Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia.
BACKGROUND
The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of the microcirculatory dysfunction seen in sepsis. The mixed endothelin receptor antagonist tezosentan and the selective endothelin A-receptor antagonist TBC3711 were used to investigate the importance of the different endothelin receptors in modulating splanchnic regional blood flow and microvascular blood flow in endotoxaemia.


METHODS
Eighteen anaesthetized pigs were i.v. infused with endotoxin (Escherichia coli lipopolysaccharide, serotype 0111:b4) for 300 min. After 120 min, six animals received tezosentan and six animals received TBC3711. Six animals served as endotoxin-treated controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and ileum. Superior mesenteric artery flow (SMA(FI)) and portal vein flow (PV(FI)) were measured with ultrasonic flow probes, and air tonometry was used to measure Pco₂ in the ileal mucosa.


RESULTS
TBC3711 did not improve splanchnic regional blood flow or splanchnic microvascular blood flow compared with endotoxin-treated controls. Tezosentan increased PV(FI) (P<0.05), but SMA(FI) was not improved compared with the other groups. In the tezosentan group, microvascular blood flow in the ileal mucosa (MCQ(muc)) improved and mucosal-arterial Pco₂ gap decreased (P<0.05 for both) compared with endotoxin-treated controls and the TBC3711 group.


CONCLUSIONS
Tezosentan improved MCQ(muc) without any concomitant increase in SMA(FI), implying a direct positive effect on the microcirculation. TBC3711 was not effective in improving regional splanchnic blood flow or splanchnic microvascular blood flow. Dual endothelin receptor antagonism was necessary to improve MCQ(muc), indicating a role for the endothelin B-receptor in mediating the microcirculatory failure in the ileal mucosa.
Andersson
A
A
Department of Anaesthesiology and Intensive Care, Karolinska University Hospital, Huddinge, Sweden. andreas.andersson@karolinska.se
Fenhammar
J
J
Weitzberg
E
E
Sollevi
A
A
Hjelmqvist
H
H
Frithiof
R
R
D000818:Animals; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D019446:Endotoxemia / Q000150:complications / Q000503:physiopathology*; D005260:Female; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control; D007082:Ileum / Q000098:blood supply; D007413:Intestinal Mucosa / Q000098:blood supply; D007555:Isoxazoles / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D034421:Sus scrofa; D013777:Tetrazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; C485107:N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013450:Sulfones; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan