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Terlipressin, a provasopressin drug exhibits direct vasoconstrictor properties: Consequences on heart perfusion and performance*

Ryckwaert, Frédérique MD, PhD; Virsolvy, Anne PhD; Fort, Aurélie PhD; Murat, Brigitte; Richard, Sylvain PhD; Guillon, Gilles PhD; Colson, Pascal H. MD, PhD

doi: 10.1097/CCM.0b013e31819b8199
Clinical Investigations

Objective: Terlipressin has been proposed as an alternative treatment to catecholamines to restore blood pressure in septic shock. Terlipressin is considered as a vasopressin prodrug capable of releasing small but sustained amounts of [Lysine8] vasopressin (LVP) and to provide prolonged biological effect. However, terlipressin may act as a direct vasopressor beyond its conversion into LVP. We investigated terlipressin direct vasoconstrictive properties and consequences on myocardial perfusion and performance.

Design: Experimental studies.

Settings: National Research Institute Laboratories.

Subjects: Rat aorta and heart, human uterine artery.

Interventions: Studies of vasoconstriction on isolated vascular rings obtained either from rat aorta or human uterine artery, and of coronary flow, ventricular performance, and heart rhythm on rat hearts using a modified Langendorff heart apparatus.

Measurements and Main Results: Terlipressin induced a rapid, saturable, and dose-dependent contraction of rat aortas and human uterine arteries. Although the maximal terlipressin-induced vasoconstriction observed on rat arteries was weaker than LVP, or arginine-vasopressin, pharmacologic properties on human arteries, such as full agonism and strong maximal effect (900% of the maximal response obtained with phenylephrine), suggest a high potential of terlipressin to directly vasoconstrict human vessels. Similarly, terlipressin induced a saturable and dose-dependent vasoconstriction of coronary arteries that was reversible and antagonized by selective V1a antagonists. Maximum rates of left ventricle pressure rise (dP/dtmax) and fall (dP/dtmin) decreased both only in proportion to the decrease in coronary flow.

Conclusions: Besides long lasting effect through slow conversion into LVP, terlipressin is a fast acting vasopressor peptide per se that has an impact on coronary circulation and myocardial function.

From the Institut de Génomique Fonctionnelle, département d’Endocrinologie (FR, BM, PC, GG), Montpellier, France; CNRS UMR 5203 (FR, BM, PC, GG), INSERM U 661, Université Montpellier I, Université Montpellier II, Montpellier, France; INSERM U 637 Montpellier (AV, AF, SR), France; Hôpital Arnaud de Villeneuve (PC), Montpellier, France.

Supported, in part, by INSERM, CNRS, and Fondation de France.

This work was performed at the Institut de Génomique Fonctionnelle, Département d’Endocrinologie, and INSERM U637, Montpellier, France.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: p-colson@chu-montpellier.fr

© 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins