Preliminary Observation on the Cytotoxic Activity of New Chlorophyllin Derivative RCD on Human Tumour Cell Lines In Vitro.

BACKGROUND: Chlorophyllin is used in traditional Chinese medicine because of its anticancer properties. This article describes the preparation and cytotoxic activity of a reduced chlorophyllin derivative (RCD) on tumour cell lines. MATERIALS AND METHODS: RCD was prepared by reducing chlorophyllin with lithium aluminium hydride, and its solubility in the alkaline and organic phases are different from that of the parent compound chlorophyllin. RESULTS: RCD also has different chromatographic behaviour from chlorophyllin on thin-layer chromatography and high-pressure liquid chromatography, and excitation and emission spectra. RCD has cytotoxic activity against ZR-75, MCF-7 and HT-29, human tumour cell lines. A clonogenic assay showed that the growth of tumour colonies on soft agar was reduced by RCD in a dose-dependent manner. CONCLUSION: RCD is a novel compound exhibiting anticancer activity.

Alterations of RNA Metabolism by Proteomic Analysis of Breast Cancer Cells Exposed to Marycin: A New Optically Active Porphyrin.

OBJECTIVE: Marycin is a porphyrin-type compound synthetically modified to spontaneously release fluorescence. This study is aimed at understanding possible mechanisms that could account for the antiproliferative effects observed in marycin. A proteomic approach was used to identify molecular effects. The proteome of proliferating MDA-MB-231 breast cancer cells was compared with that of marycin-treated cells. METHODS: Label-free proteomic analysis by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to reveal changes in protein expression and fluorescence microscopy and flow cytometry were used to detect subcellular organelle dysfunctions. RESULTS: The bioinformatic analysis indicated an enhancement of the expression of proteins remodeling RNA splicing and more in general, of RNA metabolism. Marycin did not localize into the mitochondria and did not produce a dramatic increase of ROS levels in MDA-MB-231 cells. Marycin stained organelles probably peroxisomes. CONCLUSIONS: The results could support the possibility that the peroxisomes are involved in cell response to marycin.

Activated partial thromboplastin time correlates with methoxyhydroxyphenylglycol in acute myocardial infarction patients: therapeutic implications for patients at cardiovascular risk.

BACKGROUND/AIM: Acute myocardial infarction (AMI) is associated with increased coagulation which in the presence of unstable atheroma or endothelial damage leads to occlusive coronary vessel thrombosis. AMI is usually characterized by increased levels of catecholamines. It is possible there may be a link between catecholamines and hypercoagulation, but this still remains to be determined. In the current study we sought to verify whether hypercoagulation is associated with hypersympathetic activity in AMI patients, and whether there is a correlation between increased Methoxyhydroxyphenylglycol (MOPEG) levels (a metabolite of catecholamines) and shorter APTT (a marker of hypercoagulation). RESULTS: Shorter APTT values were detected in the plasma of AMI patients, which had also increased MOPEG levels. A linear correlation between APTT and MOPEG values was observed. High levels of the coagulation marker prothrombin (fragments 1+2) were also found. CONCLUSION: Shortened APTT demonstrates hypercoagulation and high MOPEG levels indicate increased catecholamine metabolism. A direct correlation between APTT and MOPEG was found herein, demonstrating a link between catecholamines and the process of coagulation. Catecholamines may interact with the α2-adrenergic receptors located on platelets and convert factor XII to XIIa or through the kallikrein-kinin system, they may activate factor XII. The activation of factor XII initiates the intrinsic coagulation pathway, which is monitored by APTT. It is suggested to control patients with a shortened APTT and increased sympathetic activity with the aim of preventing secondary coagulation and cardiovascular accidents by administering anti-thrombotic and anti-adrenergic agents.

Ellagitannins from Rubus berries for the control of gastric inflammation: in vitro and in vivo studies.

Ellagitannins have shown anti-inflammatory and anti-Helicobacter pylori properties; however, their anti-inflammatory activity at gastric level was not previously investigated. The aim of this research was to evaluate the effects of ellagitannins from Rubus berries on gastric inflammation. Ellagitannin enriched extracts (ETs) were prepared from Rubus fruticosus L. (blackberry) and Rubus idaeus L. (raspberry). The anti-inflammatory activity was tested on gastric cell line AGS stimulated by TNF-α and IL-1ß for evaluating the effect on NF-kB driven transcription, nuclear translocation and IL-8 secretion. In vivo the protective effect of ellagitannins was evaluated in a rat model of ethanol-induced gastric lesions. Rats were treated orally for ten days with 20 mg/kg/day of ETs, and ethanol was given one hour before the sacrifice. Gastric mucosa was isolated and used for the determination of IL-8 release, NF-kB nuclear translocation, Trolox equivalents, superoxide dismutase and catalase activities. In vitro, ETs inhibited TNF-α induced NF-kB driven transcription (IC50: 0.67-1.73 µg/mL) and reduced TNF-α-induced NF-kB nuclear translocation (57%-67% at 2 µg/mL). ETs inhibited IL-8 secretion induced by TNF-α and IL-1ß at low concentrations (IC50 range of 0.7-4 µg/mL). Sanguiin H-6 and lambertianin C, the major ETs present in the extracts, were found to be responsible, at least in part, for the effect of the mixtures. ETs of blackberry and raspberry decreased Ulcer Index by 88% and 75% respectively and protected from the ethanol induced oxidative stress in rats. CINC-1 (the rat homologue of IL-8) secretion in the gastric mucosa was reduced in the animals receiving blackberry and raspberry ETs. The effect of ETs on CINC-1 was associated to a decrease of NF-κB nuclear translocation in ETs treated animals. The results of the present study report for the first time the preventing effect of ETs in gastric inflammation and support for their use in dietary regimens against peptic ulcer.

Factors involved in sudden coagulation observed in patients with acute myocardial infarction.

Coronary artery diseases (CAD) evolving into acute myocardial infarction (AMI) is associated with coagulation and thrombotic occlusion of coronary vessels in the presence of unstable atheroma. The atheromatous plaque becomes unstable when it is infiltrated by monocytes, macrophages and neutrophils capable of secreting proteases that induce plaque erosion, rupture and initialize the coagulation process. The aim of this study was (a) to analyse the plasma of patients with AMI for the presence of proteases that may activate rapid coagulation, (b) to evaluate coagulation markers as prothrombin fragment (F1+2) and antithrombin III and (c) to find an interrelation between proteases and coagulation markers. The examined plasma showed high values of prothrombin fragment (F1+2) and low levels of antithrombin III. These markers showed a highly significant negative-correlation. The plasma also exhibited increased levels of matrix metalloproteinase-9 (MMP-9) which were positively-correlated with the prothrombin fragment (F1+2). MMP-9 seems to cause the coagulation activity by increasing the level of prothrombin fragment (F1+2) and the consumption of antithrombin III. The examined plasma also exhibited high levels of neutrophil gelatinase-associated lipocalin (NGAL), which is known to modulate MMP-9 activity. The high plasma levels of MMP-9 and NGAL can be attributed to plaque instability and appear to activate sudden coagulation. MMP-9 and NGAL, in the presence of altered values of prothrombin fragment (F1+2) and antithrombin III in AMI patients, seem to be suitable markers to be studied in unstable plaque patients, for the prediction and prevention of acute coronary syndrome.

Activity of a new hydrogen sulfide-releasing aspirin (ACS14) on pathological cardiovascular alterations induced by glutathione depletion in rats.

