Effects of noradrenaline and nicotinic acid on plasma free fatty acids and oxygen consumption in cold-adapted rats.

A 3-h noradrenaline (NA) infusion (1.5 microgram kg-1 min-1) produced a sustained enhanced oxygen consumption (O2 cons.) in cold-adapted rats. Plasma free fatty acid (FFA) levels were elevated by NA in control and in cold-adapted rats, but to lesser extent in cold-adapted rats; the increase was maintained at a plateau in both groups during the entire period of NA infusion. A 1-h nicotinic acid (Nic A) infusion (1.5 mg kg-1 min-1) added to the NA infusion inhibited the calorigenic response to NA in cold-adapted rats and reduced the elevated plasma FFA concentration in control and in cold-adapted rats to values below basal levels. However, when the Nic A infusion was stopped, the O2 cons. was increased again in cold-adapted rats by the uninterrupted NA infusion, without the simultaneous increase of the plasma FFA concentration; the plasma FFA concentration was maintained in cold-adapted rats below basal values and merely brought back to basal levels in control rats. From these results, it is suggested that plasma FFA are not an essential substrate to the calorigenic response to NA observed in cold-adapted rats, as 85% of the response can occur when the plasma FFA concentration is very low.     

Lymphatic transport rate of noradrenaline during adrenergic thermogenesis

The lymphatic concentration of noradrenaline (NA) and lymph flow in the thoracic duct of cold-acclimated rats were measured under conditions of the quasi-stationary thermogenic response to i.v. infused NA. Both parameters increased linearly with increased rate of NA infusion. The lymphatic transport rate of NA is quadratically related to the infusion rate which indicates the same relation for the efflux of NA from blood into the extravascular space. This non-linear efflux of NA causes a non-linear thermogenic response to NA.     

Central angiotensin II receptors mediate hemodynamic response variability to stressors

We examined whether ANG II receptors in the central nervous system mediate hemodynamic responses to pharmacological (cocaine) and behavioral (cold water) stressors. After administration of cocaine (5 mg/kg iv), rats were classified as vascular responders (VR) if their pressor response was due entirely to an increase in systemic vascular resistance (SVR) despite a decrease in cardiac output (CO). Cocaine elicited a pressor response in mixed responders (MR) that was dependent on small increases in both SVR and CO. ANG II (30 ng/5 microl icv, 5 min before cocaine) augmented the decrease in CO in VR and prevented the increase in CO in MR. Administration of [Sar(1),Thr(8)]ANG II (20 microg/5 microl icv; sarthran) before cocaine attenuated the decrease in CO and the large increase in SVR in VR so that they were no longer different from MR. Losartan (20 microg icv) or captopril (50 microg icv) preceding cocaine administration also attenuated the decrease in CO and the large increase in SVR seen in VR only. The role of angiotensin was not specific for cocaine, because ANG II (icv) pretreatment before startle with cold water (1 cm deep) enhanced the decrease in CO and the increase in SVR in both MR and VR, whereas losartan (icv) pretreatment before startle attenuated the decrease in CO and the increase in SVR in VR so that they were no longer different from MR. These data suggest that central ANG II receptors mediate the greater vascular and cardiac responsiveness in vascular responders to acute pharmacological and behavioral stressors.     

Infusion of nicotinic acid stimulates leucine oxidation and inhibits protein synthesis in pigs before and during a meal

Leucine metabolism was measured isotopically in immature female pigs to assess the effect of acute infusions of nicotinic acid (NA) on leucine kinetics in both the fed and fasting states. After an overnight fast, immature pigs were infused with 3H-alpha-ketoisocaproate (KIC) and 14C-leucine. After a 2-hour equilibration period, an infusion of either saline or 0.4 mg/kg.min of NA was begun. NA caused a decrease in plasma glucose and an increase in plasma glucagon. During the fasting period, NA increased KIC oxidation 2-fold over controls. After feeding, plasma free fatty acids (FFA) in both groups were equivalent, but KIC oxidation was still approximately 80% higher in NA-infused animals. In addition, NA stimulated proteolysis and inhibited protein synthesis during the meal. Because plasma FFA concentrations were equal during the fed period, it is unlikely that changes in FFA concentrations are responsible for the changes in leucine metabolism observal during NA infusion.     

Responses of North American and New Zealand strains of Holstein-Friesian dairy cattle to homeostatic challenges during early and mid-lactation

This study investigated the physiological basis of differences in nutrient partitioning between the North American (NA) and New Zealand (NZ) strains of Holstein–Friesian cattle by determining the responses to homeostatic challenges at two stages of lactation. Glucose tolerance tests, epinephrine challenges and insulin challenges were carried out on consecutive days commencing on day 32 ± 0.48 (mean ± s.e.) of lactation (T1) and again commencing on day 137 ± 2.44 of lactation (T2). The insulin and non-esterified fatty acid (NEFA) responses to glucose infusion did not differ between the strains. The NZ strain had a greater clearance rate (CR) of glucose (2.04% v. 1.66%/min) and tended to have a shorter (34.4 v. 41.1 min) glucose half-life (t½) at T2 when infused with glucose. The NA cows had a greater glucose response to epinephrine infusion across T1 and T2, and tended to have a greater insulin response to epinephrine infusion. Plasma NEFA concentration declined to similar nadir concentrations for both strains at T1 in response to insulin, though from a higher basal concentration in NA cows, resulting in a greater (−2.29 v. −1.38) NEFA area under the response curve for NA cows. Glucose response to insulin varied with time, tending to be greater for NA at T1, but tending to be lower for NA at T2. The results indicated that NA cows had a greater glycogenolytic response to epinephrine, but both strains had similar lipolytic responses. The results also imply that higher basal circulating NEFA concentrations in the NA strain in early lactation were not due to diminished adipose tissue responsiveness to insulin. There were indications that glucose CR was greater in NZ cows in mid-lactation, and may form the basis of increased body tissue accretion during mid- to late-lactation in this strain.     

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipid-lowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (>60%, P < 0.01), and this effect was maintained for ≥5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P < 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment.     

Concurrent modulation of extracellular levels of noradrenaline and cAMP during stress and by anxiogenic- or anxiolytic-like neuropeptides in the prefrontal cortex of awake rats

The purpose of this study was to examine the effects of stress and the role of locally infused anxiogenic-like neuropeptides galanin, CCK-8, vasopressin, substance P and neurokinin A, and anxiolytic-like peptides NPY, nociceptin/orphanin FQ, somatostatin and neurotensin, on modulation of noradrenaline (NA) and cAMP efflux monitored simultaneously by microdialysis in the medial prefronatal cortex of awake rats. Concentrations of cAMP were determined by a newly developed method based on derivatization of cAMP with 2-chloroacetaldehyde followed by HPLC with fluorescence detection. Local infusion of forskolin (10 and 30 μM) dose-dependently increased the cAMP levels to 417% and 1050% of the control group, respectively. Similarly, local infusion of NA (10 μM) increased the cAMP to the peak level of 168%. A 5-min tail pinch and a 10-min swim stress rapidly increased the NA and cAMP levels to 167% and 203% (NA) and 141% and 161% (cAMP), respectively. Infusion of galanin and CCK-8 (0.5 nmol, and 1.5 nmol/0.5 μl) dose-dependently increased NA to the peak levels of 191% and 179% and cAMP levels to 174% and 166%, respectively. The peak levels following infusions of vasopressin, substance P and neurokinin A were 91%, 135% and 86% for NA and 131%, 83% and 76% for cAMP, respectively. Infusions of anxiolytic-like peptides at highest concentrations significantly increased (NPY, 136%) or decreased (nociceptin, 71%; somatostatin, 86%) the NA levels, whereas neurotensin had no effect. The cAMP levels decreased to 86% (NPY, neurotensin), 78% (nociceptin), somatostatin infusion was without effect. The present findings confirmed a close correlation between the stress-induced increases in prefrontal cortical NA and cAMP levels, as well as, concurrent changes in NA and cAMP levels following infusions of galanin and CCK-8 (increased levels) and nociceptin/orphanin FQ (decreased levels). Infusions of other neuropeptides showed a more complex pattern of NA and cAMP responses.     

