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OBJECTIVES We investigated whether the vasopressin-analog, terlipressin induces systemic vasoconstriction and pulmonary vasodilation in a porcine model of acute pulmonary embolism. DESIGN Controlled, animal study. SETTING Tertiary medical center research laboratory. SUBJECTS Female pigs (n = 12, Cross of Land Race, Duroc, and Yorkshire ~ 60 kg). INTERVENTIONS Acute pulmonary embolism was induced by administration of three large autologous emboli. Animals then received four increasing doses of either terlipressin (n = 6) or vehicle (n = 6). MEASUREMENTS AND MAIN RESULTS Effects were evaluated in vivo at baseline, after pulmonary embolism and after each dose by invasive hemodynamic measures, transesophageal echocardiography, and blood analysis. Isolated pulmonary arteries were evaluated ex vivo in a myograph. Pulmonary embolism caused a four-fold increase in pulmonary vascular resistance (p < 0.0001) and a two-fold increase in mean pulmonary arterial pressure (p < 0.0001) compared with baseline. Terlipressin increased mean systemic blood pressure (28 ± 5 mm Hg; p < 0.0001) and systemic vascular resistance (1,320 ± 143 dynes; p < 0.0001) compared with vehicle. In the pulmonary circulation, terlipressin decreased mean pulmonary arterial pressure (-6.5 ± 1.8 mm Hg; p = 0.005) and tended to decrease pulmonary vascular resistance (-83 ± 33 dynes; p = 0.07). Terlipressin decreased cardiac output (-2.5 ± 0.5 L/min; p < 0.0001) and increased plasma lactate (2.7 ± 0.2 mmol/L; p < 0.0001), possibly indicating systemic hypoperfusion. A biomarker of cerebral ischemia, S100b, remained unchanged, suggesting preserved cerebral perfusion (0.17 ± 0.11 µg/L; p = 0.51). Ex vivo, terlipressin relaxed pulmonary and constricted mesenteric arteries. CONCLUSIONS Terlipressin caused systemic vasoconstriction and pulmonary vasodilation in a porcine in vivo model of acute pulmonary embolism and vasorelaxation in isolated pulmonary arteries. Despite positive vascular effects, cardiac output declined and plasma lactate increased probably due to a predominantly systemic vasoconstrictor effect of terlipressin. These findings should warrant careful translation to the clinical setting and does not suggest routine use in acute pulmonary embolism.