Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats

Abstract

. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol 283: H1108-H1115, 2002. First published May 16, 2002 10.1152/ajpheart.00549. 2001.-Free radicals have been implicated in the etiology of cardiac dysfunction during sepsis, but the actual species responsible remains unclear. We studied the alterations in myocardial nitric oxide (NO), superoxide, and peroxynitrite generation along with cardiac mechanical function and efficiency in hearts from lipopolysaccharide (LPS)-treated rats. Six hours after LPS (4 mg/kg ip) or saline (control) treatment, hearts were isolated and perfused for 1 h with recirculating Krebs-Henseleit buffer and paced at 300 beats/min. Cardiac work, O2 consumption, and cardiac efficiency were markedly depressed in LPS hearts compared with controls. Plasma nitrate/nitrite level was elevated in LPS rats, and ventricular NO production was enhanced as measured by electron spin resonance spectroscopy, Ca 2ϩ -independent NO synthase (NOS) activity, and inducible NOS immunohistochemistry. Ventricular superoxide production was also enhanced in LPS-treated hearts as seen by lucigenin chemiluminescence and xanthine oxidase activity. Increased nitrotyrosine staining (immunohistochemistry) and higher lipid hydroperoxides levels were also detected in LPS-treated hearts, indicating oxygen radical-induced stress. Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats. sepsis; cardiac dysfunction; nitric oxide; superoxide and peroxynitrite SEPTIC SHOCK is characterized by severe hypotension with profound vasodilatation and multiple organ failure resulting from systemic release of inflammatory cytokines in response to an infective organism (35). Depression of myocardial contractility is a well-documented feature of septic shock (15, 34) despite the fact that assessment of intrinsic cardiac function is complicated by a marked increase in heart rate and decreased preload and afterload. Data from both clinical (32) and experimental (29) studies indicate the presence of genuine myocardial dysfunction when assessed independently of changes in hemodynamics. However, the etiological mechanism(s) of cardiac dysfunction in sepsis is not well understood, but various circulating and/or locally produced mediators have been implicated (for review see Ref. 19).Evidence from our laboratory (39, 40) and from others (2, 3) suggests that exposure of animal hearts or isolated cardiac myocytes to bacterial endotoxin (lipopolysaccharides, LPS) or proinflammatory cytokines enhanced nitric oxide (NO) generation via induction of NO synthase (iNOS). The production of large amounts of NO by this enzyme may have detrimental effects on the myocardium (2, 9, 39). On the other hand, NO may be cardioprotective (37) and may also act as an antioxidant molecule (45).Recent studies have indicated that many of the deleterious effects of NO are mediated by peroxynitrite; this powerful oxidant is generated from a f...

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

“…Myocardial dysfunction frequently accompanies severe sepsis (36), yet the distinctive feature of myocardial dysfunction does not appear to be the hypoperfusion of the heart but rather the release of circulating depressant factors, including cytokines like TNFα (37). Indeed, high levels of cytokines quantified in Fpr2/3 −/− mice could underlie organ dysfunction: There are indications that unabated circulating cytokines are predictive of early mortality in sepsis (38). Some of them, like TNFα and IL-1β, can exert a direct effect through increased expression of inducible NO synthase (39,40).…”

Pivotal Role of gp91 phox -Containing NADH Oxidase in Lipopolysaccharide-Induced Tumor Necrosis Factor-α Expression and Myocardial Depression

“…30,31 In the heart, NAD(P)H oxidase activity and O 2 Ϫ production are increased in response to LPS stimulation. 12,13 However, a causal relationship between NAD(P)H oxidase activation and myocardial dysfunction during sepsis has not been reported. In the present study, LPS-induced myocardial dysfunction was restored in gp91…”

“…7 NAD(P)H oxidase expression has also been demonstrated in cardiomyocytes 8,9 and has been considered as a critical determinant of the redox state of the myocardium. 8 -11 In response to LPS, NAD(P)H oxidase activity and O 2 Ϫ production are markedly increased in the heart 12,13 ; however, the contribution of the NADH oxidase to TNF-␣ expression in LPS-stimulated cardiomyocytes remains unknown, and the role of NADH oxidase in septic myocardial depression has not been investigated. In addition, the membrane subunit of NADH oxidase, gp91 phox (Nox2), has at least 3 other homologs, Nox1, Nox3, and Nox4.…”

Protective Effect of Potassium Against the Hypertensive Cardiac Dysfunction

“…28 The dual effects of ROS on intracellular Ca 2ϩ concentration might be involved in the mechanisms for ROS-induced cardiac dysfunction. There are reports that mitochondrial electron transport chain 29 or xanthine oxidase 30 can also induce ROS overproduction. But in our high-salt loading model, we could not obtain any data suggesting mitochondria or xanthine oxidase as a major source of ROS.…”