We investigated the effects of the hydrogen sulfide (H2S)-releasing derivatives of aspirin (ACS14) and salicylic acid (ACS21) in a rat model of metabolic syndrome induced by glutathione (GSH) depletion, causing hypertension and other pathological cardiovascular alterations. GSH depletion was induced in normal rats by the GSH-synthase inhibitor buthionine sulfoximine (BSO, 30 mmol/L day for seven days in the drinking water). Systolic blood pressure and heart rate were measured daily by the tail-cuff method, and plasma thromboxane B2, 6-keto-prostaglandin F(2α), 8-isoprostane, GSH, insulin and glucose were determined at the end of the seven-day BSO schedule. In addition, ischemia/reperfusion-induced myocardial dysfunction and endothelial dysfunction were assayed on isolated heart and aortic rings, respectively. Unlike aspirin and salicylic acid, ACS14 and ACS21 reduced BSO-induced hypertension, also lowering plasma levels of thromboxane B2, 8-isoprostane and insulin, while GSH remained in the control range. Neither ACS14 nor ACS21 caused gastric lesions. Both restored the endothelial dysfunction observed in aortic rings from BSO-treated rats, and in ischemia/reperfusion experiments they lowered left ventricular end-diastolic pressure, consequently improving the developed pressure and the maximum rise and fall of left ventricular pressure. Together with this improvement of heart mechanics there were reductions in the activity of creatine kinase and lactate dehydrogenase in the cardiac perfusate. This implies that H2S released by both ACS14 and ACS21 was involved in protecting the heart from ischemia/reperfusion, and significantly limited vascular endothelial dysfunction in aortic tissue and the related hypertension.

Pretreatment with tetrandrine has protective effects against isoproterenol-induced myocardial infarction in rabbits.

Tetrandrine, the active principle of Stephania tetrandra radix extracts, has broad pharmacological activity, including effects on the cardiovascular system: it has been shown to reduce the size of acute myocardial infarction in rats undergoing coronary vessel ligation and to improve heart lesions in the constriction/reperfusion model by means of mechanisms involving peroxidation, calcium antagonism and coagulation. The aim of this study was to investigate whether tetrandrine has anti-infarction, antioxidant and anticoagulant effects in rabbits treated with isoproterenol, a drug capable of causing peroxide generation, calcium overload and coagulation alterations, and inducing myocardial infarction. The results showed that pretreatment with tetrandrine protects against the myocardial injuries caused by isoproterenol. It counteracted the appearance of myocardial necrotic lesions and ischemic electrocardiographic modifications, such as ST segment alterations, prevented the appearance of the plasma cardiac necrosis markers c-troponin I and myoglobin, lowered malondialdehyde levels, and prolonged partial thromboplastin time. The protective effects of tetrandrine can be attributed to its antioxidant action in lowering peroxide levels and its ability to counteract coagulating activity. Tetrandrine seems to offer full protection against myocardial infarction experimentally induced by the non-invasive treatment of rabbits with isoprotenerol.

Plasma cardiac necrosis markers C-troponin I and creatine kinase, associated with increased malondialdehyde levels, induced in rabbits by means of 5-aminolevulinic acid injection.

A number of papers have described high levels of 5-aminolevulinic acid in cases of heart damage due to acute myocardial infarction, acute intermittent porphyria or chronic kidney failure, but it is not known whether the heart damage is directly associated with 5-aminolevulinic acid. The aim of this study was to verify whether such an association exists by injecting rabbits with 5-aminolevulinic acid and searching for the appearance of cardiac necrosis markers and histological heart alterations, and investigate whether the cardiotoxic activity of 5-aminolevulinic acid may involve peroxidation by seeking the presence of the peroxide marker malondialdehyde. The administration of 5-aminolevulinic acid led to the appearance of c-troponin I and creatine kinase, induced histological heart alterations and increased the malondialdehyde levels. The plasma levels of malondialdehyde and cardiac necrosis markers were also measured after the injection of 5-aminolevulinic acid in combination with the daunorubicin agent inducing peroxidation. The combined administration very significantly increased the plasma levels of 5-aminolevulinic acid, malondialdehyde, and the cardiac necrosis markers c-troponin I and creatine kinase. It therefore seems that there is a close relationship between altered 5-aminolevulinic acid levels, malondialdehyde and cardiac necrosis markers, which is attributable to the capacity of 5-aminolevulinic acid to generate toxic oxygen species that damage the heart. High plasma 5-aminolevulinic acid levels should be considered a factor contributing to cardiotoxicity and to the appearance of cardiac necrosis markers.

