An open-label dose escalation study of the nitric oxide synthase inhibitor, NG-methyl-L-arginine hydrochloride (546C88), in patients with septic shock

Grover, Robert F.; Zaccardelli, David; Colice, Gene; Guntupalli, Kalpalatha K.; Watson, David; Vincent, Jean‐Louis

doi:10.1097/00003246-199905000-00025

Cited by 186 publications

(69 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a cecal ligation and puncture (CLP) sepsis model, genetic iNOS deletion or pharmacological iNOS blockade enhanced cardiac norepinephrine responsiveness associated with improved systolic function, but seemed to be associated with compromised left ventricular relaxation (113). In septic patients, administration of a nonspecific NOS inhibitor increased arterial pressure but decreased cardiac output (114). The adverse effects of NO might also, in part, be related to interactions between NO and superoxide anions with subsequent production of peroxynitrite.…”

Section: Nitric Oxide and Peroxynitritementioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

View full text Add to dashboard Cite

Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

show abstract

Section: Nitric Oxide and Peroxynitritementioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

View full text Add to dashboard Cite

show abstract

“…Several small and uncontrolled studies demonstrated that short-term nonselective NOS inhibition increased both BP and systemic vascular resistance and decreased cardiac output in patients with septic shock (65)(66)(67). Beneficial effects on renal function were, however, not reported.…”

Section: Inhibition Of Nitric Oxide Synthasementioning

confidence: 99%

Prevention and Treatment of Acute Renal Failure in Sepsis

Vriese

2003

Journal of the American Society of Nephrology

113

View full text Add to dashboard Cite

“…In contrast, NO overproduction apparently leads to diseases such as septic shock and migraine. In these cases, clinical studies using MMA as a drug have been or are currently being conducted (28,29).The above studies clearly indicate the importance of DDAH in NO metabolism. Previously, we have demonstrated that DDAH-1 from bovine brain is a monomeric (31.2 kDa) Zn(II)-containing protein (30) and that the Zn(II) is not involved in the * This work was supported in part by the Olga Mayenfisch-Stiftung…”

mentioning

confidence: 97%

mentioning

confidence: 99%

Structural and Functional Characterization of the Zn(II) Site in Dimethylargininase-1 (DDAH-1) from Bovine Brain

Knipp¹,

Charnock²,

Garner³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

were first found as a result of post-translational modifications of Arg residues, mainly in DNA-and RNA-binding proteins (1). Further studies established that methylated L-Arg molecules also occur freely in body fluids (2-5) and various tissues (6, 7). Although degradation of Arg-methylated proteins has been shown to be a source of free MMA and ADMA (8, 9), a direct methylation of L-Arg via a so far unknown pathway has also been suggested (10, 11). The y ϩ membrane transporter system is apparently involved in the uptake or release of MMA and ADMA (11,12).Nitric-oxide synthase (NOS), which generates the free radical NO from L-Arg, exists in at least three isoforms that are involved in different biological processes. The two constitutive isoforms, nNOS (neuronal) and eNOS (endothelial), produce NO for neurotransmission and cardiovascular regulation, respectively, and are predominantly regulated by cytosolic Ca 2ϩ levels (13). It is well established that MMA and ADMA are endogenous competitive inhibitors of NOS (9,11,14). The intracellular L-Arg levels and the corresponding K m value of NOS are such that the production of NO should not depend on L-Arg supplementation (15). However, in biological studies, the addition of L-Arg increased the production of NO (16), a phenomenon called the "Arg paradox." In this context, it may be noted that recent in vitro studies have shown that the concomitant presence of varying, yet physiologically relevant, levels of MMA and ADMA dramatically affects NOS activity (17).The enzyme dimethylargininase (L-N ,N -dimethylarginine dimethylaminohydrolase (DDAH), EC 3.5.3.18) hydrolyzes both MMA and ADMA to L-citrulline (L-Cit), CH 3 NH 2 , and (CH 3 ) 2 NH, respectively (18). It has been established that DDAH regulates NOS by controlling the levels of MMA and ADMA (10). DDAH exists in at least two isoforms (19), both of which are cytosolic proteins (20). Whereas DDAH-1 is expressed predominantly in tissues containing nNOS (21-25), DDAH-2 is mainly found in tissues expressing eNOS (19,25). The role of DDAH-1 in the regulation of nNOS is also evident from recent studies showing that both proteins are up-regulated in injured neurons (26).The increased levels of MMA and ADMA in plasma and urine have been found in several diseases that are linked to vascular dysfunction characterized by low NO levels, e.g. uremia, atherosclerosis, hypercholesterolemia, diabetes mellitus, hypertension, and homocysteinemia (27). Moreover, increased levels of ADMA in plasma have been discussed as a risk factor for atherosclerosis (3,4,9). In contrast, NO overproduction apparently leads to diseases such as septic shock and migraine. In these cases, clinical studies using MMA as a drug have been or are currently being conducted (28,29).The above studies clearly indicate the importance of DDAH in NO metabolism. Previously, we have demonstrated that DDAH-1 from bovine brain is a monomeric (31.2 kDa) Zn(II)-containing protein (30) and that the Zn(II) is not involved in the * This work was supported in part by the Olga...

show abstract

An open-label dose escalation study of the nitric oxide synthase inhibitor, NG-methyl-L-arginine hydrochloride (546C88), in patients with septic shock

Cited by 186 publications

References 44 publications

Molecular Events in the Cardiomyopathy of Sepsis

Molecular Events in the Cardiomyopathy of Sepsis

Prevention and Treatment of Acute Renal Failure in Sepsis

Structural and Functional Characterization of the Zn(II) Site in Dimethylargininase-1 (DDAH-1) from Bovine Brain

Contact Info

Product

Resources

About