Beneficial Effects of L-Canavanine, a Selective Inhibitor of Inducible Nitric Oxide Synthase, on Lactate Metabolism and Muscle High Energy Phosphates During Endotoxic Shock in Rats

Lévy, Bruno; Valtier, M; Chillou, Christian de; Bollaert, Pierre‐Édouard; Cane, David E.; Mallie, Jean Pierre

doi:10.1097/00024382-199902000-00005

Cited by 38 publications

(21 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was proposed that the use of a more selective inhibitor of iNOS would provide greater benefit to the patients. Some positive experimental results have since been reported with specific molecules such as S-methylisothiourea, L-canavanine [20], and aminoguanidine, but none have been tested to date in clinical trials. However, blocking the production of NO may cause other deleterious effects [21] such as: • Altered microcirculatory flow • A decrease in NO-dependent bactericidal activity • A decrease in neutralizing activity of oxygen-derived species • A decrease in the modulation of blood coagulation • An increase in oxygen demand by improving mitochondrial respiration in tissues in which perfusion, and hence oxygen delivery, remains precarious, thereby exacerbating the oxygen supply/demand balance Thus, the current paradigm that NO and soluble guanylate cyclase (sGC) contribute to organ damage and death associated with septic shock may be challenged.…”

Section: Nitric Oxidementioning

confidence: 99%

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Lévy

Collin

Sennoun

et al. 2012

Applied Physiology in Intensive Care Medicine 2

View full text Add to dashboard Cite

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside Abstract Purpose: To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Methods: Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/ physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Results: Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H 2 S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Conclusions: Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.

show abstract

Section: Nitric Oxidementioning

confidence: 99%

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Lévy

Collin

Sennoun

et al. 2012

Applied Physiology in Intensive Care Medicine 2

View full text Add to dashboard Cite

show abstract

“…According to a previous study (14), a fixed dose of 100 mg⅐kg Ϫ1 ⅐h Ϫ1 was used. Heart rate increased from 340 Ϯ 9 to 395 Ϯ 11 beats/min (P Ͻ 0.05 vs. Control and AVP groups).…”

Section: Systemic and Regional Hemodynamics: Comparison With Baselinementioning

confidence: 99%

“…Furthermore, incremental doses of NE infusion can sometimes be ineffective in maintaining arterial pressure in septic shock. A rational, but still experimental, approach to increasing mean arterial pressure (MAP) while preserving cardiac output is to selectively inhibit inducible nitric oxide (NO) synthase (iNOS) (14). In sepsis patients, pulmonary capillary permeability for water and protein is increased early.…”

mentioning

confidence: 99%

Comparative effects of vasopressin, norepinephrine, and l-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock

Lévy

Vallée²,

Lauzier³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

. Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock. Am J Physiol Heart Circ Physiol 287: H209 -H215, 2004. First published February 26, 2004 10.1152/ajpheart.00946.2003, a standard of care, AVP, an alternative candidate, and L-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased (ϳ35%) but aortic blood flow increased during endotoxin infusion (P Ͻ 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P Ͻ 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance (ϳ3-to 4-fold), whereas AVP or LC attenuated this drop (P Ͻ 0.05 vs. control). In contrast, NE did not improve endotoxininduced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P Ͻ 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE (ϳ2-fold increase) but not AVP infusion (P Ͻ 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P (ϳ2-and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function. septic shock; vascular permeability; renal function THE HUMAN RESPONSE to septic challenge usually includes increased cardiac output, decreased peripheral resistance, low arterial pressure, and increased vascular permeability. AVP, also known as "the" antidiuretic hormone (ADH), is an emerging alternative candidate for management of redistributive shock (7). Indeed, AVP exhibits strong vasoconstrictor effects through stimulation of the V1 receptor leading to arterial pressure improvement (28). Moreover, low concentrations of exogenous AVP mediate vasodilatation in coronary, cerebral, and pulmonary arterial circulation (20). The recognized effects of AVP on renal function are complex and include association of an antidiuretic effect through stimulation of V2 receptors, an increase of diuresis/natriuresis through V1 receptors by efferent arteriolar vasoconstric...

show abstract

“…The store of high energy phosphates in skeletal muscle has been studied previously in anaesthetised rat models and was unchanged during endotoxemia [14][15][16][17]. The maintenance of skeletal muscle high energy phosphates is not surprising in stationary muscle in anaesthetised animals.…”

Section: Relationship To Previous Studiesmentioning

confidence: 99%

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

et al. 2012

View full text Add to dashboard Cite

show abstract

Beneficial Effects of L-Canavanine, a Selective Inhibitor of Inducible Nitric Oxide Synthase, on Lactate Metabolism and Muscle High Energy Phosphates During Endotoxic Shock in Rats

Cited by 38 publications

References 0 publications

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Comparative effects of vasopressin, norepinephrine, and l-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

Contact Info

Product

Resources

About