Role of prostaglandin E2 in basal and noradrenaline-induced progesterone secretion by the bovine corpus luteum

The role of prostaglandin E2 (PGE2) in basal and noradrenaline (NA)-stimulated utilization of high density lipoprotein (HDL) as a source of cholesterol for progesterone synthesis was examined. In Experiment 1, a cannula was inserted into the aorta abdominalis through the coccygeal artery (cranial to the origin of the ovarian artery) in mature heifers, to facilitate infusion of NA (4 mg/30 min; n = 3) on day 10 of the estrous cycle. Three other heifers were similarly cannulated to serve as control. Before, during, and after NA or saline infusion, blood samples from the vena cava were collected every 5-15 min for analysis of PGE2, progesterone, and cholesterol. Each NA infusion stimulated (P < 0.01) secretion of both hormones in heifers. Short-duration increases (P < 0.05) in progesterone were observed due to the infusion of NA while cholesterol was not altered significantly. In addition, increases in PGE2 concentrations (P < 0.05) compared to controls were seen after NA infusion. Therefore, we used an in vitro model to verify the effect of PGE2 on HDL utilization by luteal cells from day 5 to 10 of the estrous cycle. In the preliminary experiment, 10(-6) M of PGE2 out of four different doses examined was selected for further studies, since it evoked the highest release of progesterone. In the next experiment, it was found that HDL increases progesterone secretion by luteal cells and both PGE2 and LH increased (P < 0.05) the response to HDL while NA did not. In the last in vitro experiment, progesterone stimulated PGE2 secretion by luteal cells. In conclusion, PGE2 may be directly involved in the utilization of cholesterol from HDL for progesterone synthesis. Furthermore, PGE2 may influence NA-stimulated progesterone secretion by the corpus luteum (CL). It is concluded that there is a positive feedback loop between progesterone and luteal PGE2 during days 5-10 of the estrous cycle.     

Nutrient availability and atmospheric CO2 partial pressure modulate the effects of nutrient heterogeneity on the size structure of populations in grassland species

BACKGROUND AND AIMS: Size-asymmetric competition occurs when larger plants have a disproportionate advantage in competition with smaller plants. It has been hypothesized that nutrient heterogeneity may promote it. Experiments testing this hypothesis are inconclusive, and in most cases have evaluated the effects of nutrient heterogeneity separately from other environmental factors. The aim of this study was to test, using populations of Lolium perenne, Plantago lanceolata and Holcus lanatus, two hypotheses: (a) nutrient heterogeneity promotes size-asymmetric competition; and (b) nutrient heterogeneity interacts with both atmospheric CO2 partial pressure (P(CO2)) and nutrient availability to determine the magnitude of this response. METHODS: Microcosms consisting of monocultures of the three species were grown for 90 d in a factorial experiment with the following treatments: P(CO2) (37.5 and 70 Pa) and nutrient availability (NA; 40 and 120 mg of N added as organic material) combined with different spatial distribution of the organic material (NH; homogeneous and heterogeneous). Differences in the size of individual plants within populations (size inequality) were quantified using the coefficient of variation of individual above-ground biomass and the combined biomass of the two largest individuals in each microcosm. Increases in size inequality were associated with size-asymmetric competition. KEY RESULTS: Size inequality increased when the nutrients were heterogeneously supplied in the three species. The effects of NH on this response were more pronounced under high nutrient supply in both Plantago and Holcus (significant NA x NH interactions) and under elevated P(CO2) in Plantago (significant P(CO2) x NA x NH interaction). No significant two- and three-way interactions were found for Lolium. CONCLUSIONS: Our first hypothesis was supported by our results, as nutrient heterogeneity promoted size-asymmetric competition in the three species evaluated. Nutrient supply and P(CO2) modified the magnitude of this effect in Plantago and Holcus, but not in Lolium. Thus, our second hypothesis was partially supported.     

Angiotensin and NMDA receptors in the median preoptic nucleus mediate hemodynamic response patterns to stress

The brain renin-angiotensin system plays an important role in the regulation of arterial pressure in response to stress, in part due to activation of AT1 receptors in the hypothalamic median preoptic nucleus (MnPO) by endogenous angiotensin II (ANG II). N-methyl-d-aspartate (NMDA) receptors are also involved in the angiotensinergic signaling pathway through the MnPO. We investigated whether AT1 and NMDA receptors in the MnPO are responsible for variable hemodynamic response patterns to stress. Cocaine or startle with cold water evoked a pressor response in Sprague-Dawley rats due, in some rats [vascular responders (VR)], to a large increase in systemic vascular resistance (SVR) and, in other rats [mixed responders (MR)], to small increases in SVR and cardiac output (CO). Microinjection of the GABAA agonist muscimol into the MnPO to block synaptic transmission attenuated the cocaine- or stress-induced increase in SVR and the decrease in CO seen in VR without altering either response in MR. Likewise, administration of either an AT1 receptor antagonist, losartan, or an NMDA receptor antagonist, MK-801, attenuated the increase in SVR and the decrease in CO in VR in response to either cocaine (losartan and MK-801) or startle with cold water (losartan) without altering either response in MR. We propose that the MnPO is responsible for greater SVR responses in VR and that AT1 and NMDA receptors play an important role in greater SVR responses in VR. These data provide additional support for the critical role of the MnPO in cardiovascular responses to stress.     

Effects of dopamine on spontaneous activity generated by isolated spinal cord in 16- to 20-day-old chick embryos

The effects were investigated of applying L-DOPA, dopamine (DA), and noradrenaline (NA) on spontaneous activity (cyclic fluctuations in electrotonic dorsal and ventral root (DR and VR) potentials generated by a section of spinal cord isolated from 16 to 20-day-old chick embryos. A low concentration of L-DOPA (30–150 µm) intensified operation of the spinal generator, giving rise to above-threshold rhythm (i.e., spike activity in the DR and the VR). At a high concentration, L-DOPA produced inhibition of generator operation, although spontaneous activity did intensify during subsequent washout of the substance, with the onset of above-threshold rhythm. Both DA and NA failed to affect spontaneous activity in the VR and the DR at a concentration to 50 µM but a concentration of 100 µM produced inhibition. Application of 20 µM 2-amino-5-phosphonovaleric acid blocked the reinforced spontaneous activity produced by low L-DOPA concentrations. Activity generated by the neuronal network of the isolated dorsal horn rose under the effects of low L-DOPA concentrations; rhythmic activity was observed neither before nor after applying this substance in isolated ventral horn. Findings obtained would point to the occurrence of a direct (i.e., non-catecholamine dependent) excitatory influence of L-DOPA on the neuronal network of the chick embryo dorsal horn.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 23, No. 3, pp. 338–343, May–June, 1991.     

Increased cerebral uptake and oxidation of exogenous betaHB improves ATP following traumatic brain injury in adult rats

There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate beta-hydroxybutyrate (betaHB). Arterio-venous differences were used to determine global cerebral uptake of betaHB and production of 14CO2 from [14C]3-betaHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available betaHB showed no significant increase in cerebral uptake of betaHB or 14CO2 production. Increasing arterial betaHB concentrations 2.9-fold with 3 h of betaHB infusion failed to increase cerebral uptake of betaHB or 14CO2 production in adult sham animals. Only CCI animals that received a 3-h betaHB infusion showed an 8.5-fold increase in cerebral uptake of betaHB and greater than 10.7-fold increase in 14CO2 production relative to sham betaHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of betaHB infusion beginning immediately after CCI injury.     

