bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of diet and duration of diabetes on hypermethioninemia in streptozotocin-diabetic rats
Authors: Dyer J. R. , Greenwood C. E. , McBurney M. I.
Published: April 2011

There are conflicting reports concerning the existence of severe hypermethioninemia in rats made diabetic with the pancreotoxin, streptozotocin. To determine whether this discrepancy is due to experimental differences in the severity of diabetes or the diet fed to the animals, streptozotocin-diabetic and control rats were fed either a casein-based semipurified diet or laboratory chow for 2 or 5 weeks. Plasma methionine concentrations were elevated six- to nine-fold after 2 weeks in the casein-fed diabetics compared with both their own controls and the chow-fed diabetics, respectively. Circulating methionine levels had declined sharply by 5 weeks in the casein-fed diabetics but were still more than twice those of the casein-fed control and chow-fed diabetic levels. Since methionine intakes were only 30% greater in the casein-fed diabetics than in the chow-fed diabetics, it is unlikely that this is the sole cause of the large differences in plasma methionine levels. The reason for the difference in circulating Met levels could not be explained on the basis of overall amino acid availability, since growth, nitrogen balance, and plasma large neutral amino acid profiles (excluding Met) were similar within control and diabetic groups fed the two diets.
Blood–brain barrier and atrial natriuretic factor
Authors: Chabrier P. E. , Roubert P. , Plas P. , Braquet P.
Published: April 2011

In brain, binding sites for atrial natriuretic factor (ANF) have been characterized in areas such as circumventricular organs that lack the tight capillary endothelial junctions of the blood–brain barrier and therefore are exposed to circulating peptides. Since atrial natriuretic factor acts directly on vascular endothelium and has been proposed to be actively involved in blood pressure regulation and fluid homeostasis, it is interesting to know whether ANF receptors exist on brain capillaries that constitute the blood–brain barrier and participate in the constant fluid exchange between blood and brain. The present paper reports recent evidence of the presence of ANF receptors located on the structure. It assesses the specific binding of 125I-labelled ANF on bovine brain microvessel preparations and its coupling with a guanylate cyclase system. The potential physiological role of ANF on brain microcirculation and blood–brain barrier functions is discussed.
Evoked secretion of [3H]noradrenaline and ATP from nerve varicosities isolated from the myenteric plexus of the guinea pig ileum
Authors: Hammond James R. , MacDonald Wenda F. , White Thomas D.
Published: April 2011

Neuronal varicosities, isolated from the myenteric plexus of guinea pig ileum longitudinal muscle, were incubated with [3H]noradrenaline to label the contents of the noradrenergic secretory vesicles. Exposure of these varicosities to KCl, nicotine, or acetylcholine resulted in the Ca2+-dependent release of [3H]noradrenaline. Veratridine also evoked a large efflux of [3H] from this preparation, but this release was only partially Ca2+ dependent. The α2-adrenoceptor agonist, clonidine, inhibited the K+-, nicotine-, and acetylcholine-induced release of [3H]noradrenaline. Similarly, exogenously administered (−)noradrenaline was an effective inhibitor of the K+-evoked release of [3H]noradrenaline. The α2-adrenoceptor antagonist, yohimbine, antagonized the inhibitory actions of both clonidine and (−)noradrenaline on the K+-evoked release of [3H]noradrenaline from myenteric varicosities. Nicotine, acetylcholine, KCl, and veratridine also released ATP from these guinea pig ileal myenteric varicosities. However, the evoked release of ATP was unaffected by clonidine. These results indicate that myenteric varicosities can take up and release [3H]noradrenaline and that they possess presynaptic α2-adrenoceptors which, when activated, inhibit the release of [3H]noradrenaline. These receptors may play a role in modulating the release of noradrenaline in the myenteric plexus in vivo. In addition, the present results suggest that ATP and [3H]noradrenaline may not be released from the same population of secretory vesicles in neuronal varicosities isolated from guinea pig ileum longitudinal muscle.
GABA responses in rat dentate granule neurons are mediated by chloride
Authors: Blaxter Timothy J. , Carlen Peter L.
Published: April 2011

The dendrites of granule cells in hippocampal slices responded to γ-aminobutyric acid (GABA) with a depolarization. The response was blocked by picrotoxin in a noncompetitive manner. Reductions in the extracellular chloride ion concentration changed the reversal potential of the response by an amount predicted from the Nernst equation for chloride ion. Chloride-dependent hyperpolarizing responses were sometimes also found in the cell body of the granule cells. Since the reversal potential followed that predicted from the Nernst equation for chloride, we conclude that the response was mediated by chloride ions alone with no contribution from other ions. This has not previously been shown for the depolarizing response to GABA in central neurons.
Bethanidine increases one type of potassium current and relaxes aortic muscle
Authors: Bkaily G. , Caillé J.-P. , Payet M. D. , Peyrow M. , Sauvé R. , Renaud Jean-François , Sperelakis Nick
Published: April 2011

Using a whole-cell voltage-clamp technique, we identified two time- and voltage-dependent K+ currents: an early outward rectifier and a delayed outward rectifier in single vascular smooth muscle cells of rabbit aorta in culture. About 90% of the single cells tested showed a predominant delayed outward K+ current type. Both K+ currents were decreased by tetraethylammonium. In contrast, bethanidine sulphate (10−4 M), a pharmacological analog of the cardiac antifibrillatory drug, bretylium tosylate, decreased the early outward K+ current, increased the delayed rectifier K+ current type, and hyperpolarized the resting membrane potential. Bethanidine was found to relax vascular smooth muscle. The vasodilatory effect of bethanidine is associated with the activation of a K+ current that is probably involved in keeping the membrane potential at the resting state, thereby depressing the excitability of the aortic vascular smooth muscle.
Depressing effects of calcium antagonists on oxygen consumption in isolated skeletal muscle during potassium depolarization
Authors: Barnes William S.
Published: April 2011

The effects of two Ca2+-antagonizing drugs, dantrolene sodium (DAN) and TMB-8, on subcontracture, K+-induced increased oxygen consumption were studied in isolated frog sartorius muscles. Incubation in Ringer's solution +18 mM KCl caused a marked increase in averaged resting oxygen uptake (52.8 ± 4.1 to 278.2 ± 20.0 mm3∙g−1∙h−1). Incubation in Ringer 's +18 mM KCl containing either 0.116 mM TMB-8 or 0.035 mM DAN resulted in a significant reduction in the averaged metabolic response (264.4 ± 30.8 (control) vs. 142.3 ± 19.0 (TMB-8) vs. 72.2 ± 3.4 (DAN)). The results suggest that the enhanced metabolic rate observed upon elevating extracellular [K+] to just below contracture levels is due to increased intracellular Ca2+ release.
Organ culture of rat heart: maintained high sensitivity of fetal atria before innervation to norepinephrine
Authors: Tanaka Hikaru , Kasuya Yutaka , Saito Hiroshi , Shigenobu Koki
Published: April 2011

Changes in sensitivity to norepinephrine (NE) of fetal and neonatal rat right atria placed in organ culture were examined. The high sensitivity to NE of the 17-day fetal atria was maintained during organ culture for 5 days. The pD2 value for NE at the 17th day of gestation was 8.66 ± 0.09, and that after organ culture for 5 days was 8.62 ± 0.09. The sensitivity of 1-day-old neonatal artia was significantly lower than that of fetal atria; but when they were cultured for 24 h, there was a 10-fold increase in sensitivity. The pD2 value before culture was 7.59 ± 0.05, and that after culture was 8.54 ± 0.04. NE added to the culture medium prevented this increase in sensitivity. Similar changes were observed in the sensitivity to isoproterenol, but not in the sensitivity to forskolin, indicating that these sensitivity changes were of a postjunctional nature and most likely due to some changes in the β-receptor and (or) its coupling to adenylate cyclase. Therefore, the decrease in myocardial sensitivity to NE observed during the late fetal period is most likely to be caused by factor(s) related to sympathetic innervation.
Vasorelaxant effects of and receptors for atrial natriuretic peptides in the mesenteric artery and aorta of the rat
Authors: St-Louis Jean , Schiffrin Ernesto L.
Published: April 2011

