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(Circulation. 2001;104:3137.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Activation of Cardiac Endothelium as a Compensatory Component in Endotoxin-Induced Cardiomyopathy

Role of Endothelin, Prostaglandins, and Nitric Oxide

Alexandre Mebazaa, MD PhD; Gilles W. De Keulenaer, MD PhD; Xavier Paqueron, MD; Luc J. Andries, PhD; Philippe Ratajczak; Sophie Lanone, PhD; Christian Frelin, PhD; Dan Longrois, MD PhD; Didier Payen, MD PhD; Dirk L. Brutsaert, MD PhD; Stanislas U. Sys, MD PhD

From the Laboratoire d’Anesthöesiologie, Döepartement d’Anesthöesie-Röeanimation, INSERM U127, Hö.pital Lariboisière, Assistance Publique-Hö.pitaux de Paris, Institut Föedöeratif de Recherches Circulation, Universitöe Paris 7 Denis Diderot, Paris, France; Department of Physiology, University of Antwerp, Antwerp, Belgium; U408 INSERM, Facultöe Bichat, Paris, France; IPCM-CNRS UPR 411, Sophia Antipolis, France; and Döepartement d’Anesthöesie-Röeanimation, CHU de Brabois Nancy-Vandoeuvre, Nancy, France.

Correspondence to Alexandre Mebazaa, MD, PhD, Döepartement d’Anesthöesie-Röeanimation, Hö.pital Lariboisière, 2, Rue A. Paröe, 75475 Paris, Cedex 10, France. E-mail alexandre.mebazaa{at}lrb.ap-hop-paris.fr

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.

Methods and 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.

Key Words: prostaglandins • endocardium • myocardium • nitric oxide synthase • infection

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