EFFECT OF TERLIPRESSIN ON IN-VITRO VASCULAR HYPOREACTIVITY OF PORTAL HYPERTENSIVE RATS

Background/Aims: Isolated vessels of portal hypertensive rats exhibit decreased responsiveness to vasoconstrictors. The vasopressin analogue terlipressin is used in the treatment of portal hypertension since it is known to reduce portal pressure, an effect that is thought to aris e from splanchnic vasoconstriction via stimulation of vasoconstrictor V-1 receptors. This study assessed the effect of terlipressin on the i n vitro vascular reactivity of portal hypertensive rats to the alpha-a drenoceptor agonist methoxamine. Methods: Portal hypertension was prod uced by portal vein ligation. Sham-operated rats served as controls. I n isolated perfused mesenteric arteries of portal vein ligated and sha m-operated rats pressor responses to methoxamine (3 nmol-3 mu mol) wer e determined in the absence and presence of the nitric oxide synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME; 100 mu M), terlip ressin or the selective V-2 receptor agonist desmopressin (each 0.5 mu M). In addition, the direct pressor properties of terlipressin (3 pmo l-100 nmol) were compared to arginine vasopressin (3 pmol-1 nmol) in v essels of normal rats. Results: Mesenteric vessels of portal vein liga ted rats were markedly hyporeactive to methoxamine, even in the presen ce of L-NAME. Terlipressin alone reduced and in combination with L-NAM E abolished the difference in reactivity to methoxamine between the po rtal vein ligated and sham-operated groups, while desmopressin was ine ffective. Arginine vasopressin potently contracted vessels of normal r ats with a threshold dose of 10 pmol and was maximally effective at 30 0 pmol. In contrast, terlipressin failed to produce presser responses up to 100 nmol. Conclusions: Hyporeactivity of mesenteric vessels of p ortal vein ligated rats to methoxamine is predominantly independent of nitric oxide. Terlipressin alone ameliorates and in combination with L-NAME abolishes the hyporesponsiveness to methoxamine presumably by i nhibiting the nitric oxide-independent mechanism that underlies the re duced responsiveness to methoxamine in portal hypertension. This effec t of terlipressin appears to be independent of stimulation of V-2 as w ell as vasoconstrictor V-1 receptors.