title: Pulmonary vascular reserve during experimental pulmonary embolism: effects of a soluble guanylate cyclase stimulator, BAY 41-8543.
abstract: OBJECTIVE
  Pulmonary embolism causes pulmonary hypertension by mechanical obstruction and vasoconstriction. Therapeutic potential of pharmacologic dilation of unblocked vessels has received limited attention. We tested pulmonary vasodilator reserve using a soluble guanylate cyclase stimulator, BAY 41-8543.
  
  
  METHODS
  Controlled animal study.
  
  
  METHODS
  Medical center research laboratory.
  
  
  METHODS
  Male Sprague-Dawley rats.
  
  
  METHODS
  Pulmonary embolism was induced by infusing 25-μm plastic microspheres in the right jugular vein, producing mild or moderate pulmonary hypertension. Control animals with no pulmonary embolism received suspension medium for microspheres.
  
  
  RESULTS
  Mild pulmonary embolism increased right ventricular peak systolic pressure (from 28 to 38 mm Hg) and decreased cardiac output (from 46 to 34 mL/min) with no change in mean arterial pressure. Infusion of BAY 41-8543 (50-200 μg/kg) decreased right ventricular peak systolic pressure. Five hrs moderate pulmonary embolism increased right ventricular peak systolic pressure (from 28 to 47 mm Hg) and decreased cardiac output (from 48 to 27 mL/min), causing right ventricular peak systolic pressure/cardiac output to increase from 0.6 control with no pulmonary embolism to 1.8 mm Hg/mL/min in 5-hr moderate pulmonary embolism + solvent for BAY 41-8543. Treatment of 5-hr moderate pulmonary embolism with BAY 41-8543 (50 μg/kg) caused a 2.2-fold increase in cardiac output (59 mL/min) with a 46% reduction in right ventricular peak systolic pressure (38 mm Hg), suggesting significant pulmonary vasodilation. Moderate pulmonary embolism decreased arterial sO2 (from 83% to 71%) and increased lactate (from 0.5 to 2.3 mmol/L). Treatment with BAY 41-8543 normalized sO2 and lactate. Hemolysis occurred during moderate experimental pulmonary embolism (60-fold increase in plasma hemoglobin). Treatment with BAY 41-8543 reduced free plasma hemoglobin content by 80%.
  
  
  CONCLUSIONS
  In the setting of moderate impervious pulmonary embolism, treatment with a guanylate cyclase stimulator normalized pulmonary hemodynamics, reduced hemolysis, and improved oxygenation. These data support the hypothesis that pharmacologic dilation of nonobstructed pulmonary vasculature can effectively treat acute pulmonary hypertension from pulmonary embolism.
authors.affiliation: Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC, USA. jwatts@carolinas.org
authors.forename: John A
authors.initials: JA
authors.lastname: Watts
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gellar
authors.forename: Mary-Beth K
authors.initials: MB
authors.lastname: Fulkerson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kline
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D008168:Lung / Q000098:blood supply; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000503:physiopathology; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: C450679:BAY 41-8543; D009025:Morpholines; D011743:Pyrimidines; D014665:Vasodilator Agents; D006162:Guanylate Cyclase