Manganese reduces myocardial reperfusion injury on isolated rat heart

It has been shown that reactive oxygen species produced during the early phase of myocardial post-ischemic reperfusion are one of the main causes of reperfusion injury. This observation has led to various antioxidant strategies using many reactive oxygen species scavengers, including manganese complexes. The aim of the present work was to provide a reference study of the effects of manganese itself (MnCl2) on isolated rat hearts submitted to global total normothermic ischemia (30 min) and reperfusion (60 min). McCl2 was administered either during the first 10 min reperfusion (10(-5)M and 10(-4)M) or throughout reperfusion (10(-4)M). After 10 min reperfusion, no functional difference was evidenced between control and manganese-treated groups, whereas high energy phosphate contents were significantly higher in treated groups. MnCl2 10(-4)M enhanced the recovery of developed pressure between 40 and 55 min reperfusion. At the end of reperfusion, hearts treated during the first 10 min reperfusion showed a better metabolic recovery. The group treated throughout reperfusion showed a better metabolic recovery, but a reduced coronary flow and a weak recovery of developed pressure. These results suggest that MnCl2, administered during the early phase of reperfusion, protects against myocardial reperfusion injury. This effect might be mediated by manganese antioxidant properties.     

Ototoxicity of sodium nitroprusside

Nitric oxide (NO) not only has normal physiological roles like vasodilation and neurotransmission in the living organism, it could also have possible neurodestructive effects under certain pathological conditions. The present study aimed to determine whether direct exposure of guinea pig cochlea to a NO donor like sodium nitroprusside (SNP), or a nitric oxide synthase (NOS) inhibitor like N(G)-nitro-L-arginine methyl ester (L-NAME), would cause damage to the auditory hair cells. A piece of gelfoam was placed on the round window of the right ear of adult albino guinea pigs. It was then soaked with 0.1 ml of SNP (3.4 microM), 0.1 ml of L-NAME (9.3 microM or 18.5 microM) or 0.1 ml of injection water, the vehicle used to dissolve the above chemicals. Twelve animals receiving SNP were perfused 1 day, 2, 3 and 7 days later, with three animals being used for each survival period. Six animals receiving L-NAME were allowed to survive up to 7 days before perfusion. Eight animals receiving injection water or 0.45% saline were used as controls. With the scanning electron microscope, the inner and outer hair cells were counted over a 1 mm length of the basilar membrane in each turn of every cochlea. The results showed that, in animals treated with L-NAME at both concentrations stated, no significant loss of either inner or outer hair cells was noted in any part of the cochlea studied. However, as early as 1 day after SNP treatment, a striking loss of inner and outer hair cells was observed in the three lower turns of the cochlea. Damage to the outer hair cells was extended to the apical turn with increasing survival period, but no significant loss of inner hair cells was evident in the apical turn at any of the survival periods studied. To rule out the possibility that the effects were due to the presence of cyanide, a metabolite of SNP, hydroxycobalamin was introduced into the scala tympani of three animals through a cannula-osmotic pump device during SNP treatment. There was no significant difference in the results between the groups with and without hydroxycobalamin infusion 7 days after SNP treatment. The present study suggests that an excessive production of NO in the inner ear could lead to extensive loss of hair cells.     

Apparent role of hydroxyl radicals in oxidative brain injury induced by sodium nitroprusside

Sodium nitroprusside (disodium nitroferricyanide) has been suggested to cause cytotoxicity through either the release of cyanide and/or nitric oxide. The present study investigated a possible mechanism that after a brief release of nitric oxide, iron moiety of breakdown products of sodium nitroprusside could cause a long lasting oxidative stress, such as hydroxyl radical generation, lipid peroxidation and cytotoxicity. Intranigral administration of sodium nitroprusside (0-16.8 nmol) to rats induced an acute increase in lipid peroxidation in the substantia nigra and a chronic dopamine depletion in the caudate nucleus. Photodegraded (nitric oxide-exhausted) sodium nitroprusside, however, still produced lipid peroxidation and neurotoxicity in the midbrain. Moreover, non-iron containing nitric oxide-donor compounds, such as S-nitroso-N-acetylpenicillamine, did not cause oxidative brain injury in vivo suggesting that nitric oxide may not mediate neurotoxicity induced by sodium nitroprusside. Additional in vitro studies demonstrated that both freshly prepared (nitric oxide donor) and photodegraded (nitric oxide-exhausted) sodium nitroprusside generated hydroxyl radicals in the presence of ascorbate and also increased lipid peroxidation in brain homogenates. These pro-oxidative effects of sodium nitroprusside were blocked by nitric oxide, S-nitroso-N-acetylpenicillamine, oxyhemoglobin, and deferoxamine (iron chelator). The present results suggest that iron moiety, rather than nitric oxide, may mediate the pro-oxidative properties of sodium nitroprusside. With this new information in mind, the misuse of sodium nitroprusside as a selective nitric oxide donor in both basic and clinical uses should be urgently addressed.     

