Efficacy of inhaled prostanoids in experimental pulmonary hypertension

Objectives: To evaluate the effects of inhaled prostacyclin (PGI(2)) and inhaled as well as intravenous prostaglandin E-1 (PGE(1)) on thromboxane A(2) mimetic-induced pulmonary vasoconstriction, Active pulmonary vasoconstriction was to be distinguished from passive resistance to blood flow. Design: Prospective, randomized, crossover study, Setting: Experimental animal laboratory. Subjects: Eight anesthetized and paralyzed sheep. Interventions: The stable thromboxane A(2) mimetic, U46619, was infused in increasing dosage to obtain a stable pulmonary hypertension of similar to 30 mm Hg. Subsequently, PGE(1) aerosol (0.6, 6, 58, 259 ng/kg/min), intravenous PGE(1) (0.5 mu g/kg/min), or PGI(2) aerosol (27 ng/kg/min) were administered in randomized order. Measurements and Main Results: Active pulmonary vasoconstriction was assessed by determining the pulmonary pressure flow relationship (PPFR), For measurement of pulmonary artery flow, an ultrasound flow probe was placed around the pulmonary artery after a sternotomy, Pulmonary arterial pressure was measured with a pulmonary artery flotation catheter, Flow was varied by partial occlusion of the inferior vena cava or incremental opening of an arterio-venous fistula between the large neck vessels. The primary end points were the slope of the resulting linear pressure flow relationship, and pulmonary vascular resistance (PVR), Infusion of U46619 increased the slope of the PPFR (2.9 +/- 0.7 vs, 4.2 t 1.2 mm Hg/L/min [median +/- semi interquartile range]; p less than or equal to.05), and PVR (221 +/- 20 vs. 424 +/- 57 dyne.sec/cm(5)) (p<.05), Neither dose of PGE(1) aerosol induced changes of the slope of PPFR or PVR, In contrast, intravenous administration of the same drug reduced the slope of the PPFR (4.0 +/- 1.0 vs, 3.1 +/- 0.4) (p <.05) but left PVR unchanged. Inhalation of PGI, reduced both the slope of the PPFR, slightly but significantly, and PVR (424 +/- 98 vs. 323 +/- 26 dyne.sec/ cm(5)) (p <.05). Conclusions: This study is the first to show reduction of active pulmonary vasoconstriction by PGI(2) aerosol, Neither inhalation nor intravenous administration of PGE(1) reduced PVR but the latter reduced the slope of PPFR. We conclude that PGE(1) has potential for pulmonary vasodilation, but that it is ineffective as an aerosol, even in high doses, in sheep. PVR may fail to reflect drug induced pulmonary vasodilation.