Vasorelaxant effects of different atrial natriuretic peptides (ANP) were measured on rat aortic strips and mesenteric artery rings. These results were compared with the potency of the same peptides to displace 125I-labelled ANP (101–126) on membrane preparations of aorta and of mesenteric vascular bed. In aortic strips and mesenteric artery rings precontracted with phenylephrine (3 × 10−8 and 10−6 M, respectively), the order of potency of ANP was as follows: ANP (99–126) > ANP (101–126) > ANP (103–126) = ANP(103–125) [Formula: see text] ANP (103–123). In the displacement binding assays, the order of potency of ANP peptides was similar to that of the relaxation experiments: ANP (99–126) = ANP (101–126) > ANP (103–126) = ANP (103–125) [Formula: see text] ANP (103–123). When the vessels were precontracted by a smaller concentration of phenylephrine (10−7 M in mesenteric artery and 10−8 M in aorta), the IC50 of ANP (101–126) was significantly lower than when the higher concentration of phenylephrine was used. These results show that ANP receptors in the mesenteric artery and in the aorta have similar structural requirements, according to the order of potency of different length ANP, both for binding and myotropic responses.
Adaptive cytoprotection by 0.25 M HCl is truly "cytoprotective" and may not depend upon elevated levels of prostaglandin synthesis
Authors: MacNaughton W. K. , Williamson T. E. , Morris G. P.
Published: April 2011

The ability of a mild irritant to reduce ethanol-induced damage to the rat gastric mucosa was investigated using an ex vivo gastric chamber preparation. Exposure to 0.25 M hydrochloric acid (HCl) did not cause significant damage to the surface epithelium, but did reduce both the lesion area and the extent of superficial epithelial damage caused by subsequent exposure to 40% ethanol (EtOH). "Adaptive cytoprotection" was also demonstrated by the reduction of ethanol-induced changes in transmural potential difference and net K+ efflux, and by rapid recovery of these physiological parameters following the removal of ethanol from the chamber. Pretreatment of rats with indomethacin at a dose that has been shown to significantly inhibit gastric cyclooxygenase activity did not significantly affect the ability of 0.25 M HCl to reduce the effects of ethanol on lesion area, epithelial damage, potential difference, and net K+ efflux.
Inhibition of cardiac slow action potentials by 8-bromo-cyclic GMP occurs independent of changes in cyclic AMP levels
Authors: Thakkar Jayanti , Tang Shu-Ben , Sperelakis Nicholas , Wahler Gordon M.
Published: April 2011

Cyclic GMP inhibits the slow inward Ca current of cardiac cells. This effect could be due to a cyclic GMP-mediated phosphorylation of the Ca channel (or some protein modifying Ca channel activity), or alternatively, to enhanced degradation of cyclic AMP owing to stimulation of a phosphodiesterase by cyclic GMP. To test the latter possibility, we examined the effect of extracellular 8-bromo-cyclic GMP on cyclic AMP levels in guinea pig papillary muscles, in parallel with electrophysiological experiments. Isoproterenol (10−6 M) significantly increased the cyclic AMP levels and induced Ca-dependent slow action potentials. Superfusion with 8-bromo-cyclic GMP (10−3 M) inhibited the slow action potentials induced by isoproterenol. However, muscles superfused with 8-bromo-cyclic GMP had cyclic AMP levels identical to those of muscles superfused with isoproterenol alone. Similarly, 8-bromo-cyclic GMP had no effect on the increase in cyclic AMP levels of muscles treated with forskolin (10−6 M) or histamine (10−6 M). We conclude that the inhibitory effect of cyclic GMP on slow Ca channels in guinea pig ventricular cells is not due to a decrease in the cyclic AMP levels. We hypothesize that a cyclic GMP-mediated phosphorylation is the most likely explanation for the Ca channel inhibition observed in this preparation.
A depolarizing inhibitory postsynaptic potential activated by synaptically released γ-aminobutyric acid under physiological conditions in rat hippocampal pyramidal cells
Authors: Perreault Paul , Avoli Massimo
Published: April 2011

We report that CA1 pyramidal neurons of the rat hippocampus respond to high intensity afferent stimulation by generating a late depolarizing potential that typically occurs between the early (fast) inhibitory postsynaptic potential (IPSP) and the late (slow) IPSP. This potential is reminiscent of the response seen after the application of 4-aminopyridine and can be blocked by bicuculline, indicating that GABAA receptors are involved in its generation.
Physiological factors in fetal lung growth
Authors: Kitterman Joseph A.
Published: April 2011

Adequate pulmonary function at birth depends upon a mature surfactant system and lungs of normal size. Surfactant is controlled primarily by hormonal factors, especially from the hypophysis, adrenal, and thyroid; but these have little influence on fetal lung growth. In contrast, current data indicate that lung growth is determined by the following physical factors that permit the lungs to express their inherent growth potential. (a) Adequate intrathoracic space: lesions that decrease intrathoracic space impede lung growth, apparently by physical compression. (b) Adequate amount of amniotic fluid: oligohydramnios retards lung growth, possibly by lung compression or by affecting fetal breathing movements or the volume of fluid within the potential airways and airspaces. (c) Fetal breathing movements of normal incidence and amplitude: fetal breathing movements stimulate lung growth, possibly by stretching the pulmonary tissue, and do not affect mean pulmonary blood flow but do induce small changes in phasic flow; these changes are probably too slight to influence lung growth. (d) Normal balance of volumes and pressures within the potential airways and airspaces: in the fetus, tracheal pressure > amniotic pressure > pleural pressure. This differential produces a distending pressure which may promote lung growth. Disturbing the normal pressure relationships alters the volume of fluid in the lungs and distorts lung growth, which is stimulated by distending the lungs and is impeded by decreasing lung fluid volume. The mechanisms by which these factors affect lung growth remain to be defined. Fetal lung growth also depends on at least a small amount of blood flow through the pulmonary arteries. Although a modest reduction in flow (to 85% of control) does not affect lung growth, total obstruction of the pulmonary artery impairs lung growth. Thus, bronchial blood flow alone is insufficient to supply the nutritional demands of the growing fetal lung.
The control of cardiovascular shunts in the fetal and perinatal period
Authors: Coceani F. , Olley P. M.
Published: April 2011

The fetal circulation has two major vascular shunts, the ductus arteriosus and the ductus venosus. The ductus arteriosus connects the pulmonary artery with the descending portion of the aortic arch, hence shunting most of the right ventricular output away from the unexpanded lungs. The ductus venosus connects instead the portal sinus with the inferior vena cava and allows well-oxygenated umbilical vein blood to bypass the liver and reach the central circulation rapidly. Both blood vessels cease their function after birth and undergo permanent closure. It is now well established that prenatal patency of the ductus arteriosus is an active state sustained by a prostaglandin. A similar mechanism has been recently recognized in the fetal ductus venosus. Evidence is presented indicating that prostaglandin E2 and prostaglandin I2 are natural relaxants, respectively, for the ductus arteriosus and the ductus venosus. In addition, both vascular shunts share the dependence on an endogenous cytochrome P-450 mechanism to develop their contractile tone. This mechanism may be important in the normal process of shunt closure at birth. While broadening the knowledge of fetal cardiovascular homeostasis, advances in this field have important implications for the prevention and management of certain pathological conditions affecting the newborn.
Influence of cholinergic and adrenergic blocking drugs on hyperglycemia and brain glycogenolysis in diazinon-treated animals
Authors: Husain K. , Ansari R. A.
Published: April 2011

Diazinon, an organophosphorous compound, produced hyperglycemia and reduced the glycogen content of the brain 2 h after its administration to rats (40 mg/kg, i.p.). The activities of the glycogenolytic enzymes, glycogen phosphorylase and phosphoglucomutase, were significantly increased, while that of glucose-6-phosphatase was not altered. Atropine (20 mg/kg, i.p.) given immediately after diazinon abolished the changes; tolazoline or propranolol (each at 10 mg/kg, i.p.) injected 30 min before the administration of diazinon significantly reduced the hyperglycemia and the increase in brain glycogenolysis. A combination of tolazoline and propranolol was more effective than either of them alone and completely abolished the hyperglycemia and the changes in brain glycogenolysis. It may be concluded that diazinon initially activates central cholinergic processes leading to hyperglycemia and increased cerebral glycogenolysis in animals.
Characterization of inhibitory innervation in porcine colonic circular muscle
Authors: Jager L. P. , Schaar M. W. G. Van Der
Published: April 2011

