title: Interaction of acetylcholine and endothelin-1 in the modulation of pulmonary arterial pressure.
abstract: OBJECTIVE
  The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species.
  
  
  METHODS
  Prospective experimental study in rabbits.
  
  
  METHODS
  Experimental laboratory in a university teaching hospital.
  
  
  METHODS
  Sixty-six adult rabbits of either sex.
  
  
  METHODS
  The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs.
  
  
  RESULTS
  Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group.
  
  
  CONCLUSIONS
  The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.
authors.affiliation: Department of Anesthesiology and Operative Intensive Care Medicine, University Hospital Mannheim, University of Heidelberg, Germany. joachim.schmeck@anaes.ma.uni.heidelberg.de
authors.forename: J
authors.initials: J
authors.lastname: Schmeck
authors.forename: C
authors.initials: C
authors.lastname: Konrad
authors.forename: S
authors.initials: S
authors.lastname: Schöffel
authors.forename: M
authors.initials: M
authors.lastname: Wendel-Wellner
authors.forename: H
authors.initials: H
authors.lastname: Gluth
authors.forename: T
authors.initials: T
authors.lastname: Koch
authors.forename: P
authors.initials: P
authors.lastname: Krafft
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000502:physiology* / Q000627:therapeutic use*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology* / Q000627:therapeutic use*; D005260:Female; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D010456:Peptides, Cyclic; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects* / Q000502:physiology*; D011817:Rabbits; D013928:Thromboxane A2 / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D014662:Vasoconstrictor Agents; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D014662:Vasoconstrictor Agents; D004008:Diclofenac; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)