Sodium Nitroprusside and Cyanide Release: Reasons for Re-Appraisal

Bisset, W.I.K.; Butler, Anthony R.; Glidewell, C.; Reglinski, John

doi:10.1093/bja/53.10.1015

Cited by 46 publications

(19 citation statements)

References 12 publications

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“…Although toxic effects of SNP have been described in patients receiving SNP over a long period of time, the clinical significance of cyanide toxic ity has been questioned. According to Bisset [28], cyanide is not released from SNP in vivo, and it may well be safe to infuse larger doses than those hitherto recommended.…”

Section: Discussionmentioning

confidence: 99%

Effect of Sodium Nitroprusside on Cardiac Output during Cross-Clamping of the Descending Thoracic Aorta in Pigs

Aadahl

Aakhus²,

Strømholm

et al. 1995

Eur Surg Res

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Sodium nitroprusside (SNP) is used to control proximal hypertension during cross-clamping of the descending thoracic aorta (XC). To assess the haemodynamic effects of SNP on cardiac output (CO) during XC, 21 pigs were anaesthetized with ketamine and fentanyl. In the control group (n = 11), no vasodilating therapy was given. In the investigation group (SNP group), 2 animals died during the surgical preparation and were excluded, leaving 8 animals in the group (n = 8). In these animals, SNP was infused in order to keep the mean arterial pressure (MAP) at about 100 mm Hg during cross-clamping. In both groups, aorta was cross-clamped for 30 min, and cardiac output (CO) was measured by the thermodilution technique. Following cross-clamping, CO increased 107% in the control group and 96% in the SNP group. There was an increase in heart rate (HR) of 77% in the control group and of 110% in the SNP group, and a reduction in systemic vascular resistance of 41% in the SNP group. Stroke volume (SV) was unchanged in both groups. MAP increased 83% in the control-group. No differences were observed between the two groups regarding central venous pressure or pulmonary artery pressure. Four animals in the SNP group died 5–10 min after release of the aortic clamp. In conclusion, we found equal increase in CO in both groups. The increase in CO was related predominantly to increased HR, whereas SV was largely unaltered. Vasodilation with SNP increased the mortality following clamp removal in this experimental model.

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Section: Discussionmentioning

confidence: 99%

Effect of Sodium Nitroprusside on Cardiac Output during Cross-Clamping of the Descending Thoracic Aorta in Pigs

Aadahl

Aakhus²,

Strømholm

et al. 1995

Eur Surg Res

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“…Dose received for dose-response curve data was given in ascending order with the initial treatment counterbalanced across rats. MK-801 (Abcam, Cambridge, MA) and SNP (Sigma-Aldrich, St. Louis, MO) were dissolved in saline and drugs were protected from light exposure to prevent photodecomposition (Bisset et al 1981). …”

Section: Drug Treatmentsmentioning

confidence: 99%

“…The metabolism of SNP results in cyanide anion production of cyanide anions (Cn -) (Bisset et al 1981). Administration of SNP at too large of a dose or too quick of an infusion rate can lead to cyanide toxicity, producing metabolic acidosis, CNS dysfunction and cardiovascular instability (Bisset et al 1981).…”

Section: Nitric Oxide Sodium Nitroprusside and Schizophreniamentioning

confidence: 99%

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

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“…, for example, found a biological half-life of about 2 minutes for nitroprusside at 'therapeutic' concentrations in rats, 241 which is in agreement with the short duration of efficacy of the drug when used clinically as an antihypertensive agent. Against this, uncritical adoption of the breakdown time in vitro as being applicable to in vivo conditions has recently contributed to a serious error of judgement regarding the acute toxicity of sodium nitroprusside (Bisset et a!., 1981;Smith et a!., 1982).…”

Section: Breakdown Of Nitroprusside In Vitro and In Vivomentioning

confidence: 99%

Clinical Pharmacokinetics of Nitroprusside, Cyanide, Thiosulphate and Thiocyanate

Schulz¹

1984

Clinical Pharmacokinetics

173

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Sodium nitroprusside decomposes within a few minutes after intravenous infusion to form metabolites which are pharmacologically inactive but toxicologically important. Free cyanide, which represents 44% w/w of the sodium nitroprusside molar mass, is formed and must be detoxified in the body into thiocyanate using thisulphate as substrate. Nitroprusside penetrates cell membranes slowly. At therapeutic dose levels its distribution is probably mainly extracellular. Contact with the sulfhydryl groups in the cell walls, however, immediately initiates breakdown of the molecule. Sodium nitroprusside taken orally is not absorbed from the gastrointestinal tract to any appreciable extent. Cyanides in the body form prussic acid, which can rapidly penetrate mucous and cell membranes. In the blood, about 99% of the prussic acid binds to the methaemoglobin of erythrocytes. At normal physiological levels, however, the total body methaemoglobin of an adult human can only bind about 10mg of prussic acid; this is a small fraction of the amounts usually infused therapeutically as sodium nitroprusside. The endogenous detoxification of prussic acid exhibits zero-order kinetics. The limiting factor is a sulphur donor, principally thiosulphate, which is available in the body in only limited amounts. The rate of spontaneous detoxification of prussic acid in humans is only about 1 microgram/kg/min, corresponding to a sodium nitroprusside infusion of about 2 microgram/kg/min. This dose limit set by the prussic acid toxicity of sodium nitroprusside can, however, be increased considerably by simultaneous infusion of thiosulphate. A lack of thiosulphate can be detected early by a rise of the prussic acid concentration in the erythrocytes. Thiosulphate taken orally is not absorbed by the body. After intravenous infusion, its serum half-life is about 15 minutes. Most of the thiosulphate is oxidised to sulphate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. Thiocyanate taken orally is completely absorbed by the body. In healthy persons its volume of distribution is approximately 0.25 L/kg and the serum half-life about 3 days; elimination is mainly renal. Thiocyanate toxicity does not represent a serious therapeutic problem with intravenous infusion of sodium nitroprusside.

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Sodium Nitroprusside and Cyanide Release: Reasons for Re-Appraisal

Cited by 46 publications

References 12 publications

Effect of Sodium Nitroprusside on Cardiac Output during Cross-Clamping of the Descending Thoracic Aorta in Pigs

Effect of Sodium Nitroprusside on Cardiac Output during Cross-Clamping of the Descending Thoracic Aorta in Pigs

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

Clinical Pharmacokinetics of Nitroprusside, Cyanide, Thiosulphate and Thiocyanate

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