Diel interactions of oxygenic photosynthesis and n(2) fixation (acetylene reduction) in a marine microbial mat community

Diel variations in N(2) fixation (acetylene reduction), CO(2) fixation, and oxygen concentrations were measured, on three separate occasions, in a marine microbial mat located on Shackleford Banks, North Carolina. Nitrogenase activity (NA) was found to be inversely correlated with CO(2) fixation and, in two of the three diel periods studied, was higher at night than during the day. Oxygen concentrations within the top 3 mm of the mat ranged from 0 to 400 muM on a diel cycle; anaerobic conditions generally persisted below 4 mm. NA in the mat was profoundly affected by naturally occurring oxygen concentrations. Experimentally elevated oxygen concentrations resulted in a significant depression of NA, whereas the addition of the Photosystem II inhibitor 3(3,4-dichlorophenyl)-1,1-dimethylurea decreased oxygen concentrations within the mat and resulted in a significant short-term enhancement of NA. Mat N(2)-fixing microorganisms include cyanobacteria and heterotrophic, photoautotrophic, and chemolithotrophic eubacteria. Measured (whole-mat) NA is probably due to a combination of the NA of each of these groups of organisms. The relative contributions of each group to whole-mat NA probably varied during diel and seasonal (successional) cycles. Reduced compounds derived from photosynthetic CO(2) fixation appeared to be an important source of energy for NA during the day, whereas heterotrophic or chemolithotrophic utilization of reduced compounds appeared to be an important source of energy for NA at night, under reduced ambient oxygen concentrations. Previous estimates of N(2) fixation calculated on the basis of daytime measurements may have seriously underestimated diel and seasonal nitrogen inputs in mat systems.     

Photosynthetic Responses to Light Intensity in Intact Leaves of Some Coastal Desert and Tropical Rain Forest Plant Species in Atmospheres with Different CO2 Concentrations

The photosynthetic responses to light (A/light response) at different CO2 concentration levels were studied in five coastal desert plant species (two C4 species and three C3 species) and five tropical rain forest plant species (all C3' s) using LI-6400 Portable Photosynthesis System. The measurements were carried out in the Coastal Desert and Tropical Rain Forest mesocosms of Biosphere 2 located in Oracle, Arizona, USA. All the species measured had been growing in Biosphere 2 under very high CO2 concentrations (1500～4000 μmol · mol-1) for about four and half years. The authors measured A/light response curves in intact leaves of different species under a series of CO2 concentrations, 350 to 1500 μmol ~ mol-1. Except for the C4 grass, Panicurn maximum, the initial slopes and convexity (0) of A/light curves of all the species increased with the elevation of CO2 concentration. For most C3 species the light compensation points (LCP) and light saturation points (LSP) had increased when CO2 concentrations were elevated, especialy the LSPs. But for the C4 species, changes in LCPs and LSPs were small. In all the C3 species and the C4 shrub, Atriplesc canescens, the apparent maximum quantum yield of CO2 fixation (Φm, app) and maximum assimilation rate (Amax) increased under elevated CO2. But both Φmapp and Amax in Panicum maximum (C4) decreased. The Amax in Biosphere 2 increased by 127 % when CO2 concentration was doubled (from 375 to 750 μmol · mol-1), and C4 species by 39%. Such great enhancement could possibly be due to the fact that the plants had developed under very high CO2 concentration and large growth rooms in Biosphere 2.     

Proteome analysis of Thermococcus onnurineus NA1 reveals the expression of hydrogen gene cluster under carboxydotrophic growth

Thermococcus onnurineus NA1 is a typical sulfur-reducing hyperthermophilic archaeon. Genome sequence analysis has shown that T. onnurineus NA1 retains the metabolic pathways necessary not only for organotrophic, but also for carboxydotrophic, growth. T. onnurineus NA1 carboxydotrophic growth may result in hydrogen production, as this archaeon produces hydrogen during oxidizing formate. In this study, we profiled the proteome of T. onnurineus NA1 cultured under carboxydotrophic conditions using CO as an electron donor by the SDS-PAGE/LC-MS/MS method. A total of 1395 proteins were identified by two independent proteomic analyses, which corresponds to ~71% of the total predicted open reading frames. To our knowledge, this level of identification coverage exceeds those of other global proteome profiling studies in Archaea. Furthermore, the biological functions of the identified proteins were predicted and cognate enzymes were mapped to the appropriate metabolic pathways. More than 90% of the genes belonging to hydrogenase gene clusters such as Mbx, Sulf-I, Mbh, Hyg4-I, Hyg4-II, and Hyf4-III were expressed during CO culture. This means that hydrogenases induced under carboxydotrophic conditions surpass those induced under an organotrophic condition (yeast extract-peptone-sulfur). Our data suggest that hydrogen production is caused by the expression and functional assembly of T. onnurineus NA1 hydrogenase genes during culture in the presence of CO.     

