title: Pulmonary adrenomedullin counteracts deterioration of coronary flow and myocardial performance evoked by pulmonary endothelins in experimental acute respiratory distress syndrome.
abstract: OBJECTIVE
  We recently showed that pulmonary endothelins may affect coronary circulation under various experimental and clinical conditions. Here, we investigated the effect of pulmonary mediators on coronary tone in experimental acute respiratory distress syndrome. We focused particularly on pulmonary endothelin-1, a major vasoconstrictor in acute respiratory distress syndrome, and on adrenomedullin, a potent vasodilator that is up-regulated by inflammatory stimuli.
  
  
  METHODS
  Controlled experiment that used isolated organs.
  
  
  METHODS
  Experimental laboratory.
  
  
  METHODS
  Wistar rats.
  
  
  METHODS
  The saline effluent from an isolated lung was used to serially perfuse the coronary vessels of an isolated heart. We compared serial perfusion after 2-hr pretreatment of lungs with vehicle or endotoxin (50 microg/mL), and we used the following drugs to elucidate the coronary response observed: the endothelin type A receptor antagonist BQ-123 (2 microM), the endothelin type B antagonist A-192621 (500 nM), the endothelin-converting enzyme inhibitor phosphoramidon (50 microM), the calcitonin gene-related peptide type-1 receptor antagonist hCGRP(8-37) (2 microM), and the adrenomedullin receptor antagonist hAM(22-52) (200 nM) (n = 6 each).
  
  
  RESULTS
  In controls, serial perfusion decreased coronary flow to 87 +/- 3% of baseline (p < .05). BQ-123 and phosphoramidon prevented this effect, whereas blockade of endothelin type B and adrenomedullin-binding receptors had no effect. After endotoxin challenge, coronary flow significantly increased to 110 +/- 2%. This response was augmented by BQ-123 (124 +/- 2%) and phosphoramidon (123 +/- 3%); A-192621 had no effect. Application of hCGRP(8-37) and hAM(22-52) significantly decreased coronary flow to 81 +/- 3% and 88 +/- 2%, respectively. Flow decrease after blockade of both adrenomedullin-binding receptors (73 +/- 2%) significantly deteriorated peak left ventricular pressure, to 82 +/- 6% of baseline; rate of pressure increase, to 81 +/- 5%; and rate of pressure decline, to 77 +/- 6%. Endotoxin pretreatment elevated pulmonary venous big endothelin-1 (three-fold), endothelin-1 (two-fold), and adrenomedullin (five-fold).
  
  
  CONCLUSIONS
  In experimental acute respiratory distress syndrome, pulmonary adrenomedullin--via calcitonin gene-related peptide type-1 receptor and adrenomedullin receptor--outweighs the coronary vasoconstrictor impact of pulmonary big endothelin-1 exerted via endothelin type A receptors after conversion to mature endothelin-1. The consequence is prevention of flow-related deterioration of myocardial performance.
authors.affiliation: Medizinische Klinik und Poliklinik I (Kardiologie), Charité (Campus Mitte), Humboldt-Universität zu Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stangl
authors.forename: M
authors.initials: M
authors.lastname: Laule
authors.forename: C
authors.initials: C
authors.lastname: Richter
authors.forename: V
authors.initials: V
authors.lastname: Stangl
authors.forename: J
authors.initials: J
authors.lastname: Koch
authors.lastname: Göktas O
authors.forename: G
authors.initials: G
authors.lastname: Baumann
authors.forename: T
authors.initials: T
authors.lastname: Dschietzig
mesh_terms: D053607:Adrenomedullin; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D009200:Myocardial Contraction / Q000187:drug effects*; D010455:Peptides / Q000097:blood / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010455:Peptides; D010456:Peptides, Cyclic; D018015:Receptors, Calcitonin Gene-Related Peptide; D053607:Adrenomedullin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)