Expert opinion on tilarginine in the treatment of shock

Howes, L. G.; Brillante, D.

doi:10.1517/13543784.17.10.1573

Cited by 12 publications

(6 citation statements)

References 46 publications

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“…Numerous human and experimental studies have examined the effects of NOS inhibitors, but in general the outcomes have been disappointing (9,22). A possible reason for the lack of success is that nonselective inhibitors block not only the excessive production of NO from iNOS, which is thought to be mainly detrimental, but also the ben eficial actions of NO produced by eNOS and nNOS (12,23). In septic AKI, excessive NO derived from increased iNOS activity is believed to induce systemic vasodila tation and hyperdynamic septic shock (24) and may cause deterioration of glomerular filtration and tubular func tion.…”

Section: Discussionmentioning

confidence: 99%

Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis*

Ishikawa

Calzavacca

Bellomo

et al. 2012

Critical Care Medicine

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In hyperdynamic sepsis, intrarenal infusion of a highly selective inducible nitric oxide synthase inhibitor did not reduce the elevated renal blood flow or improve renal function. In contrast, renal blood flow was reduced by infusion of a nonselective NOS inhibitor or a high dose of a partially selective inducible nitric oxide synthase inhibitor. The renal vasodilatation in septic acute kidney injury may be due to nitric oxide derived from the endothelial and neural isoforms of nitric oxide synthase, but their blockade did not restore renal function.

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Section: Discussionmentioning

confidence: 99%

Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis*

Ishikawa

Calzavacca

Bellomo

et al. 2012

Critical Care Medicine

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“…191 However, in the best-known clinical trial for cardiogenic shock in infarction patients (the TRIUMPH trial), 192 compound 2 failed to reduce severity of heart failure or mortality and also resulted in hypertension. It was hypothesized that lack of selectivity 193 or too low a dose 194 could have been responsible for these failures. A recent study (2015) using resuscitated swine found that neither global NOS inhibition (using 1) nor more selective iNOS inhibition (using 4) improves survival or myocardial dysfunction following ventricular fibrillation in cardiac arrest (when iNOS levels increase).…”

Section: Clinical Failuresmentioning

confidence: 99%

Inducible nitric oxide synthase: Regulation, structure, and inhibition

Cinelli

Miley

et al. 2019

Medicinal Research Reviews

509

298

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A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l‐arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X‐ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS’ complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.

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“…Therapy with L-NMMA was associated with excess mortality, particularly at doses> 5 mg/(kg h), noting that septic and cardiogenic shock in the effects of a lower dose (1 mg/(kg h)) were neutral. The excessive mortality in patients with septic shock was almost certainly the result of unfavorable hemodynamic changes induced by L-NMMA (decreased cardiac output, increased pulmonary vascular resistance and impaired tissue oxygen supply) [40][41][42].…”

Section: Nos Blockersmentioning

confidence: 99%

Cardiovascular Therapeutics Targets on the NO–sGC–cGMP Signaling Pathway: A Critical Overview

Évora

Évora²,

Celotto³

et al. 2012

CDT

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In a brief overview, in NO-sGC-cGMP signaling in a blood vessel, l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Heme-dependent sGC stimulators and hem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. Studies of the 90's definitively established the role of endothelium in all cardiovascular diseases, which were associated with endothelial dysfunction by impaired release of endothelium-derived relaxing factors with consequent risk of spasm and thrombosis. The rationale of this review is based on the fact that the discovery of NO changed the concepts of cardiovascular disease mechanisms. However, considering the jargon "from the bench to clinical practice" we concluded that a potential therapeutic revolution did not follow the pathophysiological revolution. The review is focused on general aspects without regard for advanced research aspects, and designed in two main groups: the NO/cGMP positive stimulators and blockers as "future and encouraging" new therapeutic drugs. The potential vasodilators include 1) NOS uncoupling; 2) NOS enhancers (AVE compounds); 3) NO donors (nitrovasodilators); 4) NO-independent activators (BAY compounds), and; 5) PDE5 inhibitors. The potential vasoconstrictors include 1) NOS-blockers (L-NAME, L-NMMA); 2) sGC-blockers (methylene blue), and; 3) PDEs. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental and clinical experience working on vasoplegic endothelium dysfunction.

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Expert opinion on tilarginine in the treatment of shock

Cited by 12 publications

References 46 publications

Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis*

Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis*

Inducible nitric oxide synthase: Regulation, structure, and inhibition

Cardiovascular Therapeutics Targets on the NO–sGC–cGMP Signaling Pathway: A Critical Overview

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