Effects of Methylene Blue on Blood Pressure and Reactivity to Norepinephrine in Endotoxemic Rats

Paya, Dominique; Gray, Gillian A.; Stoclet, Jean‐Claude

doi:10.1097/00005344-199306000-00012

Cited by 54 publications

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“…Thus, in the last decade, several studies have pointed toward soluble guanylate cyclase as a potential target for drug development. Inhibition of enzyme activity with methylene blue increased blood pressure in anesthetized endotoxemic rats (Paya et al, 1993;Cheng and Pang, 1998) and rabbits (Keaney et al, 1994). However, the conclusions derived from studies with methylene blue should be drawn with caution, because this compound is not a specific inhibitor of soluble guanylate cyclase.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that overproduction of NO in sepsis is one of the main causes of excessive vasodilation and reduced contractile response to vasoconstrictor agents (Titheradge, 1999). Regarding the molecular mechanism of NO-mediated vascular collapse in shock, the role of cGMP-dependent mechanism seems to be well established (Fleming et al, 1991;Paya et al, 1993;Keaney et al, 1994;Silva-Santos et al, 2002). NO activates soluble guanylate cyclase, which produces the second-messenger cGMP, which in turn governs many aspects of cellular function via interaction with specific kinases, ions channels, and phosphodiesterases (Hobbs and Ignarro, 1996).…”

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confidence: 99%

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Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Fernandes¹,

Silva-Santos²,

Duma³

et al. 2005

Mol Pharmacol

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We investigated the role of soluble guanylate cyclase in lipopolysaccharide-induced hyporesponsiveness to phenylephrine. The effects of phenylephrine on the blood pressure of female Wistar rats were evaluated at 2, 8, and 24 h after lipopolysaccharide injection (12.5 mg/kg i.p.). Vasoconstrictive responses to phenylephrine were reduced 40 to 50% in all time periods. Methylene blue, a soluble guanylate cyclase inhibitor (15 mol/kg i.v.) restored the reactivity to phenylephrine in animals injected with lipopolysaccharide 2 and 24 h earlier. However, it failed to do so in animals injected with lipopolysaccharide 8 h earlier. Incubation with sodium nitroprusside (SNP) increased lung and aorta cGMP levels in control animals and in tissues of rats treated with lipopolysaccharide 24 h earlier. However, SNP failed to increase tissue cGMP in rats injected 8 h earlier.Lipopolysaccharide reduced the vasodilatory response to NO donors 8 h after injection. This effect and the decreased lung cGMP accumulation in response to SNP were reversed by an NO synthase blocker. Guanylate cyclase protein levels were lower than controls in lungs harvested from rats injected 8 h earlier and were back to normal values in lungs of rats injected 24 h earlier with lipopolysaccharide. Thus, data indicate that there is a temporal window of 8 h after lipopolysaccharide injection in which soluble guanylate cyclase is not functional and that this loss of function is NO-dependent. Thus, the putative use of soluble guanylate cyclase inhibitors in the treatment of endotoxemia may be beneficial mainly at early stages of this condition.Septic shock, the most severe complication of sepsis, is a serious disorder with significant morbidity and mortality even after the appropriate antibiotic and supportive therapy are initiated. The poor outcome is considered to be a consequence of an overactive systemic inflammatory response elicited by microbial products, mainly lipopolysaccharide. The disease state is characterized by hypotension, hyporeactivity to vasoconstrictor agents, vascular damage and disseminated intravascular coagulation, which leads to multiple organ failure and death (Karima et al., 1999). Because the mortality rate after sepsis is in excess of 50%, it is clear that the present pharmacotherapy is inadequate.Inflammatory stimuli such as lipopolysaccharide activate a pathway that leads to expression, among other proinflammatory proteins, of the inducible nitric-oxide synthase (NOS-2). Once expressed, this enzyme is active for several hours and produces large amounts of nitric oxide (Alderton et al., 2001). It is well established that overproduction of NO in sepsis is one of the main causes of excessive vasodilation and reduced contractile response to vasoconstrictor agents (Titheradge, 1999). Regarding the molecular mechanism of NO-mediated vascular collapse in shock, the role of cGMP-dependent mechanism seems to be well established (Fleming et al., 1991;Paya et al., 1993;Keaney et al., 1994;Silva-Santos et al., 2002). NO activates solu...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Fernandes¹,

Silva-Santos²,

Duma³

et al. 2005

Mol Pharmacol

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“…Nitric oxide may also mediate the sepsisinduced myocardial depression (11)(12)(13). In experimental studies, the decreased response to vasopressors is associated with an increased nitric oxide production (14)(15)(16). The hemodynamic changes seen in septic shock patients may also be related to overproduction of nitric oxide (17,18).…”

