Nm. Atucha et al., ROLE OF PROTEIN-KINASE-C IN MESENTERIC PRESSOR-RESPONSES OF RATS WITHPORTAL-HYPERTENSION, British Journal of Pharmacology, 118(2), 1996, pp. 277-282
1 Hyporesponsiveness to vasoconstrictors is a characteristic abnormali
ty of liver diseases of uncertain origin. In the present study, we hav
e evaluated the involvement of protein kinase C (PKC) in the reduced p
resser response to methoxamine (MTX) of a rat model of portal hyperten
sion induced by partial portal vein ligation (PVL). Experiments were p
erformed in the isolated and perfused mesentery. 2 The presser respons
e to MTX was reduced in PVL compared to that of control animals (Sham)
and pretreatment with N-G-nitro-L-arginine (L-NOARG, 10(-4) M) or rem
oval of the endothelium potentiated the response of both groups. Howev
er, only removal of the endothelium completely eliminated the reduced
presser response to MTX of the PVL vessels. 3 Pretreatment of the mese
ntric vessels with calphostin C (10(-6) M), a PKC inhibitor, reduced t
he response to MTX of Sham to a level similar to that of untreated PVL
vessels, but did not change that of PVL animals. 4 Mesenteric presser
responses to a PKC activator, phorbol 12,13-dibutyrate (PDBu), were s
imilar in vessels from both PVL and Sham rats and pretreatment with L-
NOARG or removal of the endothelium enhanced those responses while ind
omethacin (10(-5) M) decreased them. In all cases, the responses to PD
BU were similar in PVL vessels compared to Sham. 5 These results indic
ate that the reduced presser response to MTX of the mesenteric vascula
r bed of PVL rats is due to an endothelial alteration, compatible with
an enhanced production of nitric oxide. The lack of response to calph
ostin C in PVL vessels suggests an impairment in agonist-induced PKC a
ctivation. Since direct activation of PKC induces a normal presser res
ponse, it is concluded that the endothelial alteration interacts with
the mechanism producing PKC activation, which results in a lower press
er response of the PVL mesenteric vaculature.