Effects of stimulation of intramural nerves in the circular smooth muscle layer of the porcine colon (Sus scrofa domestica) were studied using the sucrose-gap technique. Electrical field stimulation of the preparation, superfused with Krebs solution at 21 °C, induced a transient hyperpolarization of the smooth muscle cell membrane. This hyperpolarization was an inhibitory junction potential (IJP). The responses obtained from circular muscle originating from either the centripetal or centrifugal gyri of the ascending colon did not differ significantly. The UP was characterized as being mediated by intramural, nonadrenergic, noncholinergic (NANC) nerves. The amplitude and latency of the IJP changed linearly with temperature (15–25 °C: +1 mV and −0.1 s per degree Celsius, respectively) reflecting a temperature-dependent synchronization of transmitter release. The membrane resistance decreased during the IJP. The IJP amplitude decreased or increased during conditioning hyperpolarizations or depolarizations, respectively, and reversed at membrane potentials about 30 mV more negative than the resting membrane potential. Potassium conductance blocking agents, barium (1 mM), tetraethylammonium chloride (TEA, 20 mM), 4-aminopyridine (4-AP, 5 mM), apamin (1 μM), and aminacrine (10−4 M) added to the superfusion medium increased the membrane resistance. Only barium, TEA, and apamin depolarized the smooth muscle cell membrane. The IJP amplitude decreased in the presence of aminacrine and apamin to 75 and 35%, respectively, suggesting that apamin-sensitive Ca2+-activated K+ channels are involved in this response. ATP, adenosine, and related adenine nucleotides in concentrations up to 10−3 M did not mimic the IJP. Superfusion with ATP for 15 min revealed a gradually increasing attenuation by up to 20% of the IJP. This might suggest that the release of neurotransmitter from intramural NANC nerves is modulated presynaptically via purinoceptors. Exogenously applied vasoactive intestinal polypeptide (VIP) in concentrations of 10−9 to10−4 M did not affect the preparation. Also at elevated temperatures (up to 35 °C), VIP (10−7 to 10−4 M) did not cause measurable effects. It is concluded that the inhibitory mediator of the intramural NANC nerves present in the circular muscle layers of the porcine colon is neither a purine nor VIP.
Isolation from porcine intestinal extracts of a cholecystokinin-like peptide and a peptide with homology to cytochrome oxidase polypeptide VII and chymodenin
Authors: McIntosh C. H. S. , Dahl M. A. , Kwok Y. N. , Mutt V. , Spruston N. , Brown J. C.
Published: April 2011

A number of different forms of cholecystokinin (CCK) exist in the brain and intestine. Gel permeation and ion exchange chromatography and high performance liquid chromatography have been used to isolate a peptide from partially purified porcine intestinal extracts with N-terminal homology to porcine brain CCK-58. This peptide contracted both the guinea pig ileum longitudinal muscle and gallbladder muscle and these responses were inhibited by dibutyryl cyclic GMP or proglumide. The potency was approximately 1/100 of that of CCK-8. The reason for this low potency is unclear, but it is possible that a critical part of the biologically active region is modified or that it is a truncated form of CCK-58. A further peptide was isolated with a sequence homologous to cytochrome oxidase polypeptide VII and chymodenin.
Effect of rat cardionatrin I (rat ANF 99–126) on the response of toad skin to angiotensin II
Authors: Coviello Alfredo , Soria Marcelo O. , Proto Maria C. , Berman Dora M. , Gamundi Silvia S. , Alonso Claudia E. I. , de Bold Adolfo J.
Published: April 2011

The atrial natriuretic peptide cardionatrin I (cardionatrin I is ANF 99–126) was used in studies directed to assess its effects on osmotic water permeability (Posm) and short-circuit current (SCC) in isolated toad skin. Results showed that ANF 99–126 (10−7 M) added to the dermal side of the skin had no effect on basal Posm or SCC. However, ANF 99–126 (3.3 × 10−8 M) was able to produce a 50% reversible inhibition of the maximal Posm response to angiotensin II (AH) (3.2 × 10−8 M). These effects were seen when the skins were preincubated with ANF 99–126 for 10 min or less before the addition of AII Longer preincubation appeared to inactivate ANF 99–126 through proteolysis. ANF 99–126 (10−7 M) failed to inhibit the SCC response to AII (10−5 M) in toad skin. These results are compatible with a modulatory function for ANF on several systems including those involved in the regulation of extracellular fluid volume.Key words: atrial natriuretic factor, natriuretic peptides, epithelial transport.
Thermogenesis and the energetics of pregnancy and lactation
Authors: Trayhurn P.
Published: April 2011

