tin-mesoporphyrin and Disease-Models--Animal

SnCl(2) has been reported to increase the expression of heme-oxygenase 1 (HO-1), a major antioxidant enzyme, and to decrease ischemic injury, in non-nervous tissues. This study examined the neuroprotective effect of SnCl(2) in the hippocampus of rats submitted to cerebral ischemia. SnCl(2) was administered 18 h before bilateral carotids obstruction. Changes in HO-1 expression and activity, heme content, inducible nitric oxide synthase (iNOS) expression and parvalbumin positive interneuron survival were studied. Thereafter both behavior and memory recovery were tested. The administration of SnCl(2) increased the expression of HO-1 protein and HO activity in the hippocampus and concomitantly decreased heme content at both mitochondrial and nuclear level. Furthermore, ischemized animals showed a strong increase in iNOS expression in the hippocampus, where a loss of parvalbumin positive interneurons also occurred. Pre-treatment with SnCl(2), decreased both iNOS expression in ischemized rats and increased cell survival. The beneficial effects of SnCl(2) were prevented by concomitant treatment with SnMP, a strong inhibitor of HO activity. SnCl(2) also caused an improvement in short term memory recovery. Our results showed that following SnCl(2) administration, HO-1 is strongly induced in the hippocampus and modulate iNOS expression, resulting in a strong neuroprotective effect.

Topics: Animals; Avoidance Learning; Brain Ischemia; Cell Survival; Disease Models, Animal; Heme; Heme Oxygenase (Decyclizing); Hippocampus; Interneurons; Male; Memory Disorders; Metalloporphyrins; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Nitric Oxide Synthase Type II; Parvalbumins; Rats; Rats, Wistar; Tin Compounds

Acute intravenous Tempol reduces mean arterial pressure (MAP) and heart rate (HR) in spontaneously hypertensive rats. We investigated the hypothesis that the antihypertensive action depends on generation of hydrogen peroxide, activation of heme oxygenase, glutathione peroxidase or potassium conductances, nitric oxide synthase, and/or the peripheral or central sympathetic nervous systems (SNSs). Tempol caused dose-dependent reductions in MAP and HR (at 174 micromol/kg; DeltaMAP, -57+/- 3 mmHg; and DeltaHR, -50 +/- 4 beats/min). The antihypertensive response was unaffected by the infusion of a pegylated catalase or by the inhibition of catalase with 3-aminotriazole, inhibition of glutathione peroxidase with buthionine sulfoximine, inhibition of heme oxygenase with tin mesoporphyrin, or inhibition of large-conductance Ca(2+)-activated potassium channels with iberiotoxin. However, the antihypertensive response was significantly (P < 0.01) blunted by 48% by the activation of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channels with cromakalim during maintenance of blood pressure with norepinephrine and by 31% by the blockade of these channels with glibenclamide, by 40% by the blockade of nitric oxide synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME), and by 40% by the blockade of ganglionic autonomic neurotransmission with hexamethonium. L-NAME and hexamethonium were additive, but glibenclamide and hexamethonium were less than additive. The central administration of Tempol was ineffective. The acute antihypertensive action of Tempol depends on the independent effects of potentiation of nitric oxide and inhibition of the peripheral SNS that involves the activation of K(ATP) channels.

Topics: Amitrole; Animals; Antihypertensive Agents; Blood Pressure; Buthionine Sulfoximine; Catalase; Cromakalim; Cyclic N-Oxides; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ganglionic Blockers; Glutathione Peroxidase; Glyburide; Heart Rate; Heme Oxygenase (Decyclizing); Hexamethonium; Hypertension; Infusions, Intravenous; KATP Channels; Large-Conductance Calcium-Activated Potassium Channels; Male; Metalloporphyrins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Peptides; Potassium Channel Blockers; Rats; Rats, Inbred SHR; Spin Labels; Sympathetic Nervous System; Time Factors