Section: Introductionmentioning

confidence: 99%

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Weingartner

Oliveira

Sant'Anna

et al. 1999

Braz J Med Biol Res

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To investigate the role of nitric oxide in human sepsis, ten patients with severe septic shock requiring vasoactive drug therapy and mechanical ventilation were enrolled in a prospective, open, non-randomized clinical trial to study the acute effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and metabolic variables were measured before and 20, 40, 60, and 120 min after the start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue administration caused a progressive increase in mean arterial pressure (60 [55-70] Arterial lactate concentration decreased from 5.1 ± 2.9 to 4.5 ± 2.1 mmol/ l, mean ± SD (P<0.05) after 60 min. Heart rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption did not change. Methylene blue administration was safe and no adverse effect was observed. In severe human septic shock, a short infusion of methylene blue increases systemic vascular resistance and may improve myocardial function. Although there was a reduction in blood lactate concentration, this was not explained by an improvement in tissue oxygenation, since overall oxygen availability did not change. However, there was a significant increase in pulmonary vascular tone and a deterioration in gas exchange. Further studies are needed to demonstrate if nitric oxide blockade with methylene blue can be safe for patients with septic shock and, particularly, if it has an effect on pulmonary function.

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“…19,20 Inhibition of these enzymes results in decreased production and efficacy of NO, a vasodilatory paracrine hormone. [19][20][21] Cytokines and inflammatory factors present during sepsis are thought to induce endothelial NO production in smooth muscle cells, leading to systemic vasodilation and shock. 22 Nitric oxide is also thought to decrease the sensitivity of endothelial adrenergic receptors to sympathetic vasoconstrictory stimuli, exacerbating the vasodilation that NO causes.…”

Section: Discussionmentioning

confidence: 99%

Prolonged methylene blue infusion in refractory septic shock: a case report

Dumbarton

Minor

Yeung

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Methylene blue (MB) has been advocated for the treatment of refractory hemodynamic instability in patients with septic shock. However, the use of MB infusions in septic shock is not considered standard treatment, and the available literature describes infusions of short duration, typically less than six hours. Clinical features We report a case of septic shock in a 67-yr-old male who required maximal vasopressor support with norepinephrine, epinephrine, and vasopressin. Despite standard protocols for the treatment of septic shock, the patient's hemodynamic status was refractory 80 hr post admission. However, initiation of a MB infusion resulted in the rapid restoration of hemodynamic stability and a subsequent decrease in vasopressor requirements.Multiple attempts to discontinue the MB infusion resulted in immediate and repeated increases in vasopressor requirements, necessitating a continuous infusion with a slow taper of MB for 120 hr. Ultimately, the patient survived the illness and was discharged home. We observed no adverse events that could be attributed to the use of MB. Conclusion In our patient, the use of MB resulted in hemodynamic stability unattained with standard vasopressor support. Further research is warranted on the use of MB in patients with septic shock. RésuméObjectif Le bleu de me´thyle`ne (BM) a e´te´propose´par certains chercheurs comme traitement de l'instabiliteh e´modynamique re´fractaire chez les patients en choc septique. La perfusion de BM n'est toutefois pas conside´re´e comme un traitement standard du choc septique, et la litte´rature publie´e de´crit des perfusions de courte dure´e, en ge´ne´ral de moins de six heures. É léments cliniques Nous rapportons un cas de choc septique chez un homme de 67 ans qui a eu besoin d'un soutien vasopresseur maximal avec de la nore´pine´phrine, de l'e´pine´phrine et de la vasopressine. Malgre´l'application des protocoles normalise´s pour le traitement du choc septique, l'e´tat he´modynamique du patient demeurait re´fractaire 80 h apre`s son admission. L'amorce d'une perfusion de BM a toutefois permis de re´tablir rapidement la stabilite´he´modynamique du patient et a entraıˆne´une re´duction subse´quente de ses besoins en vasopresseurs. Les nombreuses tentatives d'interruption de la perfusion de BM ont entraıˆne´des augmentations imme´diates et re´pe´te´es des besoins en vasopresseurs, c'est pourquoi une perfusion continue a`un de´bit plus bas de BM durant 120 h a e´te´mise en place. Le patient a finalement surve´cu a`la maladie et reçu son conge´de l'hôpital. Nous

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Effects of Methylene Blue on Blood Pressure and Reactivity to Norepinephrine in Endotoxemic Rats

Cited by 54 publications

References 0 publications

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Prolonged methylene blue infusion in refractory septic shock: a case report

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