1. Hyporesponsiveness to
vasoconstrictors is a characteristic abnormality of
liver diseases of uncertain origin. In the present study, we have evaluated the involvement of
protein kinase C (PKC) in the reduced pressor response to
methoxamine (MTX) of a rat model of
portal hypertension induced by partial portal vein
ligation (PVL). Experiments were performed in the isolated and perfused mesentery. 2. The pressor response to MTX was reduced in PVL compared to that of control animals (
Sham) and pretreatment with
NG-nitro-L-arginine (L-NOARG, 10(-4) M) or removal of the endothelium potentiated the response of both groups. However, only removal of the endothelium completely eliminated the reduced pressor response to MTX of the PVL vessels. 3. Pretreatment of the mesentric vessels with
calphostin C (10(-6) M), a PKC inhibitor, reduced the 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 pressor responses to a PKC activator,
phorbol 12,13-dibutyrate (PDBu), were similar in vessels from both PVL and
Sham rats and pretreatment with L-
NOARG or removal of the endothelium enhanced those responses while
indomethacin (10(-5) M) decreased them. In all cases, the responses to PDBU were similar in PVL vessels compared to
Sham. 5. These results indicate that the reduced pressor response to MTX of the mesenteric vascular bed of PVL rats is due to an endothelial alteration, compatible with an enhanced production of
nitric oxide. The lack of response to
calphostin C in PVL vessels suggests an impairment in agonist-induced PKC activation. Since direct activation of PKC induces a normal pressor response, it is concluded that the endothelial alteration interacts with the mechanism producing PKC activation, which results in a lower pressor response of the PVL mesenteric vaculature.