Neonatal jaundice is commonly encountered and rarely associated with morbidity and mortality. Nonetheless, infants with glucose-6-phosphate dehydrogenase deficiency often have hemolysis (a heme load) caused by an environmental oxidant trigger, thus increasing their risk for serious morbidity. The use of tin mesoporphyrin (SnMP) has been proposed for interdicting the development of severe hyperbilirubinemia in a variety of conditions.. We studied the in vivo effects of prophylactic oral SnMP on heme oxygenase (HO) activity and bilirubin production, as indexed by the excretion rate of carbon monoxide (VeCO), following a subsequent oral heme load.. Adult mice were exposed serially to heme and assessed for in vivo bilirubin production rates, HO-1 transcription and protein, and HO activity. The effect of prophylaxis with a single oral dose of SnMP prior to an oral heme load was assessed by measuring VeCOand tissue HO activities.. After serial heme exposures, VeCO, HO-1 transcription and protein, and liver and spleen HO activities increased incrementally. After pretreatment with oral SnMP, bilirubin production decreased in response to an oral heme load. Also, heme-mediated increases in liver, spleen, and intestine HO activities were significantly dampened.. A single oral dose of SnMP results in durable inhibition of bilirubin production and HO activity for at least 24 h in a mouse model of oral heme loading. Further studies are needed to fully elucidate the duration of this protection against hyperbilirubinemia due to a delayed heme load and any long-term consequences of prophylaxis with SnMP on HO-1 transcription and HO-1 protein.

Topics: Animals; Bilirubin; Carbon Monoxide; Disease Models, Animal; Heme; Heme Oxygenase-1; Hyperbilirubinemia; Metalloporphyrins; Mice; Mice, Transgenic; Transcription, Genetic

The aim of this study was to examine the role of heme oxygenase-1 induction in the intestinal tissue injury in a rat model of sepsis.. Randomized, masked, controlled animal study.. University-based animal research facility.. Sprague-Dawley male rats, weighing 220-250 g (n = 126).. Rats were injected with lipopolysaccharide (10 mg/kg) intraperitoneally. Another group of rats was injected with interleukin-6 (10 microg/kg) intravenously. In some rats, tin mesoporphyrin (1 micromol/kg) was administered intravenously 1 hr before lipopolysaccharide treatment.. Following lipopolysaccharide treatment, expression of heme oxygenase-1 and nonspecific delta-aminolevulinate synthase (ALAS-N), the rate-limiting enzymes of heme catabolism and biosynthesis, respectively, was examined in various regions of the intestine. Lipopolysaccharide treatment markedly increased heme oxygenase-1 messenger RNA and protein concentrations in the mucosal epithelial cells in the duodenum and the jejunum, whereas its expression in the ileum and the colon was hardly detectable and was not influenced by the treatment. ALAS-N messenger RNA was also more markedly increased in the duodenum, the jejunum, and the ileum than in the colon following lipopolysaccharide treatment. Interleukin-6 administration also induced heme oxygenase-1 and ALAS-N gene expression in a pattern similar to that following lipopolysaccharide treatment. In contrast to the marked heme oxygenase-1 expression in the upper intestine, lipopolysaccharide-induced mucosal injury and inflammation in the upper intestine were far less than observed in the lower intestine as judged both by tumor necrosis factor-alpha gene expression and by histologic analysis. Of note, inhibition of heme oxygenase activity by tin mesoporphyrin produced a significant tissue injury in the upper intestine of the lipopolysaccharide-treated animals.. Intestinal heme oxygenase-1 and ALAS-N gene expression was regulated in a site-specific manner in a rat model of sepsis. Our findings also suggest that heme oxygenase-1 induction may play a fundamental role in protecting mucosal epithelial cells of the intestine from oxidative damages that occur in sepsis.

Topics: 5-Aminolevulinate Synthetase; Animals; Disease Models, Animal; Gene Expression Regulation; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Inflammation; Interleukin-6; Intestinal Mucosa; Intestines; Lipopolysaccharides; Male; Metalloporphyrins; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Tumor Necrosis Factor-alpha

Heme oxygenase (HO) has both deleterious and protective effects in various shock models. Most of these data have been derived from experiments with hypodynamic shock states associated with depressed cardiac output. Therefore we studied the role of HO during long-term porcine hyperdynamic endotoxemia characterized by a sustained increase in cardiac output resulting from colloid resuscitation to maintain mean arterial pressure > 60 mmHg. Systemic, pulmonary, and hepatosplanchnic hemodynamic and metabolic effects of the HO-inhibitor tin-mesoporphyrin (SnMP) were assessed in anesthetized and mechanically ventilated animals. After 12 h of continuous intravenous lipopolysaccharide (LPS), animals received either vehicle (n = 6) or SnMP (n = 8; 6 micromol kg(-1) i.v. over 30 min at 12 and 18 h of LPS). Measurements were performed before LPS, before SnMP infusion, and at 24 h of LPS. SnMP did not influence systemic hemodynamics but significantly increased mean pulmonary artery pressure. Although liver blood flow was not affected, SnMP markedly impaired liver lactate clearance. HO inhibition was associated with increased plasma nitrate levels likely the result of increased NO production. Our results suggest a protective role of HO activation during hyperdynamic porcine endotoxemia possibly as a result of an interaction with the LPS-induced increase in NO formation.