Inhaled sodium nitroprusside. Non-selective reduction of thromboxane analogue-induced pulmonary vasoconstriction in healthy sheep

Both inhaled nitric oxide (NO) and inhaled prostacyclin have been shown to selectively decrease pulmonary hypertension of various origin. The aim of the present study was to assess the potential of the NO donor sodium nitroprusside (SNP) to elicit selective pulmonary vasodilation. SNP spontaneously liberates nitric oxide in the presence of reducing substances like cysteine or glutathione, ubiquitous in many different tissues. Inhaled as an aerosol in 3 healthy lambs presenting pulmonary hypertension induced by infusion of a thromboxane analogue, low concentrations of SNP (0.02-0.6 mg/ml) revealed no effect at all. In contrast, high concentrations of SNP (1.0-20.0 mg/ml) lowered pulmonary artery pressure in conjunction with systemic arterial hypotension, suggesting systemic resorption of SNP with subsequent release of its nitroso-group. Selective pulmonary vasodilation was never observed. In conclusion, the present results do not support a selective effect of inhaled SNP in the pulmonary circulation.     

Gradual reperfusion reduces infarct size and endothelial injury but augments neutrophil accumulation

BACKGROUND: Reperfusion causes injury to the coronary artery endothelium primarily by neutrophil-mediated mechanisms. However, factors other than neutrophils may govern the extent of myocardial necrosis. This study tests the hypothesis that gradual initiation of reflow will reduce reperfusion injury and preserve postischemic endothelial function. METHODS: In 16 anesthetized dogs, the left anterior descending artery was ligated for 60 minutes. In one group, reperfusion was initiated abruptly (abrupt, n = 8), whereas in the gradual reperfusion group (ramp, n = 8), flow was slowly initiated during the first 30 minutes of reperfusion. After reperfusion, coronary artery segments were isolated to assess postischemic endothelial function. RESULTS: Infarct size (area of necrosis/area at risk) was significantly reduced in the ramp group (28.2% +/- 2.0%) compared with abrupt (41.6% +/- 1.4%). Neutrophil accumulation (myeloperoxidase) in the area at risk was significantly greater in the ramp group compared with abrupt (8.0 +/- 1.3 versus 3.5 +/- 0.8 U/g tissue). In isolated postischemic left anterior descending arterial rings, the concentration of acetylcholine that elicited a response 50% of the maximum possible response was significantly greater in abrupt (-6.88 +/- 0.04 log [mol/L]) than ramp (-7.62 +/- 0.04 log [mol/L]) and control (-7.68 +/- 0.003 log [mol/L]), suggesting endothelial dysfunction. The concentration of A23187 that elicited a response 50% of the maximum possible response was similarly greater in abrupt (-7.24 +/- 0.03 log [mol/L]) versus ramp (-7.62 +/- 0.03 log [mol/L]) and control (-7.8 +/- 0.04 log [mol/L]). Smooth muscle dysfunction (response to sodium nitrite) also occurred in the abrupt rings. CONCLUSIONS: Gradual reperfusion of an ischemic area reduces infarct size and preserves endothelial function but paradoxically increases neutrophil accumulation within the area at risk.     

