Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins, and nitric oxide.
BACKGROUND
In view of growing evidence of an important endothelial paracrine regulation of cardiac function, the present study investigated the role of cardiac endothelium-derived endothelin-1 (ET-1), prostaglandins, and nitric oxide (NO) during endotoxin-induced cardiomyopathy in rabbits.


RESULTS
Immunohistochemical studies showed a marked transient coinduction of the inducible isoforms of NO synthase (NOS-2) and cyclooxygenase (COX-2) in endocardial endothelium and coronary arteriolar endothelium of hearts 12 hours after intravenous administration of lipopolysaccharide (LPS+12h); staining for both isoforms was much weaker 24 hours later (LPS+36h). Nitrotyrosine localization was similar to that of NOS-2, suggesting a NOS-2-related endothelial formation of peroxynitrite in septic hearts. Contractile performance of papillary muscles was depressed in both LPS-treated groups. In the LPS+12h group, however, isometric twitches were significantly prolonged (482+/-14 versus 420+/-14 ms in the saline-treated group, P<0.005). This twitch prolongation was completely reversed by simultaneous administration of BQ-123 and indomethacin to block endogenous ET-1 and prostaglandins, respectively. In addition, in the LPS+12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (P<0.01).


CONCLUSIONS
Cardiac endothelial activation and myocardial sensitization to endothelium-derived mediators may be part of an adaptive response in the early (12 hours) stages of septic cardiomyopathy.
Mebazaa
A
A
Laboratoire d'Anesthöesiologie, Döepartement d'Anesthöesie-Röeanimation, INSERM U127, Paris, France. alexandre.mebazaa@lrb.ap-hop-paris.fr
De Keulenaer
G W
GW
Paqueron
X
X
Andries
L J
LJ
Ratajczak
P
P
Lanone
S
S
Frelin
C
C
Longrois
D
D
Payen
D
D
Brutsaert
D L
DL
Sys
S U
SU
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001667:Binding, Competitive; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology; D016232:Endothelins / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology; D011817:Rabbits; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D011453:Prostaglandins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase