title: Efficacy of inhaled prostanoids in experimental pulmonary hypertension.
abstract: OBJECTIVE
  To evaluate the effects of inhaled prostacyclin (PGI2) and inhaled as well as intravenous prostaglandin E1 (PGE1) on thromboxane A2 mimetic-induced pulmonary vasoconstriction. Active pulmonary vasoconstriction was to be distinguished from passive resistance to blood flow.
  
  
  METHODS
  Prospective, randomized, crossover study.
  
  
  METHODS
  Experimental animal laboratory.
  
  
  METHODS
  Eight anesthetized and paralyzed sheep.
  
  
  METHODS
  The stable thromboxane A2 mimetic, U46619, was infused in increasing dosage to obtain a stable pulmonary hypertension of approximately 30 mm Hg. Subsequently, PGE1 aerosol (0.6, 6, 58, 259 ng/kg/min), intravenous PGE, (0.5 microg/kg/min), or PGI2 aerosol (27 ng/kg/min) were administered in randomized order.
  
  
  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+/-1.2 mm Hg/L/min [median+/-semi-interquartile range]; p < or = .05), and PVR (221+/-20 vs. 424+/-57 dyne x sec/cm5) (p < .05). Neither dose of PGE1 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 PGI2 reduced both the slope of the PPFR, slightly but significantly, and PVR (424+/-98 vs. 323+/-26 dyne x sec/cm5) (p < .05).
  
  
  CONCLUSIONS
  This study is the first to show reduction of active pulmonary vasoconstriction by PGI2 aerosol. Neither inhalation nor intravenous administration of PGE1 reduced PVR but the latter reduced the slope of PPFR. We conclude that PGE1 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.
authors.affiliation: Institute for Surgical Research, Ludwig-Maximilians-University of Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kleen
authors.forename: O
authors.initials: O
authors.lastname: Habler
authors.forename: C
authors.initials: C
authors.lastname: Hofstetter
authors.forename: R
authors.initials: R
authors.lastname: Pusch
authors.forename: M
authors.initials: M
authors.lastname: Mueller
authors.forename: M
authors.initials: M
authors.lastname: Welte
authors.forename: B
authors.initials: B
authors.lastname: Zwissler
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors; D000280:Administration, Inhalation; D000527:Alprostadil / Q000008:administration & dosage*; D000818:Animals; D011464:Epoprostenol / Q000008:administration & dosage*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D007262:Infusions, Intravenous; D008297:Male; D012756:Sheep; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors
chemical_list: D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D000527:Alprostadil