title: Coronary constriction and consequent cardiodepression in pulmonary embolism are mediated by pulmonary big endothelin and enhanced in early endothelial dysfunction.
abstract: OBJECTIVE
  Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animal's isolated lung.
  
  
  METHODS
  Controlled experiment using isolated organs.
  
  
  METHODS
  Experimental laboratory.
  
  
  METHODS
  Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis).
  
  
  METHODS
  Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animal's isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg.
  
  
  RESULTS
  Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups.
  
  
  CONCLUSIONS
  We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.
authors.affiliation: Medizinische Klinik und Poliklinik I, Charité, Humboldt-Universität, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Dschietzig
authors.forename: M
authors.initials: M
authors.lastname: Laule
authors.forename: K
authors.initials: K
authors.lastname: Alexiou
authors.forename: K
authors.initials: K
authors.lastname: Schrör
authors.forename: G
authors.initials: G
authors.lastname: Baumann
authors.forename: K
authors.initials: K
authors.lastname: Stangl
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000150:complications / Q000503:physiopathology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D000077868:Atrasentan; D003326:Coronary Circulation; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006020:Glycopeptides / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases; D009200:Myocardial Contraction; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000502:physiology*; D011655:Pulmonary Embolism / Q000150:complications / Q000503:physiopathology*; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D013929:Thromboxane B2 / Q000378:metabolism; D014661:Vasoconstriction
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011498:Protein Precursors; D011759:Pyrrolidines; C082887:PD 145065; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon; D000077868:Atrasentan