Carotid body adaptation to hypoxia: cellular and molecular mechanisms in vitro

Chronic hypoxia in vivo promotes long-term changes in the carotid body (CB) response to low PO2. By exposing cultured rat CB chemoreceptors (glomus cells) to 6% O2 for 1-3 weeks, we are investigating the cellular and molecular mechanisms of hypoxic adaptation. Recent studies have uncovered a series of plastic changes in glomus cells including hypertrophy, differential regulation of Na+, Ca2+, and K+ currents, and upregulation of the 'plasticity protein', GAP-43. We have also identified cyclic AMP as a possible intracellular mediator of at least some of these effects of chronic hypoxia. Associated with the changes in ionic currents, glomus cells become electrically more excitable. However, a complete understanding of the physiological response of chronically hypoxic glomus cells to chemostimuli will require more detailed knowledge of the specific alterations in the sensing and signaling pathways, including modifications in neurotransmitter (e.g. catecholamine) functions.     

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation by hypoxia or almitrine in men

1. The cardiorespiratory and renal responses to 3 h of normobaric whole-body hypoxic hypoxia (FiO2 = 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration-fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypoxia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.     

Cardiovascular responses of conscious rats to carotid body chemoreceptor stimulation by intravenous KCN

This multicentre, double-blind, randomised, crossover study compared the efficacy, safety and tolerability of subcutaneous sumatriptan (6 mg and 12 mg) with placebo in 134 in-patients with cluster headache. Headache improvement to mild or no pain at 5, 10 and 15 min after treatment was recorded. At 10 min, headache relief was reported by 25% (placebo), 49% (6 mg) and 63% (12 mg) of patients and at 15 min the results were 35% (placebo), 75% (6 mg) and 80% (12 mg) (p < 0.001 for all comparisons with placebo). The 12 mg dose was not significantly better than the 6 mg dose and was associated with more adverse events. The 6 mg dose is therefore recommended for the acute treatment of cluster headache.     

Myocardial function during hypoxia in the presence of different buffers

Electrically driven rabbit left atria were exposed to 20 min periods of either hypoxia or anoxia in the presence of a bicarbonate-phosphate buffer, a Tris buffer [tris (hydroxymethyl) aminomethane hydrochloride] or combination of both. The bicarbonate-phosphate buffer system was shown to be important for tissue survival during hypoxia or anoxia whereas recovery was diminished in the presence of Tris only. Stimulus threshold and arrhythmias were shown to increase for atria in Tris. Oxygen consumption determinations on both spontaneously beating right atria and quiescent left atria showed no difference between pre- and post-hypoxia or between different buffers. Tris was shown to elicit a positive inotropic effect without an increase in O2 consumption.     

Autoregulatory vasodilation of parenchymal vessels is impaired during cerebral vasospasm

OBJECTIVE: A recent study (Arnow, Kenardy, & Agras, 1995, Journal of Behavioral Medicine, 15, 155-170) has reported on the development and preliminary validation of the Emotional Eating Scale (EES), a questionnaire measure of the tendency to eat in response to affective state. The EES showed high levels of validity among obese binge eaters, but there was no attempt to validate the measure among nonclinical groups. The present study assessed the validity of the EES among nonclinical women, in order to determine whether or not emotional eating is related to unhealthy eating characteristics among the general population. METHODS: The participants were 51 women with no current or past eating disorder. Each completed the EES and the Eating Disorders Inventory (EDI). Validity of the EES was tested using measures of internal consistency and correlations with EDI scales. RESULTS: The EES scales showed a high level of internal consistency and specific associations with EDI scales (particularly Bulimia, Ineffectiveness, and Interpersonal Distrust). The normative scores for this population were substantially lower than among binge eaters, but similar to those found among other clinical groups. CONCLUSIONS: The EES has good levels of validity. It demonstrates that emotional eating is related to bulimic eating attitudes in the broader population, although issues of causality need to be considered. The EES may have a role in the early identification of eating problems in nonclinical groups. Its utility with other eating-disordered groups remains to be established, but there are potential roles in the targeting and evaluation of treatment.     

