Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR-2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices
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Abstract
The decrease of cyclic GMP (cGMP) level in the brain, contributing to cognitive and
memory deficit in hyperammonemia (HA), has been attributed to the interference of
ammonia with the NMDA/nitric oxide/soluble guanylate cyclase (GC)/cGMP pathway in
neurons. The present study tested the hypotheses that (a) HA also affects cGMP synthesis
elicited by stimulation of the natriuretic peptide receptor 2 (NPR-2) with its natural
ligand, C-type natriuretic peptide (CNP) and (b) the latter effect may involve astrocytes,
the ammonia-sensitive cells. In the cerebral cortical slices of control rats, CNP
stimulated cGMP synthesis in a degree comparable to the NO donor, S-nitroso-N-acetylpenicillamine
(SNAP) used at an optimal concentration. Fluoroacetate (FA), a metabolic inhibitor
specifically affecting astrocytic mitochondria, inhibited the CNP-dependent cGMP synthesis
by about 50%. Ammonium acetate-induced HA decreased by 68% the CNP-dependent cGMP
generation in slices incubated in the absence of FA. In slices incubated in the presence
of FA, cGMP synthesis in slices derived from HA rats did not differ from that in control
slices. The results indicate that HA inhibits CNP-dependent cGMP synthesis in the
FA-vulnerable, astrocytic compartment, but not in the FA-resistant compartment(s)
of the brain. HA did not affect the expression of NPR-2 mRNA in the cerebral cortex
tissue as tested using real-time PCR, indicating that the effect of ammonia involves
as yet unidentified events occurring posttranscriptionally. Deregulation of NPR-2
function in astrocytes by ammonia may contribute to neurophysiological symptoms of
HA.