HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism.
OBJECTIVE
To assess the effects of the potassium ATP (KATP) channel blocker HMR1402 (HMR) on systemic and hepato-splanchnic hemodynamics, oxygen exchange and metabolism during hyperdynamic porcine endotoxemia.


METHODS
Prospective, randomized, controlled study with repeated measures. SETTING. Animal laboratory.


METHODS
Eighteen pigs allocated to receive endotoxin alone (control group, CON, n=10) or endotoxin and HMR (6 mg/kg h(-1), n=8).


METHODS
Anesthetized, mechanically ventilated, and instrumented pigs receiving continuous i.v. endotoxin were resuscitated with hetastarch to maintain mean arterial pressure (MAP) >60 mmHg. Twelve hours after starting the endotoxin infusion, they received HMR or its vehicle for another 12 h.


RESULTS
HMR transiently increased MAP by about 15 mmHg, but this effect was only present during the first 1 h of infusion. The HMR decreased cardiac output due to a fall in heart rate, and thereby reduced liver blood flow. While liver O(2) delivery and uptake remained unchanged, HMR induced hyperlactatemia [from 1.5 (1.1; 2.0), 1.4 (1.2; 1.8), and 1.2 (0.8; 2.0) to 3.1 (1.4; 3.2), 3.2 (1.6; 6.5), and 3.0 (1.0; 5.5) mmol/l in the arterial, portal and hepatic venous samples, respectively] and further increased arterial [from 8 (3; 13) to 23 (11; 57); p<0.05], portal [from 9 (4; 14) to 23 (14; 39); p<0.05] and hepatic vein [from 7 (0; 15) to 30 (8; 174), p<0.05] lactate/pyruvate ratios indicating impaired cytosolic redox state.


CONCLUSIONS
The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.
Asfar
Pierre
P
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Parkstrasse 11, 89073 Ulm, Germany.
Iványi
Zsolt
Z
Bracht
Hendrik
H
Hauser
Balázs
B
Pittner
Antje
A
Vassilev
Damian
D
Nalos
Marek
M
Leverve
Xavier Maurice
XM
Brückner
Uwe Bernd
UB
Radermacher
Peter
P
Fröba
Gebhard
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007773:Lactates / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D010101:Oxygen Consumption; D026902:Potassium Channel Blockers / Q000097:blood / Q000627:therapeutic use*; D011773:Pyruvates / Q000097:blood; D013552:Swine; D013890:Thiourea / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*
C484286:1-((5-(2-(5-chloro-o-anisamido)ethyl)-beta-methoxyethoxyphenyl)sulfonyl)-3-methylthiourea, sodium salt; D007773:Lactates; D026902:Potassium Channel Blockers; D011773:Pyruvates; D013890:Thiourea