How is body orientation controlled during somersaulting?

How body orientation is controlled during somersaulting was investigated in 2 experiments that analyzed the kinematics of 223 backward standing somersaults. In Experiment 1, open-loop, initial-condition (flight duration), and prospective (time to contact, or TC?) control strategies were tested as candidates for the regulation of body moment of inertia during the jump. Decreasing between-trials variability of body orientation over time as well as a negative correlation between body angular velocity and TC? suggested that the moment of inertia was regulated prospectively. In Experiment 2, the visual basis for this regulation was examined by asking experts and novices to execute somersaults either with eyes closed or open. Results showed that the prospective regulation observed in the vision condition disappeared in the no-vision condition with the experts, arguing in favor of a visual control during the jump. Such a coupling was absent with the novices, thus illustrating the role played by the perception–action cycle in the learning process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Thyroid function in rats with iodine deficiency is not further impaired by concurrent, marginal zinc deficiency

The hypothesis tested was that Zn deficiency aggravates impaired thyroid function as induced by I deficiency. In two separate experiments male rats were fed on diets either deficient in Zn or in I, or deficient in both. An identical, restricted amount of food was given to each rat so that body-weight gain of the experimental groups was comparable. Zn deficiency was evidenced by reduced tibial Zn concentrations. I deficiency was evidenced by goitre, reduced urinary I excretion, reduced plasma thyroxine concentrations and reduced absolute amounts and concentrations of thyroxine in the thyroid. Zn deficiency had no effect on the raised thyroid weight as induced by I deficiency. Zn restriction from 184 mumol Zn/kg diet to 31 mumol Zn/kg diet, but not to 92 mumol Zn/kg diet, significantly lowered plasma thyroxine concentration. There were no interrelated effects of Zn and I deficiencies on thyroid hormone levels. These results indicate that marginal Zn deficiency does not influence thyroid hormone metabolism in I deficiency.     

Pulmonary function values in Friesian and double-muscled calves during acute poikilocapnic hypoxia

In the genus Eulemur (Malagasy lemurs) karyotype diversification has occurred mainly through Robertsonian mechanisms of chromosome fusion (Rumpler et al., 1976). Eulemur coronatus is the sole species to have the largest genome size, due to a very large amount of C-heterochromatin, mostly located at the pericentromeric regions of the largest chromosomes (Warter and Rumpler, 1985). This increase in C-heterochromatin was thought to be due to DNA amplification (Ronchetti et al., 1993). The aim of this work was to investigate whether the large C-heterochromatin of Eulemur coronatus might have derived by amplification of the smaller C-heterochromatin of Eulemur macaco, a closely related species with smaller genome size. To obtain information on the overall base composition of the total genomes, on the relative interspersion of AT and GC base paris along the DNA molecule and on the structural differences in C-heterochromatin, we used a quantitative cyto-chemical approach, based on fluorescence resonance energy transfer (FRET) between DNA-specific fluorochromes (i.e. the AT-specific Hoechst 33258, and the non base-specific dye, propidium iodide). Micro-spectrofluorometry and image analysis were used to investigate both the overall FRET efficiency and its spatial distribution along the chromosome arms. FRET efficiency values of the DNA in C-heterochromatin were significantly different in the two Eulemur species, indicating a different qualitative composition of repetitive DNA. This suggests that the repetitive DNA of Eulemur coronatus cannot have originated by amplification in toto of the repetitive DNA sequences of Eulemur macaco.     

Platelet aggregation is impaired during anaesthesia with sevoflurane but not with isoflurane

Oleum origani, the essential oil of Origanum onites L., is a traditional plant material used in Turkey for the treatment of several diseases, including diabetes mellitus. This study has evaluated the effect of oleum origani on streptozotocin-induced tissue injury and haematological changes. The effect of oleum origani on glycaemia was also studied. Long-term administration of oleum origani resulted in significant improvement of tissue injury induced by streptozotocin treatment. No effect on blood glucose levels was detected. In addition, any visible toxicity or disturbance of haematological parameters and tissue structure attributable to the long-term use of oleum origani were not established in normal rats. The data indicate that long-term use of oleum origani might be effective in preventing or at least in retarding the development of some complications of diabetes mellitus. Further investigation is required to determine the underlying mechanism(s) of the protective effect against tissue injury induced by streptozotocin-treatment of rats.     

