ROLE OF PROTEIN-KINASE-C IN MESENTERIC PRESSOR-RESPONSES OF RATS WITHPORTAL-HYPERTENSION

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.