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PubMed1999

The role of neurohormonal antagonists in hibernating myocardium.

Hibernating myocardium is characterized by chronic reduction of myocardial blood flow due to obstructive coronary artery disease, causing reversible left ventricular dysfunction and flow-metabolism mismatch. The condition is unstable and increasing demand may lead to further left ventricular dysfunction or necrosis causing death or worsening heart failure. Recognition of the condition is difficult and requires complex cardiac imaging protocols. Treatment protocols are also poorly defined. This review addresses both the diagnostic and therapeutic aspects of hibernating myocardium.

Chronic Disease↗
PubMed2000

Nitric oxide inhibits neonatal hepatocyte oxidative metabolism.

BACKGROUND/PURPOSE: Liver function is frequently impaired in neonates with sepsis. Nitric oxide (NO) is thought to be a mediator of organ dysfunction and liver oxidative metabolism during sepsis. The authors developed an in vitro model to investigate the effect of NO and the combined effect of NO plus H2O2 on neonatal hepatocyte oxidative metabolism. METHODS: Hepatocytes were isolated from neonatal rats. Oxygen consumption was measured polarographically. In Study A, cells were exposed to S-Nitroso-N-acetylpenicillamine (SNAP), an NO donor, at various concentrations. In study B, myxothiazol and oligomycin, inhibitors of mitochondrial respiration, were added to investigate the site of action of NO. In study C, hepatocytes were incubated in the presence of both SNAP (300 micromol/L) and H2O2 (1.5 mmol/L). In study D, morphological alterations induced by NO and NO plus H2O2 were investigated by hepatocyte electron microscopy. RESULTS: In study A, SNAP caused a dose-dependent decrease in oxygen consumption. A significant inhibition was reached at 300 micromol/L SNAP. In study B, the lack of further inhibition when SNAP was given together with myxothiazol indicates that NO acts intramitochondrially. Similarly, no further inhibition occurred when the NO donor was given together with oligomycin, suggesting that the effect of NO is mainly at the level of ATP synthase. In study C, concomitant addition of 300 micromol/L SNAP and 1.5 mmol/L H2O2 to hepatocytes caused further inhibition of oxygen consumption compared with either SNAP or H2O2 alone. In study D, mild alterations in hepatocyte morphology were noted in the presence of SNAP or SNAP plus H2O2. CONCLUSIONS: In neonatal hepatocytes, NO significantly inhibits mitochondrial oxygen consumption, possibly at the level of ATP synthase. The effect of NO is additive to that of H2O2. Morphological findings were consistent with these biochemical effects and suggest that NO and H2O2 are important mediators of liver damage during sepsis.

Adenosine Triphosphate↗
PubMed2005

[Antiischemic and metabolic effects of nebivolol and metaprolol CR/XL (betalok ZOK) in patients with postinfarction heart dysfunction].

The purpose of the study was to evaluate anti-ischemic and metabolic effects of the cardioselective beta-adrenoblockers nebivolol and retarded metoprolol-metaprolol CR/XL (betalok ZOK) in patients with postinfarction heart dysfunction, associated with type II diabetes mellitus (DM). 40 patients with coronary heart disease (CHD), functional class (FC) II-III exertional angina, postinfarction left ventricular (LV) dysfunction, and NYHA FC II heart failure, associated with type II DM, were randomized into 2 groups. The 20 patients of the 1st group were administered nebivolol in a dose of 1.25 to 5 mg per day, the 20 patients of the 2nd group - betalok ZOK in a dose of 12.5 to 100 mg per day. The course therapy lasted 8 weeks. The effects of the treatment were evaluated using paired veloergometry, echoCG, and lipid spectrum analysis. The study found that nebivolol in a mean dose of 4.2 +/- 0.3 mg per day and betalok ZOK in a dose of 46.5 +/- 6.2 mg per day reduced the frequency and severety of angina attacks (by 73.8% and 67.8%, respectively) and daily nitroglycerine uptake (by 78.6% and 69.1%, respectively), and increased activity tolerance (by 7.9% and 25.3%, respectively). None of the preparations displayed any adverse effects on carbohydrate exchange and blood lipid spectrum. Nebivolol, unlike betalok ZOK, significantly (p = 0.02) reduced triglyceride blood level by 29%. Thus, the new generation cardioselective beta1-adrenoblockers nebivolol and metoprolol CR/XL (betalok ZOK) provide anti-ischemic and metabolic effects in patients with CHD and postinfarction LV dysfunction, associated with type 2 diabetes mellitus. Nebivolol is preferable as far as blood lipid spectrum is concerned.

Adrenergic beta-Antagonists↗
PubMed2004

Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial.

CONTEXT: The metabolic syndrome has been identified as a target for dietary therapies to reduce risk of cardiovascular disease; however, the role of diet in the etiology of the metabolic syndrome is poorly understood. OBJECTIVE: To assess the effect of a Mediterranean-style diet on endothelial function and vascular inflammatory markers in patients with the metabolic syndrome. DESIGN, SETTING, AND PATIENTS: Randomized, single-blind trial conducted from June 2001 to January 2004 at a university hospital in Italy among 180 patients (99 men and 81 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III. INTERVENTIONS: Patients in the intervention group (n = 90) were instructed to follow a Mediterranean-style diet and received detailed advice about how to increase daily consumption of whole grains, fruits, vegetables, nuts, and olive oil; patients in the control group (n = 90) followed a prudent diet (carbohydrates, 50%-60%; proteins, 15%-20%; total fat, <30%). MAIN OUTCOME MEASURES: Nutrient intake; endothelial function score as a measure of blood pressure and platelet aggregation response to l-arginine; lipid and glucose parameters; insulin sensitivity; and circulating levels of high-sensitivity C-reactive protein (hs-CRP) and interleukins 6 (IL-6), 7 (IL-7), and 18 (IL-18). RESULTS: After 2 years, patients following the Mediterranean-style diet consumed more foods rich in monounsaturated fat, polyunsaturated fat, and fiber and had a lower ratio of omega-6 to omega-3 fatty acids. Total fruit, vegetable, and nuts intake (274 g/d), whole grain intake (103 g/d), and olive oil consumption (8 g/d) were also significantly higher in the intervention group (P<.001). The level of physical activity increased in both groups by approximately 60%, without difference between groups (P =.22). Mean (SD) body weight decreased more in patients in the intervention group (-4.0 [1.1] kg) than in those in the control group (-1.2 [0.6] kg) (P<.001). Compared with patients consuming the control diet, patients consuming the intervention diet had significantly reduced serum concentrations of hs-CRP (P =.01), IL-6 (P =.04), IL-7 (P = 0.4), and IL-18 (P = 0.3), as well as decreased insulin resistance (P<.001). Endothelial function score improved in the intervention group (mean [SD] change, +1.9 [0.6]; P<.001) but remained stable in the control group (+0.2 [0.2]; P =.33). At 2 years of follow-up, 40 patients in the intervention group still had features of the metabolic syndrome, compared with 78 patients in the control group (P<.001). CONCLUSION: A Mediterranean-style diet might be effective in reducing the prevalence of the metabolic syndrome and its associated cardiovascular risk.

Adult↗
PubMed1982

Endocrine-metabolic relationships in patients with leprechaunism.

Leprechaunism is a rare, heritable syndrome, associated with multiple dysmorphic and pathologic features, suggestive of an endocrine dysfunction. Few endocrine and metabolic studies have been obtained because of the rarity of the syndrome, and the small size and early demise of these infants. The authors present here the clinical, anatomic, and endocrine-metabolic studies of three patients, with a view toward careful delineation of the syndrome and further characterization of the metabolic defect.The most striking and consistent metabolic derangements present in all of these patients were fasting hypoglycemia (less than 20 mg/dL), postprandial hyperglycemia (more than 250 mg/dL), marked hyperinsulinemia (more than 2000 μU/mL), and severe insulin resistance (less than a 20 percent decrease in blood sugar with 0.3 to 1.0 U/kg of regular insulin IV). Hyperinsulinemia was observed in response to oral feedings and glucose infusion, and after tolbutamide. Insulin secretion was less marked with amino acid infusions. Normal increments in blood glucose occurred following alanine, galactose, and glycerol. Glucagon caused a rise in glucose 4 hours after a meal, but no response was seen after a 12-hour fast. Pituitary, gonadal, and adrenal hormone levels were normal, and there was a normal response pattern to GnRH and TRH. Hyperinsulinemia would appear to be the biochemical hallmark of this disease. Our previous studies were suggestive of a postreceptor defect in insulin action. The present endocrine-metabolic studies are compatible with this hypothesis. Interaction of supraphysiologic concentrations of plasma insulin with growth factor receptors, this may provide a partial explanation for some of the dysmorphic features seen in the disorder.

Adult↗
PubMed1986

Asterixis: one type of negative myoclonus.

Asterixis is a disorder of motor control characterized by irregular myoclonic lapses of posture affecting various parts of the body independently. These lapses are caused by involuntary 50- to 200-msec silent periods appearing in muscles (even antagonistic groups of muscles) which are tonically active. That is, the silent periods and postural lapses occur in muscles that have been contracting for a time whether or not there has been slow shortening or lengthening but probably do not occur during or immediately after a sudden movement at a joint. What constitutes a sudden as opposed to a slow movement remains to be defined. When bilateral asterixis is present, one cannot rule out the possibility of a focal lesion (see Table 2), but it is almost always due to a metabolic encephalopathy (with a wide variety of possible causes). Unilateral asterixis is due to a localized lesion, perhaps otherwise not clinically evident, in the contralateral cerebral hemisphere. This episodic dysfunction within neural circuits which are normally concerned with maintenance of sustained or tonic muscle contraction may be released by focal lesions only in specific CNS areas (such as ventrolateral thalamus) or by a more generalized neurochemical imbalance (metabolic encephalopathies of various kinds). The system, a lesion or metabolic dysfunction which produces asterixis, is presumably an anatomically and/or pharmacologically distinct one; asterixis is not the result of a nonspecific disorder any more than are seizures. Presumably, those aspects of each of the different factors (e.g., subdural hematomas, drugs, electrolyte imbalance, cerebrovascular accidents, intracerebral tumors) that may produce asterixis or a seizure are mediated through some fundamental neuronal or neural systems process. To label asterixis or seizures nonspecific results of CNS disorders or results of nonspecific CNS disorders may be simply to avoid confronting our ignorance of the specific pathophysiologic mechanisms involved. Although the anatomy, neurochemistry, and physiologic function of this asterixogenic system remain to be elucidated, observations that asterixis may be caused by discrete anatomic or pharmacologic (e.g., phenytoin) lesions should tell us something important about mechanisms underlying sustained muscle contraction in humans. Unfortunately clinicoanatomic correlations alone cannot provide precise answers because even those reasonably focal vascular lesions that cause asterixis are too gross to permit localization or identification of the neural systems involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain↗
PubMedDate not supplied

Receptor dysfunction and hormone resistance in human diseases--a review.

Studies of the hormone-receptor interaction have introduced a new chapter in endocrine and metabolic disorders. Receptor (R) dysfunction in human diseases, due either to an alteration in the number or affinity of the R, or to antibodies against the R, is reviewed and classified in the first part of this paper. Disorders where hormone resistance has been implicated, but where R studies are still unavailable are also presented.

Acanthosis Nigricans↗
PubMed2000

31P magnetic resonance spectroscopy study of phosphocreatine recovery kinetics in skeletal muscle: the issue of intersubject variability.

We have analyzed by (31)P MRS the relationship between kinetic parameters of phosphocreatine (PCr) recovery and end-of-exercise status under conditions of moderate and large acidosis induced by dynamic exercise. Thirteen healthy subjects performed muscular contractions at 0.47 Hz (low frequency, moderate exercise) and 0.85 Hz (high frequency, heavy exercise). The rate constant of PCr resynthesis (k(PCr)) varied greatly among subjects (variation coefficients: 43 vs. 57% for LF vs. HF exercises) and protocols (k(PCr) values: 1.3+/-0.5 min(-1) vs. 0.9+/-0.5 min(-1) for LF vs. HF exercises, P<0.03). The large intersubject variability can be captured into a linear relationship between k(PCr), the amount of PCr consumed ([PCr(2)]) and pH reached at the end of exercise (pH(end)) (k(PCr)=-3.3+0.7 pH(end)-0.03 [PCr(2)]; P=0.0007; r=0.61). This dual relationship illustrates that mitochondrial activity is affected by end-of-exercise metabolic status and allows reliable comparisons between control, diseased and trained muscles. In contrast to k(PCr), the initial rate of PCr recovery and the maximum oxidative capacity were always constant whatever the metabolic conditions of end-of-exercise and can then be additionally used in the identification of dysfunctions in the oxidative metabolic pathway.