Presyncope during progressive hypovolaemia simulated by lower body negative pressure is not prevented by high-dose naloxone

STUDY OBJECTIVE: We set the hypothesis that follow-up surveys of occupational asthma (OA) could now show better improvement in the asthmatic condition because of a more prolonged interval since removal from exposure than in previously reported studies. PATIENTS/METHODS: Ninety-nine subjects with OA were assessed and were separated into two groups according to the duration of cessation of exposure: (1) group removed for > or = 5 years: 48 subjects studied 8.9+/-2.2 years after cessation of exposure; (2) group removed for <5 years: 51 subjects with OA, comparable in terms of history and functional results at time of diagnosis, with a time lapse from last exposure of 3.1+/-1.2 years. On the follow-up visit, questionnaires including information on the current and previous use of inhaled steroids, spirometry, and methacholine tests were administered and results were compared with those obtained at the time of diagnosis. RESULTS: At the follow-up visit, no significant changes in spirometry were observed in the two groups. However, a significant improvement in provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) from a mean value of 1.5 to 3.7 mg/mL was documented (p<0.001). The proportion of subjects having normal PC20 at the follow-up visit was significantly higher in the group removed from exposure for >5 years than in the group removed for < or = 5 years (16/33 vs 8/42; p=0.01). Stepwise logistic regression showed that follow-up PC20 could be predicted from baseline PC20 (p<0.001, odds ratio [OR]=4.1, 95% confidence interval [CI]=1.8 to 9.1), duration of exposure (p=0.04, OR=0.9, 95% CI=0.8 to 1.0), the interval since removal from exposure (p=0.002, OR=1.7, 95% CI=1.2 to 2.5), and the type of agent; subjects with OA due to high-molecular-weight agent showed a less favorable outcome (p=0.04, OR=0.2, 95% CI=0.03 to 1.0). Current and past treatments with inhaled steroids were not significant predictors. CONCLUSION: Results obtained in the group of this study removed for >5 years show better prognostic figures than those reported in most previous studies. Comparison with the group removed for a shorter interval and the stepwise logistic regression analysis suggest that the longer duration of the interval from cessation of exposure appears to be a factor determining this difference.     

Is milk production impaired by dieting during lactation?

To determine the feasibility of a weight-loss program during lactation, 33 healthy, well-nourished, breast-feeding women were enrolled. Twenty-two women completed the 10-wk study, losing a mean (+/- SD) of 4.8 +/- 1.2 kg. Mean energy intake during the study was nearly 2.25 MJ (538 kcal) below the mean daily baseline intake of 9.64 +/- 2.48 MJ (2303 +/- 592 kcal). The sum of three maternal skinfold thickness, waist, and hip measurements were significantly smaller (P = 0.0001) at study completion. Mean daily milk production was 759 +/- 142 mL/d at baseline and 802 +/- 189 mL/d at week 10. The infants gained an average of 21 g/d, or 1.48 +/- 0.40 kg overall. The mean percent fat of milk at baseline and 10 wk was 4.06 +/- 2.15 and 4.00 +/- 2.56, respectively. The mean daily nitrogen content of milk at baseline and study completion was 1.82 +/- 0.32 and 1.62 +/- 27 g/L. These findings suggest that modest weight loss by healthy breast-feeding women does not adversely affect either quantity or quality of milk consumed by their infants.     

Recollection is impaired by the modification of interpretation bias.