Cyclosporin-A reduces leukocyte accumulation and protects against myocardial ischaemia reperfusion injury in rats

The present study was designed to evaluate the effect of cyclosporin A in a rat model of myocardial ischaemia reperfusion injury (MI/R). Anaesthetized rats were subjected to total occlusion (20 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum tumor necrosis factor (TNF-alpha), cardiac mRNA for TNF-alpha, cardiac intercellular adhesion molecule-1 (ICAM-1) immunostaining and myocardial contractility (left ventricle dP/dtmax) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity and myeloperoxidase activity (a marker of leukocyte accumulation) both in the area-at-risk and in the necrotic area, reduced myocardial contractility and induced a marked increase in the serum levels of the TNF-alpha. Furthermore increased cardiac mRNA for TNF-alpha was measurable within 10 to 20 min of left main coronary artery occlusion in the area-at-risk and increased levels were generally sustained for 0.5 h. Finally, myocardial ischaemia-reperfusion injury increased ICAM-1 staining in the myocardium. Administration of cyclosporin A (0.25, 0.5 and 1 mg/kg as an i.v. infusion 5 min after coronary artery occlusion) lowered myocardial necrosis and myeloperoxidase activity in the area-at-risk and in the necrotic area, decreased serum CPK activity, increased myocardial contractility, reduced serum levels of TNF-alpha and the cardiac cytokine mRNA levels, and blunted ICAM-1 immunostaining in the injured myocardium. The data suggest that cyclosporin A suppresses leukocyte accumulation and protects against myocardial ischaemia-reperfusion injury.     

Intracavernous sodium nitroprusside: inappropriate impotence treatment

On the basis of reports describing nitric oxide as a form of endothelium-derived relaxing factor and on our own experience with intracavernous use of nitric oxide-releasing substances in animal models, we undertook an approved human study of intracavernous sodium nitroprusside as a treatment for impotence. We report our early experience in which severe hypotension and only mild tumescence in our first 3 patients caused us to discontinue the trial.     

Effects of sodium nitroprusside on hemodialysis-induced platelet activation

Plasminogen activator inhibitor-2 (PAI-2), a member of the serpin gene family, is thought to serve as a primary regulator of plasminogen activation in the extravascular compartment. High levels of PAI-2 are found in keratinocytes, monocytes, and the human trophoblast, the latter suggesting a role in placental maintenance or embryo development. The primarily intracellular distribution of PAI-2 also may indicate a unique regulatory role in a protease-dependent cellular process such as apoptosis. To examine the potential functions of PAI-2 in vivo, we generated PAI-2-deficient mice by gene targeting in embryonic stem cells. Homozygous PAI-2-deficient mice exhibited normal development, survival, and fertility and were also indistinguishable from normal controls in response to a bacterial infectious challenge or endotoxin infusion. No differences in monocyte recruitment into the peritoneum were observed after thioglycollate injection. Epidermal wound healing was equivalent among PAI-2 -/- null and control mice. Finally, crossing PAI-2 -/- with PAI-1 -/- mice to generate animals deficient in both plasminogen activator inhibitors failed to uncover an overlap in function between these two related proteins.     

Neurotoxic effects of sodium nitroprusside in rat hippocampal slices

The effect of a permanent transection on myelin gene expression in a regenerating sciatic nerve and in an adult sciatic nerve was compared to establish the degree of axonal control exerted upon Schwann cells in each population. First, the adult sciatic nerve was crushed, and the distal segment allowed to regenerate. At 12 days post-crush, the sciatic nerve was transected distal to the site of crush to disrupt the Schwann cell-axonal contacts that had reformed. Messenger RNA (mRNA) levels coding for five myelin proteins were assayed in the distal segment of the crush-transected nerve after 9 days and were compared to corresponding levels in the distal segments of sciatic nerves at 21 days post-crush and 21 days post-transection using Northern blot and slot-blot analysis. Levels of mRNAs found in the distal segment of the transected and crush-transected nerve suggested that Schwann cells in the regenerating nerve and in the mature adult nerve are equally responsive to axonal influences. The crush-transected model allowed the genes that were studied to be classified according to their response to Schwann cell-axonal contact. The levels of mRNAs were 1) down-regulated to basal levels (P0 and MBP mRNAs), 2) down-regulated to undetectable levels (myelin-associated glycoprotein mRNAs), 3) upregulated (mRNAs encoding 2'3'-cyclic nucleotide phosphodiesterase and beta-actin), or 4) not stringently controlled by the removal of Schwann cell-axonal contact (proteolipid protein mRNAs). This novel experimental model has thus provided evidence that the expression of some of the important myelin genes during peripheral nerve regeneration is dependent on continuous signals from the ingrowing axons.     