Effects of alpha-lipoic acid administration on plasma glucose levels, total malondialdehyde values and withdrawal signs in rats treated with morphine or morphine plus naloxone.

Morphine (CAS 57-27-2) administration or its removal induces alterations in glucose levels and oxidative status or behaviour signs, which may be hypothetically closely related; if this is correct, controlling glucose changes may lead to modifications in peroxide levels and in behaviour profile. It therefore seems important to find a drug able to control alterations of glucose metabolism, peroxide generation and behaviour symptoms in morphine or morphine withdrawal animals. This paper describes the effects of morphine or morphine plus naloxone (CAS 51481-60-8) on the plasma levels of glucose, malondialdehyde (MDA) (CAS 100683-54-3) and behavioural signs in rats treated or not with alpha-lipoic acid (CAS 1077-28-7), known to interfere with glucose and peroxide levels. The administration of morphine or its removal by naloxone alters plasma glucose levels, increases MDA values, and also affects signs such as pain threshold values, fecal excretion and jumping behaviour. The injection of alpha-lipoic acid decreases glycemia in rats treated with morphine or morphine plus naloxone. This result may be due to the capacity of alpha-lipoic acid to facilitate glucose transport and its utilization. The administration of a-lipoic acid to rats given morphine or morphine plus naloxone lowers total MDA levels because of its peroxide scavenging capacity. In animals injected with morphine plus naloxone, which show altered pain thresholds, high fecal excretion and jumping behaviour, treatment with alpha-lipoic acid increases latency times, decreases fecal excretion and reduces jumping. These effects can be attributed to the capacity of alpha-lipoic acid to interfere with mediators or peroxides involved in the modified behaviour. The glycemia levels, MDA values and behavioural signs seem to be interconnected in the reported experiments. The administration of alpha-lipoic acid is demonstrated to control the alterations in plasma glucose levels, peroxide values or behavioural profile in animals receiving morphine or morphine plus naloxone.

Morphine or its withdrawal affects plasma malondialdehyde, vitamin E levels and absence or presence of abstinence signs in rats.

OBJECTIVES: Various experimental observations show that morphine treatment generates reactive oxygen species, and that its discontinuation leads to signs of withdrawal. We therefore investigated plasma malondialdehyde and vitamin E levels under both conditions to verify the occurrence of any alterations in oxidative metabolism, and whether these are associated with behavioural changes. METHODS: We investigated the effects of morphine or morphine plus naloxone on plasma malondialdehyde, vitamin E levels and withdrawal signs such as jumping, wet dog shakes and faecal excretion in rats. Furthermore, isopropylnoradrenaline was injected in rabbits to verify its effects on plasma malondialdehyde levels. KEY FINDINGS: Morphine treatment increased free malondialdehyde and decreased vitamin E levels. The elevation in malondialdehyde levels were exacerbated by the abrupt removal of morphine by naloxone, which also led to the appearance of withdrawal signs. The increased malondialdehyde values can be attributed to the interactions of reactive oxygen species with unsaturated fatty acids, and the lowered levels of vitamin E to its interactions with reactive oxygen species. CONCLUSIONS: A connection seems to exist between altered peroxide status and withdrawal signs in abstinent animals.

Plasma malondialdehyde levels and opiate withdrawal signs observed in rats treated with morphine plus naloxone: effects of alpha-lipoic acid administration.

