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Biomedical subjects

H Silverman

Publications and source records attributed to H Silverman.

At least 19 recordsLinked to original sources
PubMed1998

Loss of cardiac magnesium in experimental heart failure prolongs and destabilizes repolarization in dogs.

OBJECTIVES: We sought to determine whether heart failure results in loss of cardiac magnesium sufficient to alter cellular electrophysiology. BACKGROUND: Free magnesium has numerous intracellular roles affecting metabolism, excitability and RNA synthesis. Total cardiac magnesium content is reduced in heart failure, but it is unclear whether magnesium loss is primary or iatrogenic. Furthermore, it is unknown whether free magnesium levels are affected or whether a change in free magnesium would alter cellular electrophysiology. METHODS: Eight mongrel dogs underwent demand ventricular pacing (VVI) at 250 beats/min for 3 weeks to induce heart failure. Sublingual epithelial magnesium was measured before pacing and at death. Left ventricular myocytes were isolated and loaded with Mag-Indo-1 to measure free magnesium ([Mg2+]i); myocytes from eight normal dogs served as controls. To test whether changes in [Mg2+]i in this range could alter cellular repolarization, current-clamped myocytes were dialyzed with 0.5 or 1.0 mmol/liter MgCl2. RESULTS: Mean sublingual epithelial magnesium fell significantly in the paced animals, from 36.9 +/- 0.5 to 33.9 +/- 0.7 mEq/liter (p < 0.01). Mean cardiac [Mg2+]i was significantly lower in the dogs with heart failure--0.49 +/- 0.06 versus 1.06 +/- 0.15 mmol/liter (p < 0.003). Time to 90% repolarization was significantly shorter in cells dialyzed with 1.0 mmol/liter compared with 0.5 mmol/liter MgCl2 in myocytes from normal dogs or dogs with heart failure (596 +/- 34 vs. 760 +/- 58 ms in normal dogs and 586 +/- 29 vs. 838 +/- 98 ms in dogs with heart failure; p < 0.05 for each). CONCLUSIONS: Experimental heart failure results in both tissue and cardiac magnesium loss in the absence of drug therapy. Free cardiac magnesium is significantly reduced, possibly contributing to abnormal repolarization in heart failure.

Action Potentials↗
PubMed1997

Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes. Evidence for involvement of p70 S6 kinase.

The 70-kD S6 kinase (p70S6K) has been implicated in the regulation of protein synthesis in many cell types and in the angiotensin II-stimulated hypertrophy of cardiac myocytes. Our purpose was to determine whether p70S6K plays a role in cardiomyocyte hypertrophy induced by the alpha 1-adrenergic receptor (alpha 1-AR) agonist phenylephrine (PE). PE stimulated the activity of p70S6K > 3-fold, and this increase was blocked by rapamycin, an immunosuppressant macrolide that selectively inhibits p70S6K. When administered for 3 days, PE stimulated a 30% increase in total protein content, a 2-fold increase in the incorporation of [14C]phenylalanine (14C-Phe) into protein, and a 50% increase in two-dimensional myocyte area. Rapamycin pretreatment (> or = 500 pg/mL) significantly inhibited each of these PE-stimulated changes. Two days of PE treatment resulted in a 1.6-fold increase in total RNA yield per dish, a 2-fold increase in incorporation of [14C]uridine into myocyte RNA, and increases in relative mRNA levels of the hypertrophy-associated atrial natriuretic factor (ANF, 2.1-fold) and skeletal alpha-actin (SK, 2.2-fold) genes. Although rapamycin abolished the PE-stimulated increases in total RNA and incorporation of [14C]uridine, it had no effect on the induction of the ANF and SK genes. LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-K) activity, inhibited PE-stimulated increases in p70S6K activity and the incorporation of labeled precursors into myocyte protein and RNA. These results demonstrate that p70S6K is activated by the hypertrophic agent PE and that a PI3-K or PI3-K-like activity is required for p70S6K activation and myocyte hypertrophy. The data suggest that p70S6K activation may be required for PE-stimulated hypertrophy of cardiac myocytes. Our results demonstrate that intracellular signaling pathways responsible for transcriptional and translational responses diverge early after alpha 1-AR stimulation in cardiac myocytes.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1996

Analysis of fertilization and polyspermy in serotonin-spawned eggs of the zebra mussel, Dreissena polymorpha.

Eggs isolated from animals spawned with 10(-3) M serotonin were inseminated with sperm concentrations ranging from 10(3)-10(6) sperm/ml. Multiple sperm attached to the surface of the egg and sperm incorporation occurred within 3 min postinsemination (PI). Sperm mitochondria, centrioles, and flagellum were also incorporated. Incorporation was essentially complete by 6 min PI. In the egg cortex, the sperm head rotated 180 degrees, and a rapid translocation of the sperm through the cytoplasm towards the egg interior began by 5-6 min PI. In heavily polyspermic inseminations, translocations of the sperm were either minimal or nonexistent. In monospermic eggs, nuclear decondensation occurred after translocation was complete, beginning by 9-10 min PI. A male pronucleus began to develop in the cytoplasm by 21 min PI and enlarged to 20 microns before fusing with the female pronucleus. Oscillation of the egg cytoplasm and mitotic spindle apparatus was observed immediately prior to cleavage. Cleavage occurred at 60 min PI. Sperm incorporation and pronuclear formation were confirmed with fluorescent and confocal microscopy using the DNA-specific dyes Hoescht 33342 and 7-aminoactinomycin D. In sperm concentrations > 10(4) sperm/ml, 26-76% of the eggs exhibited polyspermy. The high incidence of polyspermy suggests that rapid, effective blocks to polyspermy were not present or were ineffective in a significant proportion of serotonin-spawned eggs.

Animals↗
PubMed1995

Paracellular solute uptake by the freshwater zebra mussel Dreissena polymorpha.

A hyperosmotic solution of mannitol or glucose (100 mM) in pond water caused an increase in paracellular solute movement between the bathing medium and body fluids of Dreissena polymorpha. Small molecules (< 5,000 Da) in the bath entered the mussel, and 80-85% of the sodium and chloride in the blood was lost within 12 h. Blood total solute was elevated within 4 h of exposure to hyperosmotic conditions, but the rise was attributed to the gain of glucose or mannitol from the bath and not to an elevation of ion concentration as a result of the osmotic loss of water. Lanthanum in the bathing solution was able to penetrate the paracellular junctional complex between gill epithelial cells in mussels exposed to hyperosmotic conditions but was rarely observed in pond water-acclimated animals. Colloidal gold (6 nm diam) was unable to penetrate the paracellular space but was accumulated in endocytotic vesicles in many epithelial cells. The "leakiness" of the epithelial tissue may be a critical factor in the low blood solute concentrations in freshwater mussels despite high rates of ion transport in these animals.

Animals↗
PubMed1994

Limited capacity for glyconeogenesis from alanine by diaphragm muscle.

The mammalian diaphragm (Dia) is a unique skeletal muscle because of its chronic contractile activity. Chronically active muscles have higher capacities for glycogen synthesis from lactate and glucose. In this study, the contribution of alanine to glycogen synthesis in the predominantly fast-twitch mouse Dia was determined. Chronically active fast- and slow-twitch muscles from dy2J/dy2J pseudomyotonic mice were also analyzed. Alanine aminotransferase (AlaAT) activity was significantly (P < 0.05) greater in Dia and chronically active gastrocnemius muscle (Gast) than control Gast. 14C-label incorporation into glycogen following in vivo injection of 14C-alanine, was significantly higher in Dia and chronically active Gast than control Gast. A direct incorporation of 14C from 14C-alanine into glycogen is also observed in vitro. The incorporation rate shows a linear concentration dependent relationship and a pH optimum of 6.3. Insulin had no effect on glycogen synthesis from alanine by Dia in vitro. The extensor digitorum longus muscle (EDL) and chronically active EDL and soleus muscle (Sol) had higher rates of glycogen synthesis from alanine than control Sol and Dia. The oxidation of alanine to CO2 was the primary route for alanine metabolism by the Dia. These results demonstrate that the Dia can synthesize glycogen from alanine, but only at low rates.

Alanine↗
PubMed1993

Glucose uptake and glycogen synthesis in normal and chronically active muscles.

The hindlimb muscles of the C57Bl6J dy2J/dy2J (dy2J) mouse suffer from a chronic neural stimulation (pseudomyotonia), resulting in increased contractile activity. In response to the increased contractile activity, these muscles store increased amounts of glycogen. In this study, glucose uptake and glycogenesis (glycogen synthesis from glucose) were analyzed in chronically active and normal muscles. In vivo experiments demonstrate increased 3-O-methylglucose (3-MG) uptake rates and glycogenesis by chronically active dy2J gastrocnemius muscles (Gast) vs. normal control Gast. The chronically active diaphragm muscle (Dia) showed the highest rates of 3-MG uptake, as well as glycogenesis in vivo when compared with other skeletal muscles. No differences were observed between dy2J and control Dia. The levels of blood glucose were similar between dy2J and control animals. In vitro experiments demonstrated an increased sensitivity and responsiveness to insulin for glucose uptake in the dy2J soleus muscle (Sol). Glycogenesis by dy2J Sol was elevated only at the highest insulin concentration tested (10,000 microU/ml). In contrast, the dy2J extensor digitorum longus muscle had an increased sensitivity and responsiveness to insulin for both glucose uptake and glycogenesis. This study demonstrates that chronically active muscles have elevated capacities for glucose uptake and glycogenesis and may help to explain the elevated glycogen levels in the dy2J hindlimb muscles.