Energy balance studies suggest that the overall efficiency of energy utilization does not increase during pregnancy in rodents, other than as a consequence of "hyperphagia." Diet-induced thermogenesis is not stimulated in response to the increased energy intake of the pregnant animal, the extra intake being retained at the maximum efficiency. Biochemical studies on brown adipose tissue, the main site of adaptive thermogenesis in rodents, are consistent with the energy balance data, at least in rats and mice. However, in hamsters (golden and Djungarian) some atrophy of the tissue is evident during pregnancy. In contrast to pregnancy, the thermogenic activity (mitochondrial GDP binding) and capacity (uncoupling protein content) of brown adipose tissue are substantially reduced during lactation in rats and mice. These changes result from a fall in sympathetic activity in the tissue in lactation. Sympathetic activity and thermogenic capacity are, however, fully restored following weaning of the pups. The functional atrophy of brown adipose tissue during lactation is linked to a substantial saving in maternal energy expenditure, reducing the energy requirements for milk production. The lactating–post-lactating animal provides an excellent example of a physiologically programmed reversible atrophy of brown adipose tissue.Key words: brown adipose tissue, thermogenesis, pregnancy, lactation, energetics.
Brown adipose tissue, liver, and diet-induced thermogenesis in cafeteria diet-fed rats
Authors: Ma Stephanie W. Y. , Foster David O.
Published: April 2011

Diet-induced thermogenesis (DIT) in young rats overeating a "cafeteria" (CAF) diet of palatable human foods is characterized by a chronic, propranolol-inhibitable elevation in resting metabolic rate [Formula: see text] and is associated with various changes in brown adipose tissue (BAT) that have been taken as evidence for BAT as the effector of DIT. But direct evidence for participation of BAT in DIT has been lacking. By employing a nonocclusive cannula to sample the venous effluent of interscapular BAT (IBAT) for analysis of its O2 content and measuring tissue blood flow with microspheres, we accomplished direct determination (Fick principle) of the O2 consumption of BAT in conscious CAF rats. In comparison with normophagic controls fed chow, the CAF rats exhibited a 43% increase in metabolizable energy intake, reduced food efficiency, a 22% elevation in resting [Formula: see text] at 28 °C (thermoneutrality) or 24 °C (housing temperature), and characteristic changes in the properties of their BAT (e.g., increased mass, protein content and mitochondrial GDP binding). They also exhibited the greater metabolic response to exogenous noradrenaline characteristic of CAF rats and the near elimination by propranolol of their elevation in [Formula: see text]. By the criterion of their elevated [Formula: see text], the CAF rats were exhibiting DIT at the time of the measurements of BAT blood flow and blood O2 levels. However, BAT O2 consumption was found to be no greater in the CAF rats than in the controls at either 28 or 24 °C. At 28 °C it accounted for less than 1% of whole body [Formula: see text]; at 24 °C it increased to about 10% of overall [Formula: see text] in both diet groups. Direct measurements of BAT O2 consumption during expression of the thermic response to a tube-fed meal were also made in conscious CAF and control rats. Both diet groups exhibited an approximately 15% increase in whole body [Formula: see text] at 90–120 min after the meal. The contribution by BAT to this increase was only 2–3% and did not differ significantly between groups. Thus, the results of these direct measurements of BAT O2 consumption in vivo do not support the theory that DIT in CAF rats is mainly due to increased BAT thermogenesis occurring either chronically or during assimilation of a meal. In further studies of the effector(s) of DIT in CAF rats, partial hepatectomy (two-thirds of the liver removed) was found to acutely reduce the resting [Formula: see text] of CAF rats by 1.85 mL/min, 2.3 times as much as in chow-fed controls. From this difference in response, it was estimated that in the CAF rats liver O2 consumption before hepatectomy exceeded that of the controls by about 1.5 mL/min, an amount that would be sufficient to fully account for the elevation in resting [Formula: see text] of the former. A major role for the liver in the DIT of CAF rats is thus suggested.Key words: cafeteria feeding, diet-induced thermogenesis, thermic effect of food, brown fat, liver.
Phospholipase A2 activation by melittin causes amylase release from exocrine pancreas
Authors: Heisler Seymour
Published: April 2011