A number of experimental studies have found that reactive oxygen species are involved during morphine treatment or withdrawal. The aims of this study were to analyse whether morphine administration and/or removal are related to peroxide generation and/or signs of withdrawal in rats, and whether the changes in antioxidant status induced by the administration of an antioxidant may modify peroxide levels and behavioural signs. We injected morphine or morphine and naloxone into rats and evaluated the plasma levels of peroxide malondialdehyde (MDA) and the appearance of withdrawal signs. We also investigated the effects on these parameters induced by the administration of the antioxidant alpha-lipoic acid (LA). Morphine treatment increased MDA levels. Abrupt naloxone-induced morphine withdrawal caused a further and significant increase in MDA, and the appearance of withdrawal signs such as abnormal fecal excretion, shortened latency times and jumping. The administration of LA lowered MDA levels in the rats treated with morphine or morphine plus naloxone, and also decreased MDA values and abstinence signs in the animals treated with morphine plus naloxone. The effects of LA were attributed to its capacity to scavenge peroxides and interfere with the biogenesis of the arachidonic acid metabolites involved in the expression of abstinence symptoms.

Increased urinary coproporphyrin excretion observed in patients with differently staged Hodgkin's disease treated with chemotherapy.

It has been reported that patients with Hodgkin's disease (HD) show altered porphyrin metabolism, and suggested that the cause is the neoplastic process itself. If this is true, disease progression should be associated with higher levels of porphyrin excretion. The aim of this study was to evaluate urinary coproporphyrin levels in patients with Hodgkin's disease at different stages. As many of the patients received chemotherapy, another aim was to verify experimentally whether chemotherapeutic agents might increase porphyrin levels in rabbits. All of the patients had above-normal urinary coproporphyrin levels. On the other hand, rabbits receiving the porphyrin precursor 5-aminolevulinic acid (5-ALA), and also treated with doxorubicin, showed very high plasma porphyrin levels. The increased levels of urinary coproporphyrins seem to be due to the disease itself, since the patients in stages III and IV had higher excretion values, presumably due to biochemical heme synthesis lesions that lead to the availability of the porphyrin precursor, as well as coproporphyrin accumulation and excretion. The altered porphyrin synthesis may be attributable to the cytotoxic oxygen species generated in the presence of NADH and iron. As the patients also received extensive chemotherapy regimes, the altered porphyrin metabolism may be affected by antineoplastic treatment generating oxygen reactive radicals. The alterations in porphyrin metabolism induced by chemotherapeutic agents appear to be demonstrated in rabbits in which doxorubicin increases porphyrin synthesis after porphyrin precursor treatment.

Myocardial infarction non-invasively induced in rabbits by administering isoproterenol and vasopressin: protective effects exerted by verapamil.

Myocardial infarction is usually induced in small animals by means of invasive procedures: the aim of this study was to cause heart necrosis lesions by non-invasive means. We injected rabbits with isoproterenol (3 mg/kg, i.p.) and vasopressin (0.3 mg/kg/5 min, i.v.) alone and in combination, and studied their effects on myocardial histology, electrocardiographic profiles, the appearance of the plasma cardiac necrosis marker c-troponin I (c-TPN I), hemodynamic parameters (blood pressure, heart rate), the coagulative process partial throboplastine time (PTT), and plasma nitric oxide (NO) levels. In the rabbits treated with vasopressin alone, the ischemic damage was associated with a decrease in NO values, and the appearance of electrocardiographic T-wave inversion and low plasma c-TPN I levels, whereas the animals treated with isoproterenol alone had necrotic bands in the myocardium, plasma c-TPN I, and electrocardiographic modifications (ST-segment changes and T-wave inversion). Combined treatment increased myocardial alterations such as contraction band necrosis, induced the appearance of specific hypoxic lesions such as areas of coagulative necrosis and leukocyte infiltration, and led to higher plasma c-TPN I levels and altered ECG profiles. Both drugs favored a decrease in plasma NO values and further alterations in hemodynamic parameters, such as higher blood pressure and greater procoagulant activity. The myocardial necrosis and modified cardiovascular parameters were attributed to calcium activated processes and the decrease in NO levels. As this model of myocardial damage involves the use of drugs that facilitate the opening of L-calcium channels, we also investigated their effects on cardiovascular parameters and heart histology after pretreatment with the calcium antagonist verapamil; this drug protected against the appearance of histological myocardial lesions, electrocardiographic alterations and high plasma c-TPN I levels, and prevented the hemodynamic and procoagulation changes, but did not affect the decrease in plasma NO values. The protective effects were attributed to the drug's calcium antagonist activity. In conclusion, the injection of isoproterenol and vasopressin induces a myocardial infarction non-invasively and seems to be suitable for studying early myocardial ischemic lesions and the effects of drugs interfering with myocardial damage and its related phenomena.

