Inhibition of nitric oxide synthesis by methylene blue

Mayer, Bernd; Brünner, Friedrich; Schmidt, Kurt

doi:10.1016/0006-2952(93)90072-5

Cited by 474 publications

(277 citation statements)

References 31 publications

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“…This is strong evidence that the inhibitory effect on ET-I secretion, at least of the agonists tested here, is not mediated by cyclic GMR The same conclusion was reached using 8-bromo-cyclic GMP, confirming a recent report dealing with human endothelial cells [13]. Previous reports ascribing an inhibitory role to cyclic GMP using methylene blue do not contradict our conclusion, because this dye, besides blocking guanylyl cyclase, inhibits nitric oxide synthase at even higher potency than guanylyl cyclase [14]. Moreover, the dye stimulates the production of superoxide anion [25].…”

Section: Discussionsupporting

confidence: 91%

“…All three compounds increased cyclic GMP levels, and ODQ prevented these increases, but it was again without effect on inhibition of ET-I secretion. Similarly, in the presence of 1 mM GSNO [14,23], ET-1 secretion was inhibited by 45% and cyclic GMP production was stimulated 23-fold. ODQ was without effect on ET-1 levels in the culture medium (P > 0.05), but potently reduced cyclic GMP generation (n = 6; data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…To determine if cyclic GMP or NO, or both mediate(s) the suppression of ET-1 production, cyclic GMP production must be inhibited selectively, while leaving NO unaffected. This has been attempted with methylene blue [7,8,12], but cannot be achieved with this dye since it inhibits both guanylyl cyclase and NO synthase, as we have shown recently [14]. The other tool used in the above studies, inhibition of NO synthase by L-arginine derivatives, will reduce both endogenous NO and cyclic GMP levels, thus making it impossible to differentiate between the two putative mediators.…”

Section: Introductionmentioning

confidence: 99%

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Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin‐1 secretion

1995

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin‐1 secretion

1995

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“…MB has direct inhibitory effects on nitric oxide synthases, both constitutive and inducible [101,102] and blocks accumulation of cyclic guanosine monophosphate (cGMP) by inhibiting the enzyme guanylate cyclase [101]. MB blocks the activity of NO-dependent guanylate cyclase via the oxidation of the active haemo centre [103] or by inactivation of its haemo-deficient apoenzyme [104].…”

Section: Effects Of Mb On Nitric Oxide Synthase and Guanylyl Cyclasementioning

confidence: 99%

Cerebral protection in experimental cardiopulmonary resuscitation (with special reference to the effects of methylene blue)

Miclescu¹

2010

Acta Anaesthesiol Scand

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Although survival rates are increasing, brain injury continues to be a leading cause of death after cardiac arrest (CA). Permanent brain damage after CA is determined by limited tolerance to ischemia from CA and cardiopulmonary resuscitation (CPR), as well as the unique cerebral response to reperfusion after return of spontaneous circulation (ROSC). A major pathway leading to neurotoxic cascade and neuronal injury after CA involves the increased presence of reactive oxygen and nitrogen species generated during ischemia and reperfusion. The magnitude of cerebral oxidative injury induced by free radicals increased with the duration of CA (Paper I). Nitric oxide (NO), a free radical responsible for the formation of reactive nitrogen species, is increased during global ischemia from CA and reperfusion (Paper IV). Hypothetically, the administration of a drug that counteracts the overproduction of NO and also acts as a scavenger of oxygen free radicals might be warranted in order to reduce the damage caused by nitrosative and oxidative stress. For these purposes we used methylene blue (MB), an old dye that has been used in medicine for almost half a century, and an experimental pig model of 20 min of ventricular fibrillation (VF) to reflect a clinical scenario of ischemia/reperfusion injury. Administration of MB added to a hypertonic-hyperoncotic solution (MBHSD) that was started during CPR and continued for 50 min after ROSC increased short-term survival by decreasing myocardial damage, as well as cerebral peroxidation and inflammatory injury (Paper II). Immunostaining of cerebral tissue collected at different time points after CA and ROSC (Paper IV) provided experimental evidence that cortical blood-brain barrier (BBB) disruption begins as early as during the initial phase of untreated as well as treated CA. The results indicated that MB administration reduced the neurologic injury and BBB disruption considerably, but did not reverse the ongoing detrimental processes. The demonstrated positive effects of MB were related to a decrease of nitrite/nitrate tissue content, and thus to a decrease of excess NO due to the MB inhibitory effects on NOS isoforms. A mixture of MB in hypertonic sodium lactate (MBL) was investigated to facilitate administration of MB in "the field." Based on findings that MBL cardio-and neuroprotective properties were similar to those of MBHSD, there is reason to believe that the use of MBL might be extended during ongoing CPR and after ROSC (Paper III). It would therefore make sense to try using MB as a pharmacological neuroprotectant during or after clinical CPR in order to expand the temporal therapeutic window before other measures for neuroprotection such as hypothermia are available. Keywords: Cardiac arrest, cardiopulmonary resuscitation, reperfusion injury, methylene blue, nitric oxide, nitric oxide synthases, blood-brain barrier