Adenosine Diphosphate↗
PubMed2006

Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress.

Endothelial dysfunction is a hallmark of cardiovascular disease, and the l-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with l-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (P = 0.01) than nonsmokers, whereas citrulline (17%; P < 0.05) and N-hydroxy-l-arginine (34%; P < 0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-l-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial l-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease.

Adult↗
PubMed1996

Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase.

1. We have investigated the effects of (i) several guanidines on the activity of the inducible isoform of nitric oxide (NO) synthase (iNOS) in murine cultured macrophages and rat aortic vascular smooth muscle cells (RASM); and (ii) 1-amino-2-hydroxy-guanidine, the most potent inhibitor of iNOS activity discovered, on haemodynamics, multiple organ (liver, renal, and pancreas) dysfunction and iNOS activity in rats with endotoxic shock. 2. The synthesized guanidine analogues caused concentration-dependent inhibitions of the increase in nitrite formation caused by lipopolysaccaride (LPS, 1 microgram ml-1) in J774.2 macrophages and RASM cells with the following rank order of potency: 1-amino-2-hydroxy-guanidine > 1-amino-2-methyl-guanidine > 1-amino-1-methyl-guanidine > 1-amino-1,2-dimethyl-guanidine. Interestingly, 1-amino-2-hydroxy-guanidine (IC50: J774.2, 68 microM; RASM, 114 microM) was more potent in inhibiting nitrite formation caused by LPS than NG-methyl-L-arginine, but less potent than aminoethyl-isothiourea. 3. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 115 +/- 4 mmHg (time 0) to 98 +/- 5 mmHg at 2 h (P < 0.05, n = 10) and 69 +/- 5 mmHg at 6 h (P < 0.05, n = 10). The pressor effect of noradrenaline (NA, 1 mg kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine (10 mg kg-1, i.v. plus 10 mg kg-1 h-1 starting at 2 h after LPS) prevented the delayed hypotension and vascular hyporeactivity seen in LPS-rats. However, 1-amino-2-hydroxy-guanidine had no effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 4. Endotoxaemia for 6 h caused a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT) and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine significantly attenuated the liver dysfunction caused by LPS (P < 0.05, n = 10). Injection of LPS also caused a rapid (almost maximal at 2 h) increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by 1-amino-2-hydroxy-guanidine (P > 0.05; n = 10). Endotoxaemia also caused a dysfunction of pancreas (rise in serum levels of lipase) as well as a metabolic acidosis (falls in PCO2, HCO3 and base excess). Both pancreatic dysfunction and metabolic acidosis were largely attenuated by treatment of LPS-rats with 1-amino-2-hydroxy-guanidine. In rats infused with saline rather than LPS, 1-amino-2-hydroxy-guanidine had no effect on liver, renal or pancreatic function (n = 4). 5. Endotoxaemia for 6 h resulted in a rise in the serum levels of nitrite (11.0 +/- 0.8 microM, P < 0.01, n = 10), which was significantly reduced by 1-amino-2-hydroxy-guanidine (6.5 +/- 0.7 microM, P < 0.05, n = 10). Endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with 1-amino-2-hydroxy-guanidine. In addition, endotoxaemia for 6 h resulted in a significant increase in myeloperoxidase activity (MPO), an indicator of neutrophil infiltration, in the liver. Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine did not affect the rise in MPO-activity in the liver caused by endotoxin. 6. Thus, 1-amino-2-hydroxy-guanidine is a potent inhibitor of iNOS activity in macrophages or RASM in culture as well as in rats with endotoxic shock. Inhibition of iNOS activity with 1-amino-2-hydroxy-guanidine prevents the delayed circulatory failure and attenuates the dysfunction of liver, and pancreas, as well as the metabolic acidosis caused by endotoxaemia.

Animals↗
PubMed2000

Prediction of global left ventricular function after bypass surgery in patients with severe left ventricular dysfunction. Impact of pre-operative myocardial function, perfusion, and metabolism.

AIMS: Previous studies have compared the accuracy of various tests of viability for the prediction of recovery of regional left ventricular function; global left ventricular recovery has been less well studied, although it has important prognostic and functional ramifications. We sought to identify the relative contribution of ischaemia, regional and global contractile reserve, perfusion and metabolic function to changes in left ventricular volumes and global function after coronary artery bypass surgery in patients with severe left ventricular dysfunction. METHODS AND RESULTS: Dipyridamole stress Rb-82, fluorodeoxyglucose positron emission tomography and low and high-dose dobutamine-atropine stress echocardiography were obtained in 66 patients with left ventricular impairment. Myocardial segments were considered viable if ischaemia or either metabolic or contractile reserve were present, on positron emission tomography or dobutamine echocardiography. Resting left ventricular function was reassessed after surgery (mean 10+/-3 weeks) in the 59 patients who had not suffered a major peri-operative event; functional improvement was defined by a 5% increment of ejection fraction. Myocardial viability was found in 37 (63%) patients using positron emission tomography and in 42 (71%) patients using dobutamine echocardiography; post-operative functional improvement was noted in 28 (47%) patients. In univariate analyses, predictors of global post-operative functional recovery included: the extent of viability according to positron emission tomography [OR (odds ratio): 2.08 for each additional viable segment, 95% CI (confidence interval): 1.33-3. 25, P=0.001] or dobutamine echocardiography (OR: 2.06 for each additional viable segment, 95% CI: 1.28-3.30, P=0.003) and the increase in ejection fraction with low-dose dobutamine (OR: 1.9 for each 1% increase in ejection fraction with low dose dobutamine, 95% CI 1.39-2.61, P<0.0001). In a multivariate model which included evidence of viability by either technique, and change in ejection fraction with low-dose dobutamine echocardiography, only change in ejection fraction with low-dose dobutamine echocardiography was predictive of post-operative left ventricular functional recovery (adjusted OR: 1.81, 95% CI: 1.30-2.52, P=0.0005). CONCLUSION: Among patients with severe left ventricular dysfunction who are referred for surgical revascularization, the overall accuracies of positron emission tomography and dobutamine echocardiography for the prediction of post-operative myocardial recovery are comparable. However, the strongest predictor of overall improvement of post-operative left ventricular function is an increase of ejection fraction with a low-dose dobutamine infusion.

Aged↗
PubMed2005

Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity.

Previous studies have suggested an involvement of inducible nitric oxide synthase (iNOS) in obesity, but the relation, if any, between this and mechanisms underlying endothelial dysfunction in obesity is unknown. We studied mice fed an obesogenic high-fat or standard diet for up to 8 weeks. Obesity was associated with elevated blood pressure; resistance to the glucoregulatory actions of insulin; resistance to the vascular actions of insulin, assessed as the reduction in phenylephrine constrictor response of aortic rings after insulin preincubation (lean -21.7 +/- 11.5 vs. obese 18.2 +/- 15.5%; P < 0.05); and evidence of reactive oxygen species (ROS)-dependent vasodilatation in response to acetylcholine in aortic rings (change in maximal relaxation to acetylcholine after exposure to catalase: lean -2.1 +/- 6.0 vs. obese -15.0 +/- 3.8%; P = 0.04). Obese mice had increased expression of iNOS in aorta, with evidence of increased vascular NO production, assessed as the increase in maximal constriction to phenylephrine after iNOS inhibition with 1400W (lean -3.5 +/- 9.1 vs. obese 42.1 +/- 11.2%; P < 0.001). To further address the role of iNOS in obesity-induced vascular and metabolic dysfunction, we studied the effect of a high-fat diet in iNOS knockout mice (iNOS KO). Obese iNOS KO mice were protected against the development of resistance to insulin's glucoregulatory and vascular effects (insulin-dependent reduction in maximal phenylephrine response: obese wild-type 11.2 +/- 15.0 vs. obese iNOS KO -20.0 +/- 7.7%; P = 0.02). However, obese iNOS KO mice remained hypertensive (124.0 +/- 0.7 vs. 114.9 +/- 0.5 mmHg; P < 0.01) and had evidence of increased vascular ROS production. Although these data support iNOS as a target to protect against the adverse effects of obesity on glucoregulation and vascular insulin resistance, iNOS inhibition does not prevent the development of raised blood pressure or oxidative stress.

Acetylcholine↗
PubMed1985

Phosphate loading attenuates renal tubular dysfunction induced by maleic acid in the dog.

The metabolic pathogenesis of the complex renal tubular dysfunction of type II renal tubular acidosis and Fanconi's syndrome (RTA II/FS) acutely induced by maleic acid could depend on the occurrence of a positive feedback loop in cells of the proximal renal tubule: impaired mitochondrial oxidation----increased glucose uptake----increased formation and concentration of phosphorylated glycolytic intermediates----limitation on availability of cellular inorganic phosphate----more severely impaired mitochondrial oxidative metabolism. To test this hypothesis we intravenously administered maleic acid both alone and after initiating intravenously administered neutral sodium phosphate, sodium sulfate, or sodium chloride to 10 unanesthetized trained female dogs undergoing water diuresis. We made the following observations: 1) Administration of maleic acid alone predictably induced dose-dependent increments in urine flow (V) and in renal clearance of HCO3-, Na+, K+, and alpha-aminonitrogen and a pronounced increase in the renal clearance and excretion of citrate. 2) Prior phosphate loading, which increased the plasma concentration of phosphate from 2.5 +/- 0.20 to 11.3 +/- 2 mg/dl: a) attenuated the increment in renal clearance of HCO3- by one-half even though the filtered load of bicarbonate was higher by 37%, owing to the higher values of both GFR and plasma bicarbonate concentration that obtained with phosphate loading; b) prevented the increment in renal clearance and excretion of alpha-aminonitrogen; c) significantly attenuated the increments in V and renal clearance of K+; but d) did not affect the increment in renal clearance and excretion of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Renal Tubular↗
PubMed1985

The oxygen free radical system and myocardial dysfunction.

The pathways for the metabolism of molecular oxygen involve one electron-transfer reaction with the subsequent production of reduced-oxygen intermediates. These reduced-oxygen intermediates include the superoxide anion (.O2-), hydrogen peroxide (H2O2), and the hydroxyl radical (.OH), which are highly reactive, short-lived species. Normally intracellular enzyme systems that include superoxide dismutase, catalase, and glutathione peroxidase are responsible for "scavenging" these products of oxygen metabolism. However, in many pathological states such as inflammation, ischemia, and reperfusion, there is an increased production of these reduced-oxygen intermediates, which are capable of extensive tissue damage. It is the purpose of this symposium to examine, in depth, the role of oxygen free radical systems as mediators of myocardial dysfunction and expand our knowledge of myocardial ischemia, ischemia-reperfusion injury, and the inflammatory response of the myocardium.

Coronary Disease↗
PubMed2001

Metabolic alterations in the prefrontal and cingulate cortices are related to behavioral deficits in a rodent model of attention-deficit hyperactivity disorder.

Rats with a deficit in selective attention accompanied by impulsivity can be identified using a five-choice serial reaction time task (5-CSRT) and have been proposed to represent a rodent model of attention-deficit hyperactivity disorder (ADHD). The aim of the present study was to investigate which brain areas are important for visuospatial attention and to test the specific hypothesis that dysfunction of the frontal cortex is related to the behavioral deficits observed in poorly performing rats. Therefore, [(14)C]deoxyglucose (DG) uptake, an index of brain metabolic activity, was measured during the performance of a 5-CSRT task in two populations of rats (poorly and well-performing rats) to study the relationships between the regional brain activity and behavioral output. While performing a 5-CSRT task, poorly performing rats exhibited lower DG uptake in the cingulate and ventrolateral orbital cortices than did well-performing rats,. Moreover, there was a positive correlation between choice accuracy and DG uptake in several areas, especially in the frontal and parietal regions, whereas there was an inverse correlation between the percentage of premature responses and DG uptake in the ventrolateral orbital and cingulate cortices. These results, which demonstrated that the poorly performing rats exhibited metabolic dysfunction in the cingulate and prefrontal cortices, provide a basis for the face validity of the rodent model of ADHD. Moreover, they suggest that the neural network of attention in rats is remarkably analogous to that described in primates.

Animals↗