Isoproterenol-induced myocardial infarction in rabbits. Protection by propranolol or labetalol: a proposed non-invasive procedure.

Myocardial infarction is usually induced in small animals by means of invasive techniques based on mechanical coronary obstruction. As it has been reported that isoproterenol can cause ischemic myocardial alterations, lipid peroxide generation and procoagulant activity, we administered it to rabbits in order to induce a non-invasive myocardial infarction associated with above mentioned cardiovascular risk factors. Considerable ischemic alterations were observed in the animals treated with isoproterenol, including areas of myocardial necrosis, contraction band necrosis, increased plasma levels of cardiac necrosis markers (c-troponin I and myoglobin), and electrocardiographic modifications (ST segment changes and T wave inversion). The myocardial infarction was attributed to the inotropic activity of isoproterenol leading to intracellular calcium overload. The cardiac necrosis phenomena appear to be associated with isoproterenol-induced lipid peroxide generation (as shown by the decrease in plasma Vitamin E levels) and increased procoagulant activity (a shortened PTT). As this model of myocardial damage is based on the use of beta-stimulatory isoproterenol, the beta-blockers propranolol and labetalol were administered to isoproterenol-treated animals. Pretreatment with propranolol or labetalol counteracted the appearance of the myocardial histological alterations and the associated ECG and biochemical lesions. This protective activity was attributed to the beta-blockade. The results of this study demonstrate that myocardial infarction can be induced chemically and non-invasively in small laboratory animals. The procedure is proposed for the study of early ischemic myocardial lesions and the screening of drugs (such as beta-blockers) that can prevent myocardial necrosis damage and the associated risk factors.

Increased excretion of urine coproporphyrins during daunorubicin administration in patients affected by acute myelogenous leukemia.

Increased erythrocyte porphyrin values and high urine porphyrin levels have been reported in leukemic patients, but it is not clear whether the alteration in porphyrin metabolism is due to the leukemia or its treatment. The aim of this study was to compare porphyrin levels in leukemic patients undergoing chemotherapy or not. We analysed porphyrin values in patients with acute emyelogenous leukemia, who had or had not received chemotherapy according to Gale. Erythrocyte and urine porphyrin levels were increased as a result of the leukemic process, but urine coproporphyrins were further increased by daunorubicin treatment. These higher urine coproporphyrin levels were attributed to the activity of daunorubicin, which is known to interfere with the coproporphyrinogen decarboxylation process leading to the accumulation and high excretion of coproporphyrins in urine.

Drugs modifying nitric oxide metabolism affect plasma cholesterol levels, coagulation parameters, blood pressure values and the appearance of plasma myocardial necrosis markers in rabbits: opposite effects of L-NAME and nitroglycerine.

UNLABELLED: Various experiments have shown that decreased nitric oxide values alter plasma lipid levels or coagulation parameters or blood pressure values or cause myocardial necrosis phenomena, but it is not clear whether these alterations are reciprocally connected, or whether nitric oxide changes are involved in the appearance of some coronary disease risk factors (lipid, coagulation, blood pressure alterations) and myocardial necrosis. AIMS: We modified nitric oxide levels in rabbits using L-NAME (a NO synthase blocker) or nitroglycerine (a NO donor), and simultaneously evaluated variations in total and HDL cholesterol levels, some coagulation parameters, mean blood pressure values and myocardial necrosis patterns. RESULTS: L-NAME lowered plasma nitric oxide values, increased plasma total cholesterol and decreased HDL cholesterol levels, enhanced the amount of plasma fibrinogen, shortened prothrombin times, elevated the mean blood pressure values and caused the appearance of cardiac necrosis markers (c-troponin I, creatine kinase) in plasma and coagulative necrosis lesions in the myocardium. The administration of nitroglycerine to rabbits treated with L-NAME increased plasma nitric oxide levels and reversed the biochemical lesions caused by L-NAME. CONCLUSIONS: Our data show that the studied alterations in cholesterol values, coagulation parameters, increased mean blood pressure values and myocardial necrosis markers are strictly related to modified plasma nitric oxide levels, and that the regulation of nitric oxide metabolism affects the presence or absence of some coronary disease risk factors (lipid, coagulation and blood pressure alterations) and plasma indicators of myocardial necrosis.