3-O-Methylglucose↗
PubMed1993

Effect of blockade of the ATP-sensitive potassium channel on metabolic coronary vasodilation in the dog.

The hypothesis that the ATP-sensitive potassium channel provides the link between change in coronary blood flow and myocardial oxygen demand was tested in 9 dogs instrumented to measure coronary flow and regional wall thickening in the basal state and at a high level of myocardial oxygen consumption produced by systemic infusion of phenylephrine and simultaneous atrial pacing at an elevated heart rate. Measurements were recorded before and after blockade of ATP-sensitive potassium channels with intracoronary glibenclamide (2 mumol/min). While glibenclamide reduced the absolute level of coronary flow in the basal state, the increase in flow due to increased metabolic demand was unchanged compared with control. Thus, activity of the ATP-sensitive potassium channel determines the set point from which adjustments of coronary flow in response to metabolic stimuli occur, but does not provide a link between changes in oxygen demand and changes in coronary flow.

Adenosine Triphosphate↗
PubMed1992

Changes in monoamine transmitter concentration in freshwater mussel tissues.

Freshwater mussels were analyzed for biogenic amine transmitter substances in gill tissue, suprabranchial nerve and blood. Gill tissue from normal pondwater-acclimated mussels contained significant amounts of monoamine neurotransmitter substances. In comparison with the suprabranchial nerve the gill tissue contained 42% of the dopamine, 7% of the serotonin and 490% of norepinephrine. Exposing the animals to deionized water (salt-depleted) resulted in a loss of transmitter substances from gill tissue, but serotonin reduction was modest. The mussel gill tissue content of serotonin and the precursor tryptophan was regulated at nearly constant levels. Serotonin is an important transmitter substance in mussels and the many functions it controls, including sodium transport regulation, would depend on its continued presence.

Animals↗
PubMed1992

Mechanisms for dominance: Adh heterodimer formation in heterozygotes between ENU or X-ray induced null alleles and normal alleles in Drosophila melanogaster.

To study mechanisms for dominance of phenotype, eight ENU- and four X-ray-induced mutations at the alcohol dehydrogenase (Adh) locus were analyzed for partial dominance in their interaction with normal alleles. All ENU and one of the X-ray mutations were single base substitutions; the other three X-ray mutations were 9-21 base deletions. All but one of the 12 mutant alleles were selected for this study because they produced detectable mutant polypeptides, but seven of the 11 producing a peptide could not form dimers with the normal peptide and the enzyme activity of heterozygotes was about half that of normal homozygotes. Four mutations formed dimers with a decreased catalytic efficiency and two of these were near the limit of detectability; these two also inhibited the formation of normal homodimers. The mutant alleles therefore show multiple mechanisms leading to partial enzyme expression in heterozygotes and a wide range of dominance ranging from almost complete recessive to nearly dominant. All amino acid changes in mutant peptides that form dimers are located between amino acids 182 and 194, so this region is not critical for dimerization. It may, however, be an important surface domain for catalyzation.

Alcohol Dehydrogenase↗
PubMed1992

Diaphragmatic fiber type specific adaptation to endurance exercise.

Recent evidence suggests that exercise training results in a significant improvement in the oxidative capacity of the mammalian diaphragm; however, limited data exist concerning which diaphragmatic fiber types are metabolically altered due to training. To test the hypothesis that exercise training increases the oxidative capacity of diaphragmatic type I and IIa fibers only, we examined the effects of endurance training on the fiber type specific changes in oxidative capacity, cross-sectional area, and capillarity of the costal diaphragm. Female Fischer-344 rats (age ca 180 days) were divided into either sedentary control group (n = 6) or an exercise training group (n = 6). The trained animals exercised for 10 wks on a motor-driven treadmill (60 min.day-1; 5 days.wk-1) at a work rate equal to ca 55-65% VO2max. Capillaries were identified histologically and fiber types determined using ATPase histochemistry. Fiber cross-sectional area (CSA) and succinate dehydrogenase (SDH) activity in individual fibers were measured using a computerized image analysis system. Compared to control animals, training did not increase the capillary to fiber ratio in any diaphragm fiber type (P greater than 0.05); however, training increased capillary density (capillary No./CSA) in type IIa fibers due to a reduction in cell CSA (P less than 0.05). Further, training resulted in significant (P less than 0.05) increases in total diaphragmatic SDH activity (delta increase = 17.5%) and an increase in SDH activity in both type I (delta increase = 14%) and IIa fibers (delta increase = 17.4%). In contrast, training did not alter (P greater than 0.05) SDH activity in type IIb fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1992

Exercise-induced cellular alterations in the diaphragm.

Limited data exist concerning the effects of exercise training on cellular oxidative capacity in the diaphragm of senescent animals. In this study we examined the changes in cellular oxidative capacity, muscle cell cross-sectional area (CSA), and capillarity within the costal diaphragm of senescent animals after a 10-wk endurance-training program. Twelve 24-mo-old female Fischer 344 rats were divided into either a sedentary control group (n = 6) or exercise training group (n = 6). The trained animals exercised on a motor-driven treadmill (60 min/day, 5 days/wk) at a work rate equal to approximately 55-65% VO2max. Capillaries were identified histologically and fiber types determined using adenosinetriphosphatase (ATPase) histochemistry. Succinate dehydrogenase (SDH) activity and CSA in individual fibers were measured using a computerized image analysis system. Exercise training did not increase (P > 0.05) the capillary-to-fiber ratio for any fiber type. However, training significantly decreased CSA (P < 0.05) and increased capillary density (capillary number/CSA) (P < 0.05) in type I, type IIa, and type IIb fibers. Furthermore, exercise training resulted in small but significant increase in SDH activity (P < 0.05) in type I and IIa fibers, whereas training did not alter SDH activity (P > 0.05) in type IIb fibers. These data demonstrate that endurance training in senescent animals results in small relative improvements in both oxidative capacity and capillary density in costal diaphragmatic type I and IIa muscle fibers. The increase in both capillary density and fiber SDH activity was largely due to a reduction in fiber CSA.

Aging↗
PubMed1992

Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin E1 Study Group.

STUDY OBJECTIVE: To determine the epidemiology of multiple organ failure (MOF) in patients with the adult respiratory distress syndrome. PATIENTS: We followed up 50 patients with serial determinations of respiratory and nonrespiratory organ function for seven days after diagnosis. DESIGN: Data were stratified between patients who died and those who survived (defined as hospital discharge). MEASUREMENTS AND RESULTS: Values that did not differ at any time between the two groups of patients included oxygen availability, oxygen consumption, oxygen extraction, PaCO2, respiratory rate, heart rate, systolic blood pressure, cardiac output, stroke index, systemic vascular resistance, and temperature. Patients who died had greater defects in oxygenation (from day 1 through day 7). They also exhibited decreased arterial oxygen content (from day 1 to day 4), decreased mixed venous oxygen content (day 1), increased peak inspiratory pressure (present on day 2, persisted to day 5, reappeared on day 7), decreased diastolic blood pressure (seen on days 1 through 3, reappeared on day 7), and increased mean pulmonary artery pressure (seen on days 2 and 3). Nonsurvivors also exhibited greater degrees of thrombocytopenia (from day 1 to day 4). Decreases in pH (seen on day 1, reappeared from days 4 to 7), abnormalities in liver function (seen only on day 1), and increases in serum creatinine levels (appeared on day 7) were also observed. CONCLUSIONS: Multiorgan dysfunction (MOD) was frequently observed in both groups of patients. Alterations in organ function and the pattern of abnormalities were often subtle and would not be characterized as significant organ dysfunction by most available organ scoring systems. Adult respiratory distress syndrome is a manifestation of systemic disease produced by widespread increases in endothelial permeability; lung dysfunction dominates the early clinical course. When respiratory function is supported, it becomes evident that alterations occur in other organs. Multiorgan failure is really a misnomer; the term emphasizes end-stage changes. Multiorgan dysfunction is common and often resolves without progressing to MOF. Alternatively, MOD can progress to MOF.

Blood Pressure↗
PubMed1992

The effects of prostaglandin E1 on non-pulmonary organ function during clinical acute respiratory failure. The Prostaglandin E1 Study Group.

The effects of prostaglandin E1 (PGE1) on non-pulmonary vital organs in critically ill patients are not well defined. This study evaluated the role of exogenous PGE1 in systemic homeostasis during the adult respiratory distress syndrome (ARDS). Indicators of end-organ function were analyzed retrospectively in 146 septic or post-trauma patients with ARDS who received PGE1 (30/ng/kg/min) or placebo IV for up to 7 days in a randomized, double-blind clinical trial. Hemodynamic variables and serum levels of creatinine, bilirubin, and SGOT, platelet count, and changes in the white blood cell count were measured daily. Our results indicate that mean arterial pressure, pulmonary artery pressure, and systemic and pulmonary vascular resistance indices were significantly lower in the PGE1 group versus the placebo-treated group. Cardiac index, stroke index, and oxygen delivery index were significantly increased in the PGE1 group. Serum bilirubin and SGOT were decreased significantly among PGE1-treated patients compared with placebo-treated patients, while the white blood cell count increased more significantly from baseline values with PGE1 treatment. Intergroup differences in platelet count and serum creatinine levels were not statistically significant. The results indicate that PGE1 improves cardiovascular performance, hepatic function, and leukocyte availability during clinical ARDS. Prostaglandin E1 did not affect platelet counts and renal function in this study.

Acute Disease↗
PubMed1992

Treatment of common eye emergencies.

Some ocular conditions represent serious emergencies requiring immediate treatment. Chemical exposure requires prompt irrigation with saline. Major trauma with possible globe perforation requires eye shielding and referral for surgical evaluation. Sudden loss of vision may represent vascular occlusion and should be evaluated promptly by an ophthalmologist. Angle closure glaucoma is rare; drug treatment may be instituted in consultation with an ophthalmologist. Patients with orbital cellulitis should be hospitalized for intravenous antibiotic therapy. Less urgent eye conditions can be treated within 24 hours of onset. Minor trauma with hyphema requires cycloplegic medications, eye shielding and ophthalmologic consultation. Visual floaters, light flashes or "curtains" may represent vitreous or retinal detachment and should be evaluated by an ophthalmologist. Foreign bodies can usually be removed by irrigation or careful instrumentation.

Emergencies↗
PubMed1991

Age-related changes in enzyme activity in the rat diaphragm.

Limited data exist concerning the effect of growth and aging on the metabolic properties of the diaphragm. Therefore, we investigated age-related changes in protein concentration and glycolytic and Krebs cycle enzyme activity in the diaphragm as well as the plantaris muscle of female Sprague-Dawley rats ranging in age from 1 to 12 months. Samples from the costal and crural diaphragm and the plantaris muscle were obtained from 38 animals in the following age groups: (1) 1 month old (N = 7); (2) 4 month old (N = 6) (3) 6 month old (N = 13); and (4) 12-month-old (N = 12). Body weight and diaphragm weight increased rapidly by a factor of 6 and in parallel during 1-4 months postpartum before reaching a plateau at 6 months of age. No significant difference (P greater than 0.05) existed in the ratio of diaphragm weight to body weight among age groups. Protein concentration was significantly higher (P less than 0.05) in the costal diaphragm and plantaris at 4 and 6 months when compared to 1 and 12 months of age. In the crural diaphragm, protein concentration was significantly lower (P less than 0.05) at 1 month postpartum when compared to all other age groups. Succinate dehydrogenase (SDH) activity was significantly higher (P less than 0.05) at 1 month of age in the plantaris, the costal diaphragm and the crural diaphragm when compared to older animals. In contrast, the activity of lactate dehydrogenase (LDH) in the plantaris, the costal diaphragm and the crural diaphragm was significantly lower (P less than 0.05) in the 1-month-old animals when compared to all other ages.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Glyconeogenic and glycogenic enzymes in chronically active and normal skeletal muscle.

The chronically active (pseudomyotonic) gastrocnemius muscle in the C57B16J dy2J/dy2J mouse contains both elevated lactate and glycogen as well as fibers that have high amounts of glycogen and enhanced glyconeogenic activity. In the present study we analyze the activities of some key glyconeogenic enzymes to assess the causes of elevated muscle glycogen and to determine the pathway for glycogen synthesis from lactate. Glycogen synthase, malate dehydrogenase, phosphoenolpyruvate carboxykinase, and malic enzyme were all elevated in homogenates of the chronically active muscle. Activities of glycogen phosphorylase and fructose 1,6-bisphosphatase were decreased in whole muscle homogenates. Histochemistry demonstrated that the high-glycogen fibers were typically fast-twitch glycolytic fibers that had high glycogen synthase, glycogen phosphorylase, and malic enzyme activities. Malate dehydrogenase activity followed succinate dehydrogenase activity and did not correlate to high-glycogen fibers. Thus the high-glycogen fibers have an elevated enzymatic capacity for glycogen synthesis from lactate, and the pathway may involve use of the pyruvate kinase bypass enzymes.

Animals↗