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“…Bilateral microinjection of methylene blue into the NTS also attenuated the Bezold Jarisch reflex elicited by intravenous infusion of serotonin (26). However, methylene blue may also inhibit NOS (27). Therefore, we sought to determine if the blockade of NOS by injection of L-nitroarginine methyl ester (L-NAME; 1 µmol) into the NTS altered responses to L-SNC (250 pmol) injected at the same site up to 60 min later.…”

Section: Wt Talmanmentioning

confidence: 99%

The myth of nitric oxide in central cardiovascular control by the nucleus tractus solitarii

Talman¹

1997

Braz J Med Biol Res

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Considerable evidence suggests that nitroxidergic mechanisms in the nucleus tractus solitarii (NTS) participate in cardiovascular reflex control. Much of that evidence, being based on responses to nitric oxide precursors or inhibitors of nitric oxide synthesis, has been indirect and circumstantial. We sought to directly determine cardiovascular responses to nitric oxide donors microinjected into the NTS and to determine if traditional receptor mechanisms might account for responses to certain of these donors in the central nervous system. Anesthetized adult Sprague Dawley rats that were instrumented for recording arterial pressure and heart rate were used in the physiological studies. Microinjection of nitric oxide itself into the NTS did not produce any cardiovascular responses and injection of sodium nitroprusside elicited minimal depressor responses. The S-nitrosothiols, Snitrosoglutathione (GSNO), S-nitrosoacetylpenicillamine (SNAP), and S-nitroso-D-cysteine (D-SNC) produced no significant cardiovascular responses while injection of S-nitroso-L-cysteine (L-SNC) elicited brisk, dose-dependent depressor and bradycardic responses. In contrast, injection of glyceryl trinitrate elicited minimal pressor responses without associated changes in heart rate. It is unlikely that the responses to L-SNC were dependent on release of nitric oxide in that 1) the responses were not affected by injection of oxyhemoglobin or an inhibitor of nitric oxide synthesis prior to injection of L-SNC and 2) Land D-SNC released identical amounts of nitric oxide when exposed to brain tissue homogenates. Although GSNO did not independently affect blood pressure, its injection attenuated responses to subsequent injection of L-SNC. Furthermore, radioligand binding studies suggested that in rat brain synaptosomes there is a saturable binding site for GSNO that is displaced from that site by L-SNC. The studies suggest that S-nitrosocysteine, not nitric oxide, may be an interneuronal messenger for cardiovascular neurons in the NTS.

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Inhibition of nitric oxide synthesis by methylene blue

Cited by 474 publications

References 31 publications

Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin‐1 secretion

Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin‐1 secretion

Cerebral protection in experimental cardiopulmonary resuscitation (with special reference to the effects of methylene blue)

The myth of nitric oxide in central cardiovascular control by the nucleus tractus solitarii

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