Cardiac necrosis markers associated with low nitric oxide levels in the plasma of rabbits after treatment with vasopressin: protective effects of nitroglycerin administration.

It has been reported that the administration of vasopressin induces myocardial ischaemia in rats, which causes electrocardiographic ST segment alterations according to many authors. But rat electrocardiogram (ECG) lacks ST segment. Consequently it appears important to study the effects of vasopressin in rabbits, which show ST segment present in the ECG. Since cardiac necrosis markers are released in the plasma of humans with myocardial infarction, as well as in a variety of experimental models of myocardial necrosis, it is possible that the same may occur in rabbits with myocardial ischaemia induced by vasopressin. The main aim of this study was to investigate whether the administration of vasopressin causes the appearance of specific myocardial necrosis markers, such as cardiac troponin I, myoglobin or creatine kinase MB (CK MB) in rabbits in the presence or absence of modified ECG profile, and to also verify whether these markers are associated with the alterations in some coagulation parameters, that are known to be induced by vasopressin. As the effects of vasopressin are counteracted by nitric oxide (NO), another aim was to verify whether vasopressin also affects plasma NO levels and whether the administration of a NO donor can reverse these effects. Vasopressin was administered to rabbits and caused ischaemic alterations such as electrocardiographic changes, and significantly increased the levels of plasma cardiac necrosis markers (c-troponin I, myoglobin and CK MB). It also elevated diastolic blood pressure (BP), lowered heart rate (HR), increased procoagulation activity, and lowered plasma NO levels. The appearance of heart necrosis, demonstrated by plasma cardiac necrosis markers in the animals receiving vasopressin, was attributed to a drug-induced increase in vasoconstriction and coagulation activity. The intense vasoconstriction and thrombosis may lead to endothelium necrosis and a consequent drop in NO production. The administration of the NO donor nitroglycerin (NG) in the vasopressin treated animals restored NO values, and was capable of preventing the appearance of the plasma cardiac necrosis markers and altered coagulation values. The protective activity of NG was attributed to NO release, which lowers BP values and counteracts coagulation activity in vasopressin-treated animals. The described procedure may also be proposed for the study of early ischaemic myocardial lesions and the screening of NO donors preventing myocardial damage.

High-dose vitamin E lowers urine porphyrin levels in patients affected by porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is a metabolic disorder of heme biosynthesis, characterized by reduced uroporphyrinogen decarboxylase (UROD) activity and increased urinary excretion of eight and seven carboxyl group porphyrins. Specific factors such as iron, alcohol and halogenated compounds further inhibit enzyme activity by generating reactive oxygen species. Antioxidant vitamin E has frequently been used to counteract oxidative stress in porphyria patients, but a number of studies have failed to detect any significant effect on porphyrin metabolism. Since the use of vitamin E in the treatment of porphyria is a debated question, it seemed of interest to administer high doses to five patients with PCT in order to evaluate the effects on urine porphyrin excretion. The patients had high urinary porphyrin excretion levels, but vitamin E significantly reduced the urinary excretion of eight carboxyl group porphyrins. This result is attributable to the increase in UROD activity caused by the vitamin, which is a known scavenger of the oxygen reactive species that interfere with the activity of the enzyme. In conclusion, this paper shows that vitamin E high doses significantly lowers the urine porphyrin excretion in studied patients affected by PCT.