Document Detail

Interaction of acetylcholine and endothelin-1 in the modulation of pulmonary arterial pressure.
MedLine Citation:
PMID:  11153628     Owner:  NLM     Status:  MEDLINE    
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. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Sixty-six adult rabbits of either sex. INTERVENTIONS: 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. MEASUREMENTS AND MAIN 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.
J Schmeck; C Konrad; S Schöffel; M Wendel-Wellner; H Gluth; T Koch; P Krafft
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Critical care medicine     Volume:  28     ISSN:  0090-3493     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2000 Dec 
Date Detail:
Created Date:  2001-01-10     Completed Date:  2001-01-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3869-75     Citation Subset:  AIM; IM    
Department of Anesthesiology and Operative Intensive Care Medicine, University Hospital Mannheim, University of Heidelberg, Germany.
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MeSH Terms
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Acetylcholine / physiology*,  therapeutic use*
Cyclooxygenase Inhibitors / pharmacology
Diclofenac / pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Drug Interactions
Endothelin-1 / physiology*,  therapeutic use*
Hypertension, Pulmonary / chemically induced,  drug therapy*,  physiopathology*
Peptides, Cyclic
Pulmonary Circulation / drug effects*,  physiology*
Pulmonary Wedge Pressure / drug effects*,  physiology*
Receptors, Endothelin / antagonists & inhibitors
Thromboxane A2 / physiology
Vascular Resistance / drug effects,  physiology
Vasoconstriction / drug effects*,  physiology*
Vasoconstrictor Agents
Vasodilation / drug effects*,  physiology*
Reg. No./Substance:
0/Cyclooxygenase Inhibitors; 0/Endothelin-1; 0/Peptides, Cyclic; 0/Receptors, Endothelin; 0/Vasoconstrictor Agents; 136553-81-6/cyclo(Trp-Asp-Pro-Val-Leu); 15307-86-5/Diclofenac; 51-84-3/Acetylcholine; 57576-52-0/Thromboxane A2; 76898-47-0/15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid

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