The interpretation paradigm of cognitive-bias modification (CBM-I) was modified with instructions used in process-dissociation procedures for the purpose of investigating processes contributing to performance on the transfer task. In Experiment 1, nonanxious students were trained to interpret ambiguous situations in either a negative or benign way (or they read nonambiguous scenarios). They were then asked to respond to new ambiguous situations, in the same way as contextually similar analogues during training, or to respond differently. Benign training proactively impaired memory for negative outcomes. This effect was replicated by anxious students in Experiment 2 and discussed with respect to the assumptions underlying process-dissociation procedures and directions for future research. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Cardiac myofilament protein function is altered during sepsis

Male Sprague-Dawley rats (350-500 g) were made septic by intraperitoneal injection of 200 mg/kg cecal material in 5% dextrose in water (D5W; 5 ml/kg). Control rats (n = 11) received D5W. Preparations were studied on days 1 (n = 7), 3 (n = 7), and 7 (n = 8) of sepsis. In isolated hearts, ventricular function was depressed on days 3 and 7 of sepsis. Densitometric analysis of myofilament proteins from septic rats separated by SDS-PAGE showed no differences in relative amounts of actin, troponin, tropomyosin and myosin light chains compared to control. Myofilament function, assessed by measuring ATPase activities, was altered during sepsis. CA(2+)-independent Mg-ATPase activity was elevated on days 1 and 3 of sepsis, returning toward control by day 7. Maximal ATPase activity was unchanged on day 1, but was increased on days 3 and 7 sepsis. Myofibrillar myosin K(EDTA)-, Ca(2+)-, and Mg(2+)-ATPase activities were not altered, nor were there any apparent changes in myosin heavy chain isoform populations. Our data are the first to demonstrate alterations in minimal and maximal ATPase activities and myofilament CA(2+)-sensitivity during chronic peritoneal sepsis. These alterations may contribute to observed changes in ventricular function.     

Bait-shyness acquisition is impaired by VMH lesions that produce obesity.

Lesioned Carworth CFE female rats in the area of the ventromedial nucleus of the hypothalamus (VMH) before or after avoidance learning. Prelesioned Ss learned to avoid familiar saccharin-sweetened water associated with apomorphine less rapidly, and during extinction lost the avoidance more rapidly than controls. Ss lesioned after avoidance learning continued to avoid, and during extinction lost the avoidance at the same rate as controls. When given ad-lib food and water, lesioned Ss became obese. 1 tentative interpretation is that VMH-lesioned rats overrespond to environmental stimuli, including their food. This interferes with gustatory-visceral associations needed for satiety and bait-shyness acquisition. Another possibility is that overresponding to environmental stimuli and impaired gustatory-visceral associations are both direct consequences of VMH lesions. (32 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes

Cardiomyocytes suppress contraction and O2 consumption during hypoxia. Cytochrome oxidase undergoes a decrease in Vmax during hypoxia, which could alter mitochondrial redox and increase generation of reactive oxygen species (ROS). We therefore tested whether ROS generated by mitochondria act as second messengers in the signaling pathway linking the detection of O2 with the functional response. Contracting cardiomyocytes were superfused under controlled O2 conditions while fluorescence imaging of 2, 7-dichlorofluorescein (DCF) was used to assess ROS generation. Compared with normoxia (PO2 approximately 107 torr, 15% O2), graded increases in DCF fluorescence were seen during hypoxia, with responses at PO2 = 7 torr > 20 torr > 35 torr. The antioxidants 2-mercaptopropionyl glycine and 1,10-phenanthroline attenuated these increases and abolished the inhibition of contraction. Superfusion of normoxic cells with H2O2 (25 microM) for >60 min mimicked the effects of hypoxia by eliciting decreases in contraction that were reversible after washout of H2O2. To test the role of cytochrome oxidase, sodium azide (0.75-2 microM) was added during normoxia to reduce the Vmax of the enzyme. Azide produced graded increases in ROS signaling, accompanied by graded decreases in contraction that were reversible. These results demonstrate that mitochondria respond to graded hypoxia by increasing the generation of ROS and suggest that cytochrome oxidase may contribute to this O2 sensing.     