Some aspects of sodium nitroprusside reaction with human erythrocytes

Sodium nitroprusside is an excellent agent for lowering blood pressure in hypertensive emergencies, for producing controlled hypotension during anesthesia, and for treating acute myocardial infarction and chronic heart failure. Toxic effects of this drug have been reported and above-normal cyanide and thiocyanate concentrations have been observed in the blood of a small proportion of subjects receiving nitroprusside. Nitrite, syanide, and thiocyanate are major decomposition products of nitroprusside, resulting from an in vitro reaction with human blood. On the basis of the conversion mechanism, we suggest that, in the cyanide/thiocyanate cycle, only cyanide is directly responsible for any acute toxicity attributed to sodium nitroprusside. In this work, the extent of cyanide production by erythrocytes in vitro was studied. The rate of detoxification of cyanide by human liver in vitro was experimentally determined and data from a search for a possible inhibitor of the nitroprusside/hemoglobin reaction are presented. Also, the possible mechanism of the nitroprusside/hemoglobin reaction is discussed.     

Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin

Reading disability (RD), or dyslexia, is a complex cognitive disorder manifested by difficulties in learning to read, in otherwise normal individuals. Individuals with RD manifest deficits in several reading and language skills. Previous research has suggested the existence of a quantitative-trait locus (QTL) for RD on the short arm of chromosome 6. In the present study, RD subjects' performance in several measures of word recognition and component skills of orthographic coding, phonological decoding, and phoneme awareness were individually subjected to QTL analysis, with a new sample of 126 sib pairs, by means of a multipoint mapping method and eight informative DNA markers on chromosome 6 (D6S461, D6S276, D6S105, D6S306, D6S258, D6S439, D6S291, and D6S1019). The results indicate significant linkage across a distance of at least 5 cM for deficits in orthographic (LOD = 3.10) and phonological (LOD = 2.42) skills, confirming previous findings.     

Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation

Magnaporthe grisea, the causal agent of rice blast, forms a dome-shaped melanized infection structure, an appressorium, to infect its host. Environmental cues that induce appressorium formation by this fungus include hydrophobicity and hardness of contact surface, and chemicals from the host. To determine if the calcium/calmodulin-dependent signaling systems are involved in appressorium formation in M. grisea, we tested the effects of the calcium chelator, calcium ionophore, diverse intracellular calcium modulators, and calmodulin antagonists on appressorium formation. Several calcium modulators and calmodulin antagonists inhibited appressorium formation at the microM level, while conidia germination remained unaffected. There was an inhibition of appressorium formation by EGTA, a calcium chelator, which was restored by the addition of exogenous CaCl2. Neomycin, a phospholipase C inhibitor, specifically inhibited appressorium formation at concentrations from 10 microM to 100 mM. These data suggest that a calcium/calmodulin-dependent signaling system is involved in the appressorium formation of M. grisea.     

Inhibition of endogenous nitric oxide synthesis potentiates the effects of sodium nitroprusside but not of adenosine in experimental pulmonary hypertension

The authors review the research on childhood antecedents and personality contributions to the somatoform disorders, as well as research on social influences during adulthood. Based on these data, the authors hypothesize that somatizing patients display anxious attachment behavior that derives from childhood experiences with caregivers. Early exposure to illness increases the likelihood that distress will be manifested somatically. When under stress as adults, somatizers use physical complaints to elicit care. Somatizers' interpersonal interactions with others, including physicians, ultimately lead to rejection that reinforces the somatizer's belief that he or she will be abandoned. Modification of physicians' responses to these patients may improve treatment outcomes.     

Do sodium nitroprusside and L-NAME affect pyrogen fever in rabbits?

Thermoregulatory responses after treatment with nitric oxide (NO) donor, sodium nitroprusside (SNP-3 mg/kg/h), or NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME-100 mg/kg) were investigated in febrile rabbits (lipopolysaccharide E. coli-1 meg/kg). Pretreatment with SNP attenuated pyrogen fever as well as metabolic rate. L-NAME also inhibited postpyrogen increases in metabolism; however, this effect did not lead to antipyresis.