Muscular adaptations induced by dobutamine and their influence on G-tolerance in miniature swine.
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Adaptation, Physiological↗
Biomedical subjects
A J Merola
Publications and source records attributed to A J Merola.
Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome.
The adult respiratory distress syndrome (ARDS) is a devastating clinical illness characterized by refractory hypoxemia and high-permeability pulmonary edema. Reactive oxygen species such as hydrogen peroxide and hypochlorous acid may play a key role in the pathogenesis of the acute lung injury. Glutathione (GSH) is a tripeptide that is able to react with and effectively neutralize oxidants such as hydrogen peroxide and hypochlorous acid. The present study found that the alveolar epithelial lining fluid of patients with ARDS was deficient in total GSH compared to normal subjects (21.7 mumols +/- 7.8 mumols vs 91.8 mumols +/- 14.5 mumols; p = 0.002). In addition, if GSH was measured in unconcentrated bronchoalveolar lavage (BAL) fluid and indexed to total BAL protein, there was also a deficiency in patients with ARDS compared to normal subjects (0.004 +/- 0.003 nmol of GSH per microgram of total protein vs 0.026 +/- 0.005 nmol of GSH per microgram of total protein; p = 0.002). Since patients with ARDS are subjected to an increased burden of oxidants in the alveolar fluid, principally released by recruited neutrophils, this deficiency of GSH may predispose these patients to enhanced lung cell injury.
Adult↗
Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure.
A reduction in exercise capacity is a common feature of congestive heart failure. We hypothesized that depressed aerobic enzyme activity of skeletal muscle may contribute to this exercise intolerance. Biopsy samples of vastus lateralis muscle were obtained from seven patients with severe chronic heart failure and analyzed for aerobic enzyme activity. Compared with normal laboratory controls, the patients with heart failure had a moderate reduction (greater than 60%) in skeletal muscle citrate synthase and a marked reduction (greater than 90%) in succinate dehydrogenase and cytochrome oxidase (all p less than 0.001). Depression of aerobic enzyme activity of skeletal muscle is associated with severe chronic heart failure and is likely one of the contributory factors for impaired exercise capacity seen in the advanced stages of this condition.
Aerobiosis↗
Cellular glutathione and the response of adult rat heart myocytes to oxidant stress.
Freshly isolated adult rat heart myocytes contain total glutathione and reduced glutathione (GSH) at levels quite comparable to those in intact rat heart. Total glutathione can be depleted from 11 to 1 nmol/mg protein or less by treatment with cyclohex-2-ene-1-one without effect on either cellular ATP, rod-cell morphology or the integrity of the sarcolemma. Glutathione levels and redox state are not altered significantly when the Ca-tolerant, quiescent cells are subjected to a period of anoxia followed by reoxygenation. This oxygen paradox protocol results in irreversible hypercontracture of the contractile elements into an amorphous mass in the bulk of the cells, but little loss of sarcolemmal integrity. When the myocytes are subjected to an externally applied oxidant stress by the addition of either diamide or t-butylhydroperoxide, GSH is rapidly depleted with accumulation of oxidized glutathione (GSSG. On continued aerobic incubation both of these reagents promote a slower depletion of cellular ATP and a parallel hypercontracture. Cells treated with t-butylhydroperoxide, but not those with diamide, also generate increasing amounts of thiobarbituric acid reactive species as an indication of lipid peroxidation and show a parallel loss of sarcolemmal integrity. It is concluded that respiring myocytes and those subjected to the oxygen paradox do not produce oxygen radicals in sufficient amounts to displace the GSH/GSSG redox poise and depletion of myocyte glutathione per se is not detrimental to the short term survival of the cells. In addition, aerobic myocytes subjected to external oxidant stress can be damaged irreversibly by two pathways, a hypercontracture that correlates with depletion of ATP and a loss of sarcolemmal integrity that correlates with lipid peroxidation.
Animals↗
Early changes in the permeability of the blood-brain barrier produced by toxins associated with liver failure.
Our study was designed to determine whether substances that appear in the serum during the course of liver failure have a detrimental effect on the passive permeability of the blood-brain [blood-cerebrospinal fluid (CSF)] barrier. Lactic acid, octanoic acid, and ammonia were infused into rabbits for 4 h. The permeability changes of the blood-brain barrier were quantified by infusing polyethylene glycol 400 (PEG 400) and measuring the quantity and average mol wt of the PEG 400 that entered the CSF. The lipid solubility and effective diffusional radius of the PEG molecules were also quantified to provide greater precision for measurements using this probe. None of the animals receiving toxic infusions became seriously ill during the infusions. Low dose infusions of lactic acid, octanoic acid, and ammonia increased the effective pore diameter of the blood-brain barrier from 7.3 A to an average of 8.5 A. The amount of PEG entering the CSF increased from 1.7 to 4.0 (p less than 0.025), 4.7 (p less than 0.025), and 6.7 (p less than 0.001) mmol/L, respectively. Rabbits with galactosamine-induced liver failure had 10.1 mmol/L PEG 400 in the CSF (P less than 0.001) before any evidence of cerebral edema. These changes occur soon after these toxins accumulate in the plasma and may alone or together with other toxins account for the permeability changes that allow neurotoxic substances to enter the brain during hepatic disease and encephalopathies such as Reye's syndrome.
Animals↗
Skeletal muscle antioxidant enzyme levels in rats after simulated weightlessness, exercise and dobutamine.
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Animals↗
Peroxide mediated effects of homocysteine on arterial prostacyclin synthesis.
The effects of homocysteine on the synthesis of arterial prostacyclin (PGI2) were investigated. Homocysteine at 10 mM and 1 mM concentration inhibited PGI2 synthesis from both exogenous and endogenous arachidonic acid. While concentrations of 100 microM and 1 microM stimulated PGI2 synthesis. Similar inhibitory effects of H2O2 on PGI2 synthesis were observed. High concentrations (100 microM and 500 microM) of H2O2 inhibited PGI2 production while low concentrations (1 microM) of H2O2 stimulated it. Catalase overcame the inhibitory effect of H2O2 (100 microM). Homocysteine induced O2 uptake and catalase inhibited the O2 uptake by homocysteine. Thus the inhibitory and stimulatory effect of homocysteine may be dependent on the oxidation of homocysteine and subsequent H2O2 generation.
6-Ketoprostaglandin F1 alpha↗
Exercise reduces diffusion distances in skeletal muscles of rabbits fed an atherogenic diet.
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Animals↗
Inhibition of citrulline synthesis by octanoate and its modulation by adenine nucleotides.
Liver mitochondria from octanoate-treated rabbits showed an impaired ability to synthesize citrulline. Two methods were used to evaluate citrulline synthesis in rat liver mitochondria. Under these conditions octanoate inhibited citrulline synthesis by over 50%. When ATP was included in the assay medium the inhibitory effect of octanoate was prevented. In the absence of ATP in the suspending medium, octanoate did not significantly lower total adenine nucleotides in rat liver mitochondria. However, under these conditions octanoate caused a change in the adenine nucleotide profile such that ATP content was decreased and AMP content was increased. When ATP was present in the assay medium, octanoate caused a similar increase in AMP content. However, ATP decreased only slightly. The alterations in mitochondrial adenine nucleotide profile by octanoate and the reversal of the effect by exogenous ATP suggests that octanoate inhibits citrulline synthesis via reduced intramitochondrial ATP levels. The ability of octanoate to lower mitochondrial ATP and elevate mitochondrial AMP may be related to its intramitochondrial activation by the medium chain fatty acid activating enzyme.
Adenine Nucleotides↗
Peroxidase-mediated oxidation of isoniazid.
Oxidation of isonicotinic acid hydrazide (isoniazid) by horseradish peroxidase at the expense of H2O2 yielded reactive species which were able to reduce nitroblue tetrazolium and bleach p-nitrosodimethylaniline. Nicotinic acid hydrazide oxidation did not cause these effects. At slightly alkaline pH, oxidation of isonicotinic acid hydrazide by horseradish peroxidase proceeded at the expense of molecular O2, and the reaction was oxygen consuming. The addition of H2O2 abolished O2 consumption. Bovine liver catalase enhanced the rate of nitroblue tetrazolium reduction and decreased the maximal velocity of the reaction proportionately to catalase concentration. During oxidation of isonicotinic acid hydrazide by horseradish peroxidase-H2O2, splitting of the heme group of horseradish peroxidase took place as shown by the disappearance of the Soret and minor bands in the visible region of the spectrum.
Catalase↗
Evidence for the generation of active oxygen by isoniazid treatment of extracts of Mycobacterium tuberculosis H37Ra.
Crude extracts of Mycobacterium tuberculosis H37Ra, an isonicotinic acid hydrazide (isoniazid) (INH)-susceptible strain which has peroxidase activity, catalyzed the production of catechol from phenol in the presence of INH and H2O2 as shown by the development of the 444-nm absorption peak of oxidized catechol product. Extracts of the INH-resistant strain of M. tuberculosis H37Ra, which has no peroxidase, did not catalyze the reaction. The rate of development of the 444-nm peak increased proportionately with increased superoxide dismutase concentrations. The hydroxyl radical (. OH) scavengers dimethylsulfoxide and mannitol inhibited the reaction. Isonicotinamide, isonicotinic acid, and nicotinic acid could not replace INH.
Bacterial Proteins↗
Enzymatic and nonenzymatic superoxide-generating reactions of isoniazid.
During the course of horseradish peroxidase-mediated oxidation of either o-dianisidine or 2-2'-azino-di(3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS), no O2 consumption took place. When isonicotinic acid hydrazide (isoniazid) (INH) was included in the reaction mixture, O2 was consumed in amounts linearly related to the INH concentration. Nicotinic acid hydrazide at equimolar concentrations induced lower rates of O2 consumption. Superoxide dismutase activated O2 consumption. At equimolar concentrations, INH, nicotinic acid hydrazide, and phenylhydrazine induced bleaching of p-nitrosodimethylaniline in the horseradish peroxidase mediation of ABTS oxidation. Bleaching was not inhibited by hydroxyl radical (. OH) scavengers. After a short lag period, INH reacted with NADH at alkaline pH to produce superoxide radical (O2-), as detected by superoxide dismutase-inhibitable Nitro Blue Tetrazolium reduction. Nicotinic acid hydrazide with NADH caused a lower rate of O2- production after a longer lag period than INH.
Catalysis↗
Responses of the normal rat kidney to sequential ischemic events.
UNLABELLED: This study was undertaken to help define how one episode of renal ischemia, insufficient to cause acute renal failure, influences the susceptibility of the kidney to a second more severe ischemic event. Female Sprague-Dawley rats underwent either 15 min of bilateral renal artery occlusion (RAO) or sham RAO. They were subjected 30 min, 3.5 h, or 24 h later to 25 min of RAO. Renal function (GFR, BUN, creatinine), histology, and adenine nucleotide concentrations were compared before and after the 25-min ischemic event. Only the rats with a 30-min hiatus between the 15- and 25-min bouts of RAO had significantly worse renal failure than controls subjected to a single 25-min ischemic event. Three findings were noted only in the rats with increased susceptibility: tubular cell swelling and luminal membrane injury prior to 25 min of RAO and a relative failure of ATP formation immediately following 25 min of RAO. Susceptibility to 25 min of RAO did not correlate with preischemia ATP content. CONCLUSION: prior mild ischemic injury transiently lowers renal resistance to a second ischemic event. Normal resistance is rapidly restored once improvements in prior cell membrane injury, cell volume regulation, and cellular energetics occur. However, resistance to additional ischemia can be normal despite persisting depressions in renal ATP content.
Acute Kidney Injury↗
Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin.
The purpose of this study was to correlate the exercise-induced changes of oxidant stress enzymes with possible modification of the response to the putative oxidant stressor doxorubicin. Enzymatic and histological changes were studied in mice placed on a 21-wk swim training program (1 h/day, 5 days/wk) with and without anthracycline administration. Doxorubicin (4 mg/kg) was administered intravenously through a tail vein on 10 separate days over a 7-wk period (twice weekly during weeks 10, 11, 14, 15, and 16). Blood, liver, and heart levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GP) were measured following the 9th and 21st wk. Myocardial histomorphological observations were made by light microscopy after 21 wk. Following 9 wk of training swim-trained animals had significantly elevated levels of CAT, SOD, and GP in blood, as well as elevated GP in liver. After 21 wk, trained animals, regardless of drug status, had elevated blood CAT and SOD activity and increased liver CAT and GP. Training also produced increases in blood GP, liver SOD, and heart CAT; however, in conjunction with doxorubicin these changes were not seen. The degree of cardiotoxicity was significantly greater in the sedentary drug-treated animals than in the swim-trained drug-treated animals. The results suggest a correlation between antioxidant enzyme levels in blood and liver and the degree of damage caused by an anthracycline drug. It was concluded that exercise ameliorates severe toxic damage caused by doxorubicin administration, possibly by increasing enzymes that combat free radical damage.
Animals↗
Prevention of bedrest-induced physical deconditioning by daily dobutamine infusions. Implications for drug-induced physical conditioning.
The effects of intermittent infusions of dobutamine were studied in young normal male subjects during a period of bedrest deconditioning to determine whether this synthetic catechol affects physical conditioning processes in humans. 24 volunteers were placed at bedrest and randomized to daily 2-h treatments of saline infusions (control), dobutamine infusions, or maintenance exercise (control). Exercise, hemodynamic, and metabolic studies were performed at base line and at the termination of the 3-wk treatment period. Maximal exercise (duration, oxygen consumption, and workload) fell for the saline group and remained unchanged for the dobutamine and exercise groups. Hemodynamics during exercise were maintained the same as pretreatment base line for the dobutamine and exercise groups, whereas stroke volume and cardiac output dropped and heart rate rose for the saline group. The metabolic profile showed an increased blood lactate response at rest and during submaximal exercise after 3 wk of bedrest for the saline group, and essentially no change for the exercise and the dobutamine groups. Extraction of oxygen across the exercising lower limb rose for the dobutamine group, as did the activity of the skeletal muscle oxidative enzymes, citrate synthetase, and succinate dehydrogenase. In contrast to the exercise control group, the saline and dobutamine groups developed orthostatic hypotension, tachycardia, and accentuation of the renin-aldosterone response over the 3-wk treatment period; for the saline group, this is best explained by the observed fall in blood volume and for the dobutamine group, by the blunting of vascular vasoconstrictive responses. During a period of bedrest deconditioning in humans, infusions of dobutamine maintain many of the physiologic expressions of physical conditioning.
Adult↗
Effects of mannitol on the postischemic kidney. Biochemical, functional, and morphologic assessments.
UNLABELLED: To determine the effects of mannitol on the postischemic kidney rats were subjected to 25 minutes of renal artery occlusion and immediately after vascular clamp release they received a 2-ml intravenous mannitol bolus (20%). Equimolar urea-injected rats and sham-injected rats served as controls. Postischemic renal blood flow, tubular metabolic work (renal O2 consumption), adenine nucleotide pools, renal oxidant stress (tissue glutathione, malondialdehyde levels), and tubular cell/mitochondrial swelling (histomorphometry) were assessed at variable times during the early vascular reflow period (15 to 60 minutes). The severity of acute renal failure was determined by serial blood urea nitrogen and serum creatinine studies (24, 48 hours), and by renal histology (48 hours). Mannitol increased postischemic renal blood flow (2-fold), renal O2 consumptions (3-fold), and urine flow compared to urea-injected and sham-injected controls. Postischemic glutathione levels were equally depressed (reduced 33%) in all three treatment groups. Malondialdehyde did not rise. Mannitol significantly lowered total adenine nucleotide content without changing ATP at 15 minutes post renal artery occlusion. At 60 minutes post renal artery occlusion, mannitol- and urea-treated groups had comparable ATP levels, 25% higher than the noninjected controls. Mannitol and urea induced comparable decrements in proximal tubular cell swelling, returning cell volumes to normal values. However, mitochondrial swelling was unabated. Mannitol and urea caused significant and nearly identical degrees of functional and morphologic amelioration of renal injury. CONCLUSIONS: Mannitol administered after renal ischemia ameliorates both functional and morphologic aspects of acute tubular injury despite dramatically increasing tubular aerobic work. This protection appears not to be due to early postischemic improvements in adenine nucleotide content, to increased renal blood flow, to increased urine flow, or to a lessening of oxidant stress. The data are consistent with the view that protection results from acute hypertonic solute loading which either directly or indirectly decreases tubular cell but not mitochondrial swelling.
Acute Kidney Injury↗
Effects of immediate blood flow enhancement on the postischemic kidney: functional, morphologic, and biochemical assessments.
Our purpose was to assess the influence of blood flow enhancement to the immediate postischemic kidney on tubular cell energetics and on the severity of the resulting ischemic acute renal failure (IARF). Female Sprague-Dawley rats were subjected to 40 minutes of bilateral renal artery occlusion (RAO). Half of the rats received a 5% body weight infusion of iso-oncotic saline solution (IOS; over 50 minutes) to acutely increase renal blood flow (RBF) immediately after vascular clamp release. The remaining half of the rats served as controls. The short-term effects (0 to 1 hour after vascular reflow) of IOS infusion on RBF, clearance iothalamate sodium (Cioth), urine Na excretion (UNaE), urine flow rate, tubular metabolic work (renal oxygen consumption, Qo2), adenine nucleotide concentrations, and renal histologic findings were assessed. The severity of the IARF (Cioth histologic findings) was also compared between the IOS-treated and the control groups 24 hours later. Postischemic (0 to 1 hour) RBF in control IARF rats and IOS-treated IARF rats was 2.3 +/- 0.3 and 13.6 +/- 0.4 ml/min, respectively (P less than 0.01) (normal RBF 6.1 +/- 0.4 ml/min). At 0 to 1 hour after reflow IOS-treated IARF rats had significantly higher Cioth (13 X), UNaE (18 X), urine flow (18 X), and Qo2 (4 X) than the control IARF group. Despite the fourfold increase in aerobic tubular work induced by IOS infusion, renal adenosine triphosphate (ATP) content did not decrease. At 24 hours after vascular reflow the severity of IARF was the same in the control and IOS-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Kidney Injury↗
Independent preclerkship study: a five year experience.
An independent study program (ISP) was instituted in 1970 for a group of 32 preclerkship medical students picked randomly from a group of 64 volunteers. The academic achievements of these classes, as measured by mean National Board scores, is compared with their classmates in the lecture discussion (LD) program where possible. The significant differences noted obtain even when the ISP students are compared only with LD students matched for premedical point-hour ratios and Medical College Admissions Test scores. These data attest to the overall success of the ISP program. The differences appear to us to be due mainly to factors related to motivation and maturity. The ease of preparations, convenience, and economy of the associated computer-assisted instruction make these methods attractive for use in residency training and continuing medical education where maturity and motivation may well be presumed.
Curriculum↗