The onset of rocuronium, but not of vecuronium or mivacurium, is modified by tourniquet inflation

A previous investigation showed that inflation of a tourniquet did not interrupt onset of vecuronium neuromuscular block. To test the hypothesis that this effect depended on potency, twitch tension was measured in an arm with a tourniquet inflated during onset and compared with a control arm in 30 patients under fentanyl-thiopental-nitrous oxide-isoflurane anesthesia. Patients were randomly allocated to receive either vecuronium 0.1 mg/kg (n = 10), rocuronium 0.6 mg/kg (n = 10), or mivacurium 0.2 mg/kg (n = 10). The electromyographic response of the first dorsal interosseus to single twitch stimulation of the ulnar nerve every 10 s was recorded in both arms. When neuromuscular block was 20% (i.e., twitch tension was 80% of control), the tourniquet was inflated to a pressure of 300 mm Hg. It was deflated 5 min later. In the vecuronium and mivacurium groups, the tourniquet did not influence onset of block. In the rocuronium group, maximum neuromuscular block was (mean +/- SD) 79% +/- 10% in the tourniquet arm, compared with 96% +/- 4% in the perfused arm (P < 0.05). The maximum rate of onset was half that of the perfused arm. The difference in maximum neuromuscular block between arms was 17% +/- 7%, 5% +/- 5%, and 0% +/- 2% in the rocuronium, vecuronium, and mivacurium groups (P < 0.05). To explain that onset of block continues in spite of interruption of blood flow, drug molecules must gain access to the neuromuscular junction via routes other than the circulation. The results of this investigation are consistent with the hypothesis that there is redistribution of drug from extrajunctional to junctional areas during onset of action of muscle relaxants and this process is more important for the more potent drugs (vecuronium and mivacurium) than for rocuronium.     

Evidence that the slowing caused by acute hypoxia is modality dependent

BACKGROUND: AFM (Additive Factors Method) experiments conducted with visual stimuli suggest that the slowing produced by acute hypoxia is located at the earliest preprocessing stage of information processing and that later stages are unaffected (the bottleneck hypothesis). METHODS: To determine the contribution of degraded visual functioning to slowing, we bypassed this modality and measured reaction time in an AFM paradigm to auditory (Experiment 1) and kinesthetic (Experiment 2) stimuli. In both experiments hypoxia was induced with low oxygen mixtures and arterial blood oxygen saturation (SaO2) was controlled at 65%. Task difficulty was manipulated in Experiment 1 with tones that differed in intensity and in Experiment 2 with lifted cylinders that differed in weight. RESULTS: The results for Experiment 1 showed an interaction between task difficulty and hypoxia, indicating slowing of the preprocessing stage. Slowing was not found in Experiment 2. The absence of slowing in Experiment 2 is surprising and indicates that slowing may be confined to vision and audition and may not involve later, more central, stages. We discuss the need to measure cerebral oxygenation in order to understand the sharp differences between the the bottleneck hypothesis, developed by controlling SaO2, and the more traditional behavioral model which postulates multiple cognitive deficits.     

Excitatory amino acid receptors in the paraventricular hypothalamic nucleus mediate pressor response induced by carotid body chemoreceptor stimulation in rats

In urethane-anesthetized rats with spinal transection, antagonists of excitatory amino acid receptors, P2 purinoceptors and adrenoceptors were microinjected into the paraventricular hypothalamic nucleus (PVN) and their effects on the pressor response evoked by carotid body chemoreceptor stimulation were examined. Microinjections of the non-selective excitatory amino acid antagonist kynurenate, the non-NMDA receptor antagonist CNQX and the NMDA antagonist 2-amino-5-phosphonovalerate (AP5) into the PVN inhibited the chemoreceptor reflex-induced pressor response. The excitatory amino acid agonist L-glutamate injected into the PVN produced an increase in blood pressure. The P2 purinoceptor antagonist suramin did not affect the pressor response and ATP did not affect basal blood pressure. The alpha adrenoceptor antagonist phentolamine, prazosin and yohimbine also inhibited the chemoreceptor-induced pressor response, while the beta antagonist propranolol did not affect it. These findings indicate that excitatory amino acid receptors and alpha adrenoceptors in the PVN are involved in mediating the pressor response induced by carotid body chemoreceptor stimulation in rats.