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

Abstract

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 (LPSϩ12h); staining for both isoforms was much weaker 24 hours later (LPSϩ36h). 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 LPSϩ12h group, however, isometric twitches were significantly prolonged (482Ϯ14 versus 420Ϯ14 ms in the saline-treated group, PϽ0.005). 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 LPSϩ12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (PϽ0.01). Conclusions-Cardiac

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

“…An acute, endoxin-induced septic model of cardiac failure in rabbit was shown by immunostaining to exhibit transient coinduction of iNOS and inducible COX (COX 2 ) in EE and endothelium of coronary arterioles, peaking at ϳ10 -12 h, with normalization after 36 h (370). Simultaneously, the baseline supportive actions of endogenous cardiac ET and PGI 2 on myocardial inotropism were transiently accentuated, and the inotropic response to exogenous ET-1 was also significantly enhanced during this FIG. 12.…”

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

“…Due to their role in the pathophysiological mechanisms underlying some relevant inflammatory disorders, the possible interaction between NO and PG biosynthetic pathways has been studied to verify a possible combined approach in the treatment of many disease states (Fig. 4) (Abramson et al, 2001;Mebazaa et al, 2001;Beierwaltes, 2002;Davel et al, 2002;Gallo et al, 2002;Naoki et al, 2002;Sanchez et al, 2002;Shinmura et al, 2002;Takeuchi et al, 2002;VayssettesCourchay et al, 2002;Kawabe et al, 2003;Slomiany and Slomiany, 2003).…”

Molecular Events in the Cardiomyopathy of Sepsis

“…Despite all these findings, isolated rabbit papillary muscles or rat cardiomyocytes harvested during the acute phase of sepsis and ex vivo studies show a persistent decrease in contractility in spite of the absence of direct contact with septic plasma (36,45,46). This raises questions as to whether cardiodepressant factors in serum represent an exclusive pathophysiological mechanism of sepsis-associated cardiomyopathy.…”

“…Following experimental sepsis, reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro, both of which could be reversed by in vivo administration of a blocking antibody to C5a (Figure 2). in vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and septic cardiomyocytes, suggesting that excessive in vivo generation of C5a during sepsis causes dysfunction of cardiomyocytes (36).Despite all these findings, isolated rabbit papillary muscles or rat cardiomyocytes harvested during the acute phase of sepsis and ex vivo studies show a persistent decrease in contractility in spite of the absence of direct contact with septic plasma (36,45,46). This raises questions as to whether cardiodepressant factors in serum represent an exclusive pathophysiological mechanism of sepsis-associated cardiomyopathy.…”