISCHEMIA-REPERFUSION DAMAGE OF THE RAT-LIVER, Hepatology, 28(5), 1998, pp. 1309-1317
The aim of our studies was to investigate hormonal prevention of hepat
ic preservation damage by the atrial natriuretic peptide (ANP) and the
mechanisms involved. Isolated perfusion of rat livers was performed i
n a nonrecirculating fashion. Twenty minutes of preischemic perfusion
was performed with or without different concentrations of ANP, followe
d by 24-hour storage in cold University of Wisconsin (UW) solution. Tw
o hundred nanomoles of ANP prevented hepatocellular damage during a 2-
hour reperfusion period as indicated by a marked attenuation of the si
nusoidal efflux of lactate dehydrogenase (LDH) and purine nucleoside p
hosphorylase (PNP), and by reduced Trypan blue uptake. Furthermore, po
stischemic bile flow as an indicator of liver function was significant
ly improved by about 60% with 200 nmol/L ANP, No protection was convey
ed by 20 nmol/L ANP nor by pretreatment with 200 nmol/L ANP for only 1
0 minutes. The effects of ANP seemed to be mediated by the guanylate c
yclase-coupled A (GC-A) receptor and cyclic guanosine monophosphate (c
GMP), whereas expression of both GC-A and GC-B receptors as well as of
the GC-C receptor was found, cGMP did protect from ischemia-reperfusi
on damage, but selective ligands of the B and C receptor did not. To b
egin to determine the mechanisms of ANP-mediated protection, different
parameters were investigated: ANP had no effect on portal pressure as
an indicator of hepatic circulation, nor on intracellular energy depl
etion determined by adenosine nucleotide concentration. However, the m
arked augmentation of nuclear factor kappa B (NF-kappa B) binding acti
vity during reperfusion was prevented in ANP-pretreated livers. In con
clusion, pretreatment with ANP protects the rat liver from cold ischem
ia-reperfusion damage. This effect is mediated via the GC-A receptor a
nd cGMP, and may be linked to an influence of ANP on NF-kappa B activa
tion. Thus, ANP signaling via the GC-A receptor should be considered a
s a new pharmacological target to prevent preservation injury of the l
iver.