title: Arrhythmogenic effects induced by coronary conversion of pulmonary big endothelin to endothelin: aggravation of this phenomenon in heritable hyperlipidemia.
abstract: OBJECTIVE
  We investigated whether endogenous pulmonary big endothelin has arrhythmogenic properties under normal conditions and in heritable hyperlipidemia.
  
  
  BACKGROUND
  Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is unclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis.
  
  
  METHODS
  In a lung-heart model in which a Langendorff heart is serially perfused with the effluent from the isolated lung of the same animal, we evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits.
  
  
  RESULTS
  In both controls (n=12) and WHHL (n=8), serial perfusion evoked a decrease in coronary flow (controls, -11+/-3%; WHHL, -25+/-6%) and a fourfold increase of ventricular extrasystoles (VES) (controls, 40.7+/-8; WHHL, 40.2+/-5 VES/40 min, p < 0.05). However, WHHL developed more and longer nonsustained ventricular tachycardias (VT) compared with controls (incidence, 1.38+/-1.1 vs. 0.33+/-0.5 VT/40 min, p < 0.05; length, 14.36+/-3.1 vs. 7.25+/-1.5 beats/VT, p < 0.05). Arrhythmias were not ischemia-induced because corresponding mechanical flow reduction had no arrhythmogenic effect (n=6 in controls and WHHL). Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET(A) antagonists (BQ-123, 2 micromol/liter; A-127722, 20 micromol/liter). The ET-converting enzyme inhibitor phosphoramidon (50 micromol/liter) completely suppressed arrhythmias and vasoconstriction. The ET(B) antagonists (IRL-1038, 4 micromol/liter; IRL-1025, 5 micromol/liter) had no effect (n=6).
  
  
  CONCLUSIONS
  Endogenous pulmonary big ET produces arrhythmogenic effects that are aggravated in heritable hyperlipidemia. These effects, requiring coronary conversion of big ET into ET, are partly ET(A)-mediated and ET(B)-independent.
authors.affiliation: Medizinische Klinik und Poliklinik I, Charité, Humboldt-Universität zu Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Alexiou
authors.forename: T
authors.initials: T
authors.lastname: Dschietzig
authors.forename: O
authors.initials: O
authors.lastname: Simsch
authors.forename: M
authors.initials: M
authors.lastname: Laule
authors.forename: J
authors.initials: J
authors.lastname: Hundertmark
authors.forename: G
authors.initials: G
authors.lastname: Baumann
authors.forename: K
authors.initials: K
authors.lastname: Stangl
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D005117:Cardiac Complexes, Premature / Q000209:etiology* / Q000503:physiopathology; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism*; D006020:Glycopeptides / Q000494:pharmacology; D006949:Hyperlipidemias / Q000150:complications* / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism*; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000209:etiology* / Q000503:physiopathology
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon