EFFICACY OF INHALED PROSTANOIDS IN EXPERIMENTAL PULMONARY-HYPERTENSION

Objectives: To evaluate the effects of inhaled prostacyclin (PGI(2)) a nd inhaled as well as intravenous prostaglandin E-1 (PGE(1)) on thromb oxane A(2) mimetic-induced pulmonary vasoconstriction, Active pulmonar y vasoconstriction was to be distinguished from passive resistance to blood flow. Design: Prospective, randomized, crossover study, Setting: Experimental animal laboratory. Subjects: Eight anesthetized and para lyzed sheep. Interventions: The stable thromboxane A(2) mimetic, U4661 9, was infused in increasing dosage to obtain a stable pulmonary hyper tension 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) ae rosol (27 ng/kg/min) were administered in randomized order. Measuremen ts and Main Results: Active pulmonary vasoconstriction was assessed by determining the pulmonary pressure flow relationship (PPFR), For meas urement of pulmonary artery flow, an ultrasound flow probe was placed around the pulmonary artery after a sternotomy, Pulmonary arterial pre ssure was measured with a pulmonary artery flotation catheter, Flow wa s 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 m m 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), N either 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.se c/ cm(5)) (p <.05). Conclusions: This study is the first to show reduc tion of active pulmonary vasoconstriction by PGI(2) aerosol, Neither i nhalation nor intravenous administration of PGE(1) reduced PVR but the latter reduced the slope of PPFR. We conclude that PGE(1) has potenti al for pulmonary vasodilation, but that it is ineffective as an aeroso l, even in high doses, in sheep. PVR may fail to reflect drug induced pulmonary vasodilation.