Effect of terlipressin on in vitro vascular hyporeactivity of portal hypertensive rats.
OBJECTIVE
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 arise from splanchnic vasoconstriction via stimulation of vasoconstrictor V1 receptors. This study assessed the effect of terlipressin on the in vitro vascular reactivity of portal hypertensive rats to the alpha-adrenoceptor agonist methoxamine.


METHODS
Portal hypertension was produced by portal vein ligation. Sham-operated rats served as controls. In isolated perfused mesenteric arteries of portal vein ligated and sham-operated rats pressor responses to methoxamine (3 nmol-3 mumol) were determined in the absence and presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), terlipressin or the selective V2 receptor agonist desmopressin (each 0.5 microM). In addition, the direct pressor properties of terlipressin (3 pmol-100 nmol) were compared to arginine vasopressin (3 pmol-1 nmol) in vessels of normal rats.


RESULTS
Mesenteric vessels of portal vein ligated rats were markedly hyporeactive to methoxamine, even in the presence of L-NAME. Terlipressin alone reduced and in combination with L-NAME abolished the difference in reactivity to methoxamine between the portal vein ligated and sham-operated groups, while desmopressin was ineffective. Arginine vasopressin potently contracted vessels of normal rats with a threshold dose of 10 pmol and was maximally effective at 300 pmol. In contrast, terlipressin failed to produce pressor responses up to 100 nmol.


CONCLUSIONS
Hyporeactivity of mesenteric vessels of portal 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 inhibiting the nitric oxide-independent mechanism that underlies the reduced responsiveness to methoxamine in portal hypertension. This effect of terlipressin appears to be independent of stimulation of V2 as well as vasoconstrictor V1 receptors.
Heinemann
A
A
Department of Experimental and Clinical Pharmacology, Karl Franzens University, Graz, Austria.
Stauber
R E
RE
D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008236:Lypressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008729:Methoxamine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000187:drug effects; D000077585:Terlipressin; D014664:Vasodilation / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D017483:Receptors, Vasopressin; D008236:Lypressin; D000077585:Terlipressin; D008729:Methoxamine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester