Role of protein kinase C in mesenteric pressor responses of rats with portal hypertension

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 presser 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 presser response 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 removal of the endothelium potentiated the response of both groups. However, only removal of the endothelium completely eliminated the reduced presser 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 presser 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 presser 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 presser response, it is concluded that the endothelial alteration interacts with the mechanism producing PKC activation, which results in a lower presser response of the PVL mesenteric vaculature.