Correlation between endogenous noradrenaline and glucose released from the liver upon hepatic sympathetic nerve stimulation in anesthetized dogs

The metabolic role of neurally released noradrenaline (NA) was studied in the liver of anesthetized dogs. Sustained stimulation with various frequencies was directly applied on the anterior plexus of hepatic nerves. Stimulation-induced changes in plasma concentrations of endogenous catecholamines in hepatic venous blood were determined in correlation with concomitant changes in those of glucose (GL). Mean basal values for hepatic venous NA, adrenaline, dopamine, and GL were 0.062, 0.022, 0.032 ng/mL, and 97.9 mg%, respectively. Among these catecholamines, NA was the only one being released significantly during stimulation. While hepatic venous NA increased rapidly during stimulation, being maximum within 3 min, hepatic venous GL increased gradually, reaching a maximum value 5 min after the onset of stimulation. A highly significant correlation (r = 0.90, P less than 0.001) was found between changes in hepatic venous NA and GL concentrations observed during stimulation at various frequencies (2-16 Hz). However, hepatic vasoconstricting responses to stimulation were not correlated with increased hepatic venous GL. An alpha-blockade with phentolamine (2 mg/kg, iv) resulted in diminished release of GL by approximately 50% (P less than 0.05) and reduced hepatic arterial vasoconstriction by approximately 47% (P less than 0.01) upon stimulation (8 Hz, 5 min), even though NA release was markedly enhanced. We conclude that in the dog, NA is the sole catecholamine released within the liver in response to direct hepatic nerve stimulation, and NA thus released mediates the hepatic glycogenolysis via alpha-adrenoceptors.     

Sensitivity to endotoxin in rabbits is increased after hemorrhagic shock.

The immunoinflammatory response following trauma and hemorrhage may predispose to the development of sepsis and multiple-organ failure syndrome. Cardiac output (CO), arterial pressure, arterial PO2, and pulmonary permeability index were measured. We examined the sensitivity of rabbits to infusions of lipopolysaccharide (LPS) after hemorrhagic shock. Shock was produced by reducing CO to 40% of baseline for 90 min, followed by resuscitation with shed blood and then with lactated Ringer solution to maintain CO near baseline. Animals were assigned to three groups: 1) hemorrhagic shock only, 2) LPS only, and 3) hemorrhagic shock + LPS. Groups 1 and 3 were subjected to hemorrhagic shock on day 1. Escherichia coli LPS was infused (1.0 microgram/kg i.v.) into groups 2 and 3 on day 2. Fluid resuscitation with lactated Ringer solution was continued in an effort to maintain CO at baseline. Five hours after LPS infusion, 125I-albumin was injected intravenously, and rabbits were killed 1 h later for measurement of pulmonary permeability index. LPS infusion after shock (group 3) caused significant decreases in CO, arterial pressure, and PO2 and an increase in pulmonary permeability. These changes were not seen in the groups 1 and 2. We conclude that hemorrhagic shock and resuscitation result in a proinflammatory state, leading to increased sensitivity to subsequent exposure to LPS.     

