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At least 235 records · Page 13Linked to original sources
PubMed1995

Altered physiology and action of insulin-like growth factor 1 in skeletal muscle in chronic renal failure.

Chronic renal failure is associated with abnormalities of skeletal muscle that include reduction in size, fibrosis, protein depletion, and functional disorders. These disorders may be caused by several factors, including protein-calorie malnutrition, acidemia, and superimposed illnesses. However, animal research suggests that these abnormalities may occur with chronic renal failure per se in the absence of the above complications. Insulin-like growth factor 1 (IGF-1) is an anabolic hormone that, in skeletal muscle, stimulates intracellular amino acid and glucose transport and protein synthesis, suppresses protein degradation, and causes hypertrophy. In chronic renal failure, there is evidence for inhibition of the actions of IGF-1. Studies in humans with chronic renal failure given a subcutaneous injection of recombinant human IGF-1 (rhIGF-1) indicate that the rhIGF-1 induced acute suppression of plasma amino acids, insulin, and C peptide is impaired. In skeletal muscle of rats with chronic renal failure, we observed reduced IGF-1 and IGF-1 mRNA levels, resistance to the rhIGF-1-induced suppression of protein degradation, and stimulation of protein synthesis, increased IGF-1 receptor mRNA and IGF-1 receptor number and impaired receptor tyrosine kinase activity. These findings suggest that in skeletal muscle in chronic renal failure there are several abnormalities in the physiology of IGF-1 and the sensitivity to IGF-1. It is possible that these alterations contribute to the disorders of skeletal muscle structure and function in chronic renal failure. Notwithstanding these abnormalities, repeated subcutaneous injections of rhIGF-1 in malnourished patients undergoing continuous ambulatory peritoneal dialysis led to strongly positive nitrogen balance that was sustained for the 20 days of study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions.

Insulin-like growth factor-binding protein-3 and -5 (IGFBP-3 and -5) have been shown to bind insulin-like growth factor-I and -II (IGF-I and -II) with high affinity. Previous studies have proposed that the N-terminal region of IGFBP-5 contains a hydrophobic patch between residues 49 and 74 that is required for high affinity binding. These studies were undertaken to determine if mutagenesis of several of these residues resulted in a reduction of the affinity of IGFBP-3 and -5 for IGF-I. Substitutions for residues 68, 69, 70, 73, and 74 in IGFBP-5 (changing one charged residue, Lys(68), to a neutral one and the four hydrophobic residues to nonhydrophobic residues) resulted in an approximately 1000-fold reduction in the affinity of IGFBP-5 for IGF-I. Substitutions for homologous residues in IGFBP-3 also resulted in a >1000-fold reduction in affinity. The physiologic consequence of this reduction was that IGFBP-3 and -5 became very weak inhibitors of IGF-I-stimulated cell migration and DNA synthesis. Likewise, the ability of IGFBP-5 to inhibit IGF-I-stimulated receptor phosphorylation was attenuated. These changes did not appear to be because of alterations in protein folding induced by mutagenesis, because the IGFBP-5 mutant was fully susceptible to proteolytic cleavage by a specific IGFBP-5 protease. In summary, residues 68, 69, 70, 73, and 74 in IGFBP-5 appear to be critical for high affinity binding to IGF-I. Homologous residues in IGFBP-3 are also required, suggesting that they form a similar binding pocket and that for both proteins these residues form an important component of the core binding site. The availability of these mutants will make it possible to determine if there are direct, non-IGF-I-dependent effects of IGFBP-3 and -5 on cellular physiologic processes in cell types that secrete IGF-I.

Amino Acid Substitution↗
PubMed1970

Alterations of synaptic action in chromatolysed motoneurones of the cat.

1. Monosynaptic EPSPs in lumbosacral motoneurones undergoing chromatolysis were studied by intracellular recording from 7 to 20 days after section of the appropriate ventral roots of the cat.2. The maximum monosynaptic EPSPs evoked in chromatolysed motoneurones by afferent volleys from the biceps-semitendinosus or the triceps surae muscles ranged from 1.0 to 9.5 mV in amplitude. The time-to-peak of these EPSPs was 1.7 msec on the average. These values were significantly smaller and longer, respectively, than the amplitude and the time-to-peak of monosynaptic EPSPs observed in normal motoneurones. The long time-to-peak of EPSPs in chromatolysed motoneurones could not be accounted for by asynchronous transmitter release.3. The mean number of unit EPSPs responding to a single afferent impulse (m) in chromatolysed motoneurones was comparable to that found in normal motoneurones.4. The amplitude of unit EPSPs estimated from the mean EPSP amplitude and the m value following stimulation of a single afferent fibre was significantly smaller in chromatolysed motoneurones than in normal motoneurones. This difference was attributed to a difference in synaptic location.5. The shape of monosynaptic EPSPs evoked in chromatolysed motoneurones by stimulation of single afferent fibres was analysed on the basis of Rall's compartment model. The analysis suggested that there is a lack of the excitatory synaptic input to the cell body in chromatolysed motoneurones.6. Similar alterations were also found in IPSPs. The degree of change in synaptic responses evoked by stimulation of various pathways appears to depend on the synaptic location.7. Following the study of the interaction of several inputs on the motoneurone and of their dependence on membrane potential, a tentative model of the synaptic distribution of different pathways is proposed.

Animals↗
PubMed1998

The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure.

Action potential prolongation is a common finding in human heart failure and in animal models of cardiac hypertrophy. The mechanism of action potential prolongation involves altered expression of a variety of depolarising and hyperpolarising currents in the myocardium. In particular, decreased density of the transient outward potassium current seems to play a prominent role, regardless of species, precipitating factors or the severity of hypertrophy. The decreased density of the transient outward current appears to be caused by reduced transcription of Kv4.2 and Kv4.3 and may be caused in part by an inhibitory effect of alpha-adrenoceptor stimulation. During the early stage of the disease process, action potential prolongation may increase the amplitude of the intracellular calcium transient, causing positive inotropy. We argue therefore, that action prolongation may be a compensatory response which may acutely support the compromised cardiac output. In severe hypertrophy and end-stage heart failure however, despite continued action potential prolongation, the amplitude of the calcium transient becomes severely reduced. The mechanism underlying this event appears to involve reduced expression of calcium handling proteins, and these late events may herald the onset of failure. At present the events leading to the late changes in calcium handling are poorly understood. However, chronic activation of compensatory mechanisms including action potential prolongation may trigger these late events. In the present article we outline a hypothesis which describes a potential role for action potential prolongation, and the associated elevation in the levels of intracellular calcium, in maladaptive gene expression and the progression toward cardiac failure.

Action Potentials↗
PubMed1982

The bacteriostatic action of captan: alterations of RNA metabolism in E. coli.

The growth of E. coli in broth cultures was inhibited in a concentration dependent manner by the addition of captan. Treated cells showed no evidence of lysis and maintained a viable character. Following a single exposure to 500 microM captan, cells exhibited a lag period of approximately six hr and then grew to maximum density. During the period of arrested growth, captan apparently inhibited the synthesis of RNA as measured by the incorporation of tritiated uridine into acid-insoluble material. This apparent inhibition was due in part to a captan mediated decrease in the uptake of uridine from the media into the soluble nucleotide pool. By means of RNA isolation, polyacrylamide gel electrophoresis, and RNA quantitation, it was demonstrated that captan caused a selective loss of large (16 and 23 S) ribosomal RNA's. However, cellular concentrations of transfer RNA and 5S ribosomal RNA were unaffected by captan treatment.

Captan↗
PubMed1990

Evidence for the functional compartmentalization of spike generating regions of rat midbrain dopamine neurons recorded in vitro.

The regulation of spike generation in rat midbrain dopamine (DA) neurons was investigated using in vitro intracellular recordings. DA neurons fired long (greater than 1.8 ms) action potentials that exhibited comparatively depolarized spike thresholds (approx. -35 to -45 mV). Depolarization of the DA neuron increased the duration and the threshold of subsequent action potentials. The action potential was composed of two distinct components, a fast (0.8-1.5 ms duration) initial segment (IS) spike which triggered a slow (1.5-3 ms duration) somatodendritic (SD) component. Cobalt application (2 mM) blocked the SD spike component and revealed fast TTX-sensitive spikes. These fast spikes were also observed in untreated neurons following large hyperpolarizing pulses, and showed consistent changes in threshold and amplitude during membrane depolarization. Administration of 4-aminopyridine decreased the threshold of this TTX-sensitive spike, whereas tetraethylammonium (TEA) had no effect. When the fast spike was blocked by TTX, depolarization was ineffective in triggering further spike activity. However, after the administration of TEA (but not 4-AP), high threshold cobalt-sensitive spike activity could be triggered by relatively small depolarizations. TEA increased the duration of the SD portion of the action potential without altering the action potential threshold. The effect of 4-AP on spike threshold and the increase in SD spike duration caused by TEA were similar in nature to the changes in action-potential waveforms produced by polarizing the DA neuron membrane. Drawing from evidence gathered here and in previous in vivo studies, the properties of the TTX-sensitive fast spike are consistent with those of the IS spike component of the action potential, whereas the SD component is similar in nature to the high threshold calcium spike. One hypothesis that can be drawn from these studies is that dendritic and axonal spiking regions may exist in different functional subcompartments of the DA neuron, and may be independently modulated by pharmacologically distinct conductances. Under these conditions, synaptic influences could exist to modulate dendritic excitability and thus regulate putative dendritic spike-dependent functions, such as neuronal activity state, electrical coupling, and dendritic DA synthesis and release.

4-Aminopyridine↗
PubMed1992

Chronic treatment with ethanol alters the physiological action of nicotine.

1. Ethanol decreases the release of acetylcholine through effects on presynaptic neurons at both muscarinic and nicotinic junctions. 2. Blockade of the release of acetylcholine should produce denervation supersensitivity at both muscarinic and nicotinic cholinergic junctions. 3. Chronic but not acute treatment with ethanol produces supersensitivity to the hypothermic effects of a muscarinic agonist in the rat. 4. The authors now report that chronic treatment with orally administered ethanol blunts (rather than enhances) the hypothermic response to nicotine in the rat. 5. This could have major public health implications. 6. Smoking and the use of ethanol containing beverages positively covary. 7. Ethanol induced reduction in sensitivity to nicotine suggests that the heavy consumption of ethanol may necessitate that one drink more than otherwise in order to obtain the desired effects of nicotine.

Animals↗
PubMedDate not supplied

Brain calcium in the rabbit: site of action for the alteration of body temperature.

Body temperature was recorded in the unanesthetized rabbit during push-pull perfusion of regions of the hypothalamus. Both the anterior and posterior hypothalamus were perfused with physiological solutions containing Ca++ in a concentration 2.0 or 5.0 times that of extracellular fluid. The animals were placed in an ambient temperature of 4.0 +/- 2.0degrees C for at least 1 hr before the perfusion and all experiments were carried out at this temperature. In the posterior hypothalamic area Ca++ produced a sharp fall in body temperature but did not cause body temperature to alter when it was perfused through the anterior hypothalamic area. These results indicate that the rabbit is similar to the cat and monkey since the effect of Ca++ on body temperature is localized to the posterior hypothalamic region.

Animals↗
PubMed2005

Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol.

Microarray analysis of human alcoholic brain and cultured cells exposed to ethanol showed significant changes in expression of genes related to immune or inflammatory responses, including chemokines and chemokine receptors. To test the hypothesis that chemokines exhibit previously undiscovered pleiotropic effects important for the behavioral actions of ethanol, we studied mutant mice with deletion of the Ccr2, Ccr5, Ccl2 or Ccl3 genes. Deletion of Ccr2, Ccl2 (females) or Ccl3 in mice resulted in lower preference for alcohol and consumption of lower amounts of alcohol in a two-bottle choice test as compared with wild-type mice. Ethanol treatment (2.5 g/kg, i.p.) induced stronger conditioned taste aversion in Ccr2, Ccl2 or Ccl3 null mutant mice than in controls. Ccr2 and Ccr5 null mutant mice did not differ from wild-type mice in ethanol-induced loss of righting reflex (LORR), but mice lacking Ccl2 or Ccl3 showed longer LORR than wild-type mice. There were no differences between mutant strains and wild-type mice in severity of ethanol-induced withdrawal. Genetic mapping of chromosome 11 for the Ccl2 and Ccl3 genes (46.5 and 47.6 cM, respectively) revealed that an alcohol-induced LORR QTL region was contained within the introgressed region derived from 129/SvJ, which may cause some behavioral phenotypes observed in the null mice. On the contrary, known QTLs on Chr 9 are outside of 129/SvJ region in Ccr2 and Ccr5 (71.9 and 72.0 cM, respectively) null mutant mice. These data show that disruption of the chemokine network interferes with motivational effects of alcohol.

Alcohol Drinking↗
PubMed2005

Altered diaphragm muscle action potentials in Zucker diabetic fatty (ZDF) rats.

The Zucker diabetic fatty (ZDF) rat is a model of type 2 diabetes, being characterized by obesity, diabetes, and dyslipidemia. In vitro studies tested the hypothesis that diaphragm muscle from ZDF rats has abnormal resting membrane potential and action potentials, similar to type 1 diabetic rodents. Resting membrane potential was comparable for muscle from ZDF and control rats. Diaphragm from ZDF rats had augmented action potential peak height (92.1 mV versus 82.4 mV, P<0.00001), overshoot (15.6 mV versus 8.1 mV, P<0.001) and area (80.7 mV ms versus 68.6 mV ms, P<0.001) compared with that from controls. Action potential rate of depolarization and repolarization were not affected. The K(+) blocker, 3,4-diaminopyridine, augmented action potential duration and area of muscle from ZDF and controls, but without significant differences between animal groups. These findings in ZDF rats contrast with type 1 diabetic rats, suggesting that isolated hyperglycemia differs from hyperglycemia combined with other metabolic perturbations with respect to diaphragm electrophysiological derangements.

Action Potentials↗
PubMed2004

Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling.

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. Moreover, several kinases able to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases and defining the precise role of serine phosphorylation events in IRS-1 regulation represent important goals. Such studies may enable rational drug design to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.

Animals↗
PubMed1993

Evidence for an altered mode of action of the sodium-lithium countertransporter in vivo in patients with untreated essential hypertension.

OBJECTIVE: To study the activity of the sodium-lithium (Na(+)-Li+) countertransport system in vivo in the erythrocytes of patients with untreated essential hypertension. DESIGN: Lithium substitutes for sodium efflux in the sodium-sodium (Na(+)-Na+) countertransport system. In essential hypertension the efflux of lithium from cells in vitro has been used as a measure of the activity of the Na(+)-Na+ countertransporter and has been shown to be increased. We administered oral lithium and used its disposition in erythrocytes to measure Na(+)-Li+ countertransporter activity in vivo. PATIENTS: Ten men with essential hypertension who had never taken any antihypertensive treatment were matched with 10 male controls for age, weight, and plasma and erythrocyte sodium and potassium concentrations. METHODS: Repeated measurements were made of plasma and intra-erythrocytic lithium concentrations during the 48h after the oral administration of 16.2 mmol lithium carbonate. Data were analysed using standard pharmacokinetic techniques. RESULTS: The rate of lithium efflux from the erythrocytes was increased in all patients with hypertension and in none of the normotensive controls. Hill plots derived from in vivo activation curves for erythrocytic Na(+)-Li+ countertransport showed that the normotensive participants had a Hill slope of 1 (SD 0.1), whereas the hypertensives had a Hill slope of 3.2 (SD 1.0). CONCLUSIONS: The activity of the Na(+)-L+ countertransport system is increased in untreated essential hypertension in vivo; this confirms in vitro findings. A new finding is that there is a change in either the stoichiometry or the co-operativity of lithium efflux via the Na(+)-L+ countertransport system, suggesting that the rate of sodium efflux may be greater than that of influx in the cells of people with hypertension.

Antiporters↗
PubMed1995

Are the cardiovascular actions of dopamine altered by isoflurane?

Dopamine seems theoretically to be a rationale choice when adrenergic support is needed to counter undesired cardiovascular depressant effects of isoflurane. Although the cardiovascular effects of isoflurane (ISO) and exogenous dopamine (DA) are well documented, there are no reports on their pharmacological interaction. The effects of ISO 1.4% (MAC 1.0) on the cardiovascular response to exogenous DA were studied in dogs during chloralose anesthesia. Instrumentation included catheterizations of the femoral artery (for aortic pressures and heart rate, HR), the pulmonary artery (for thermodilution cardiac output, CO, and pulmonary arterial pressures) and the left ventricle (for tip-manometer measured left ventricular end-diastolic pressure, LVEDP). ISO per se decreased HR (-16%), mean arterial pressure (MAP; -33%), CO (-29%), left ventricular dP/dt (LV dP/dt; -51%), and increased pulmonary artery occlusion (PAOP; +64%) and LVEDP (+28%). Prior to ISO, DA increased MAP, CO stroke volume (SV), LV dP/dt and LV dP/dt/SAP (systolic arterial pressure) at the dose 10 micrograms.kg-1.min-1. At the dose 20 micrograms.kg-1.min-1 DA, besides these effects, increased PAOP and mean pulmonary artery pressure (MPAP). During ISO, DA at the dose 10 micrograms.kg-1.min-1 restored MAP, CO, and SV to pre-ISO control levels, while LV dP/dt was increased to +96% above the pre-ISO control level. At the dose 20 micrograms.kg-1.min-1, DA increased MAP (+33%), LV dP/dt (+172%), PAOP (+132%) and MPAP (+50%) above pre-ISO control levels. The cardiac effects of DA were similar to when it was given alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics, Inhalation↗