Topics: Animals; Blood Volume; Chronic Disease; Disease Models, Animal; Endotoxemia; Enzyme Inhibitors; Glutathione; Heme Oxygenase (Decyclizing); Hemodynamics; Hydrogen-Ion Concentration; Isoprostanes; Lactates; Lipopolysaccharides; Lung; Metalloporphyrins; Oxygen Consumption; Pulmonary Artery; Swine; Time Factors

Spontaneous intracerebral hemorrhage (ICH) is the stroke subtype with highest mortality and morbidity. ICH can also occur following traumatic brain injury and thrombolysis for ischemic stroke and myocardial infarction. Development of ICH-induced hemispheric edema can elevate intracranial pressure and cause death. In survivors, edema-related white matter injury can lead to life-long neurological deficits. At present, there are no scientifically proven treatments for ICH. Heme oxygenase products, particularly iron and bilirubin, can be toxic to cells. In cerebral ischemia models, metalloporphyrins that are potent heme oxygenase inhibitors, reduce edema and infarct size. Tin-mesoporphyrin (SnMP) is a neuroprotectant that has also been used clinically to treat hyperbilirubinemia. Presently, we tested the hypothesis that SnMP treatment would reduce edema development following experimental ICH. We produced hematomas in pentobarbital-anesthetized pigs (9-11 kg) by infusing autologous blood into the frontal white matter. To maximize tissue concentrations, SnMP (87.5 microM in DMSO) or DMSO (vehicle controls) was included in the infused blood. Pig brains were frozen in situ at 24 hrs. following ICH and hematoma and edema volumes were determined on coronal sections by computer-assisted image analysis. We also examined the effects of SnMP in vitro on ferritin iron release, the formation of iron-induced thiobarbituric acid reactive substances (TBARS) and initial clot formation and hemolysis. SnMP treatment significantly reduced intracerebral mass following ICH. This was due to significant decreases in hematoma (0.68+/-0.08 vs. 1.39+/-0.30 cc, vehicle controls p<0.025) and edema volumes (edema = 1. 16+/-0.33 vs. 1.77+/-0.31 cc, p<0.05). In vitro, SnMP did not stabilize ferritin iron against reductive release nor did it decrease iron-induced TBARS formation in brain homogenates. SnMP or DMSO added to pig blood did not alter clot weights. In conclusion, SnMP reduced intracerebral mass in an ICH model by decreasing both hematoma and edema volumes SnMP's mechanism of action is presently unknown but may involve its potent inhibition of heme oxygenase activity. SnMP's effect appears unrelated to ferritin iron release, antioxidant activity or initial clot formation. Since SnMP treatment could be brain protective following ICH, further investigations into neurological and neuropathological outcomes and as well as into its mechanism of action are warranted.

Topics: Animals; Antioxidants; Blood Coagulation; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Enzyme Inhibitors; Ferritins; Hematoma; Heme Oxygenase (Decyclizing); In Vitro Techniques; Iron; Metalloporphyrins; Swine

Sn-mesoporphyrin (SnMP), a potent inhibitor of heme oxygenase (HO), controlled hyperbilirubinemia in rats of the mutant strain EHBR/Eis. This mutant strain displays pronounced conjugated hyperbilirubinuria and dark pigmentation of hepatocytes, characteristics of the Dubin-Johnson syndrome. SnMP administered at a dose of 10 mumol/kg body weight produced an immediate decrease in plasma bilirubin concentrations which could be maintained by weekly injections of this synthetic heme analogue. Marked inhibition of HO activity was demonstrated in liver, kidney and spleen but not in brain. These results demonstrate that SnMP can lower plasma bilirubin concentrations for extended periods in a new mutant rat model of Dubin-Johnson syndrome.

Topics: Animals; Bilirubin; Disease Models, Animal; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Hyperbilirubinemia; Jaundice, Chronic Idiopathic; Kidney; Liver; Metalloporphyrins; Rats; Rats, Inbred Strains; Spleen