Clonidine Prevents Transient Loss of Noradrenaline in Response to Cholinergic Hypofunction Induced by Ethylcholine Aziridinium (AF64A)

Intracerebroventricular injection of ethylcholine aziridinium (AF64A) (2 nmol/ventricle) induced a considerable decrease in the level of acetylcholine (ACh) in hippocampus (from 21.14 +/- 0.84 to 10.04 +/- 0.59 pmol/mg of tissue; p less than 0.001) 4 days after application. The reduction of cholinergic function was accompanied by a decrease in the level of noradrenaline (NA) (from 1.96 +/- 0.08 to 1.41 +/- 0.06 pmol/mg of tissue; p less than 0.001). Two days after administration of AF64A (1 or 2 nmol/ventricle), the dose-dependent decrease in NA level was associated with an increase in the level of its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), resulting in a considerable increase in the MHPG/NA molar ratio (from 0.84 +/- 0.06 to 1.62 +/- 0.17; p less than 0.002). Chronic treatment of AF64A-injected rats with clonidine (0.02-0.2 mg/kg, i.p., every 8-12 h) had no significant effect on the loss of ACh content, whereas the decrease in NA content in hippocampus was completely prevented. Clonidine induced aggressive behavior in the AF64A-treated rats, in contrast to sedation in vehicle-injected rats. The response to clonidine under these experimental conditions and the increased MHPG/NA molar ratio in response to AF64A suggest that the transient loss of NA content following AF64A administration results from increased NA release. The increased noradrenergic activity in hippocampus may be linked to the reduction of tonic inhibitory cholinergic input. These results are discussed in relation to possible implications for senile dementia of the Alzheimer type.     

Respiratory responses to intravenous and intrapulmonary CO2 in awake dogs

Ventilatory responses to CO2 inhalation and CO2 infusion were compared in the awake dog. The CO2 was introduced directly into the systemic venous blood via a membrane gas exchanger in a femoral arteriovenous shunt circuit, and the extracorporeal blood flow, QX, was maintained constant at one of two rates: low, 0.5 l/min; or high, 2.0 l/min. A total of 13 experiments was performed in four dogs comprising 50 control and 25 inhalation and infusion observations at each of the two flow rates. Comparison of CO2-response curve slopes, S = delta V E/delta PaCO2, between CO2 inhalation and infusion showed no significant difference either within or between flow rates. The mean value of S for all conditions was 1.88 l/min per Torr with a 95% confidence interval of 1.66 -2.14. An independent additive ventilatory drive amounting to 28% of low-flow control VE was found at the highflow rate. We conclude that at constant blood flow the responses to both CO2 inhalation and infusion are hypercapnic and not significantly different.     

Vectorcardiography analysis of the repolarization response to pharmacologically induced autonomic nervous system modulation in healthy subjects

Autonomic nervous system activity is essential for regulation of ventricular repolarization (VR) and plays an important role in several arrhythmogenic conditions. This study in 31 healthy adult subjects (16 men, 15 women) evaluated the VR response to pharmacologically modulated autonomic nervous system activity applying vectorcardiography (VCG) analysis. During continuous VCG recording, 0.01-0.1 μg·kg(-1)·min(-1) isoprenaline (Iso) was infused at an increasing flow rate until three targeted heart rates (HR) were reached. After Iso washout, one intravenous bolus of 0.04 mg/kg atropine was given followed by an intravenous bolus of 0.2 mg/kg propranolol. A 5-min steady-state VCG recording was analyzed for each of the seven phases (including baseline 1 and 2). Furthermore, during the first 4 min following atropine, six periods of 10-s VCG were selected for subanalysis to evaluate the time course of change. The analysis included QRS, QT, and T-peak to T-end intervals, measures of the QRS and T vectors and their relation, as well as T-loop morphology parameters. By increasing HR, Iso infusion decreased HR dependent parameters reflecting total heterogeneity of VR (T area) and action potential morphology (ventricular gradient). In contrast, Iso prolonged QT HR corrected according to Bazett and increased the T-peak to T-end-to-QT ratio to levels observed in arrhythmogenic conditions. HR acceleration after atropine was accompanied by a transient paradoxical QT prolongation and delayed HR adaptation of T area and ventricular gradient. In addition to the expected HR adaptation, the VR response to β-adrenoceptor stimulation with Iso and to muscarinic receptor blockade with atropine thus included alterations previously observed in congenital and acquired long QT syndromes, demonstrating substantial overlap between physiological and pathophysiological electrophysiology.