Phospholipase A2-induced deacylation of membrane phospholipids is associated with changes in membrane fluidity. The importance of this reaction in the pancreatic amylase secretory process was tested using melittin, a phospholipase A2 stimulating peptide. Phospholipase A2 activity (using [3H]arachidonic acid release as an index) and amylase secretion were both increased in a time- and concentration-dependent manner by melittin. Phospholipids prelabelled with [3H]oleic acid or [14C]linoleic acid also released radioactive free fatty acids in response to melittin. Prostaglandin synthesis was not involved in the melittin response, since inhibitors of arachidonic acid oxidation (indomethacin, 5,8,11,14-eicosatetraynoic acid) did not alter the ability of melittin to release [3H]arachidonic acid or amylase. When melittin was co-applied with carbachol, cholecystokinin octapeptide, or vasoactive intestinal peptide, amylase secretion was additive. The effect of melittin on both fatty acid and amylase release was dependent on extracellular calcium, though melittin's effects were not dependent on the intracellular accumulation of second messengers such as calcium or cAMP. The data suggest that activation of phospholipase A2 by melittin results in the triggering of the secretory process in exocrine pancreas by a different mechanism than that for other pancreatic secretagogues.Key words: melittin, phospholipase A2, pancreatic acinar cells, amylase secretion.
L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor
Authors: Gillard J. , Ford-Hutchinson A. W. , Chan C. , Charleson S. , Denis D. , Foster A. , Fortin R. , Leger S. , McFarlane C. S. , Morton H. , Piechuta H. , Riendeau D. , Rouzer C. A. , Rokach J. , Young R. , MacIntyre D. E. , Peterson L. , Bach T. , Eiermann G. , Hopple S. , Humes J. , Hupe L. , Luell S. , Metzger J. , Meurer R. , Miller D. K. , Opas E. , Pacholok S.
Published: April 2011

L-663,536 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human polymorphonuclear leukocytes (PMN) (IC50, 2.5 nM). Similarly, L-663,536 inhibited A23187-induced LTB4 formation by rat peripheral blood and elicited PMN. At concentrations where inhibition of leukotriene biosynthesis occurred in human whole blood (1.1 μM), no effect was seen on cyclooxygenase or 12-lipoxygenase, an effect also observed in washed human platelets. The compound had no effect on rat or porcine 5-lipoxygenase indicating that L-663,536 is not a direct 5-lipoxygenase inhibitor. When administered in vivo L-663,536 was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED50, 0.036 mg/kg p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1 mg/kg p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED50, 0.2 mg/kg p.o.), an inflamed rat paw model (ED50, 0.8 mg/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea-pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED50, 2.5 mg/kg p.o. and 0.6 μg topically). The results indicate that L-663,536 is a potent inhibitor of leukotriene biosynthesis both in vitro and in vivo indicating that the compound is suitable for studying the role of leukotrienes in a variety of pathological situations.Key words: leukotriene, 5-lipoxygenase, polymorphonuclear leukocytes, leukotriene B4, leukotriene inhibitor.
Direct evidence that an increase in aortic norepinephrine level in response to insulin-induced hypoglycemia is due to increased adrenal norepinephrine output
Authors: Yamaguchi Nobuharu , Briand Richard , Brassard Martine
Published: April 2011

This study reports on the major source of circulating norepinephrine that is known to increase, progressively, during sustained hypoglycemia induced by intravenous insulin administration. Plasma concentrations of epinephrine, norepinephrine, and dopamine were simultaneously determined for adrenal venous and aortic blood in dogs anesthetized with sodium pentobarbital. The model used allowed us to perform a functional adrenalectomy (ADRX), while continuously monitoring the adrenal medullary secretory function. Under basal conditions, the net output (μg/min) of adrenal epinephrine, norepinephrine, and dopamine were 0.169 ± 0.074, 0.067 ± 0.023, and 0.011 ± 0.003, respectively. Plasma concentrations (ng/mL) of aortic epinephrine, norepinephrine, and dopamine were 0.132 ± 0.047, 0.268 ± 0.034, and 0.034 ± 0.009. Following insulin injection (0.15 IU/kg, i.v.), the net output (μg/min) of adrenal epinephrine, norepinephrine, and dopamine increased gradually (p < 0.05), reaching the values of 0.918 ± 0.200, 0.365 ± 0.058, and 0.034 ± 0.007 30 min after insulin administration. Similarly, aortic epinephrine, norepinephrine, and dopamine concentrations (ng/mL) increased significantly (p < 0.05) to 0.702 ± 0.144, 0.526 ± 0.093, and 0.066 ± 0.024. The aortic glucose concentration (mg/dL) was diminished from 81.8 ± 4.1 to 36.9 ± 3.4 (p < 0.01). After taking the blood sample at 30 min following insulin administration, ADRX was immediately performed. Five minutes after the onset of ADRX, the net output (μg/min) of adrenal epinephrine, norepinephrine, and dopamine increased further to 1.707 ± 0.374 (p < 0.05), 0.668 ± 0.139 (p < 0.05), and 0.052 ± 0.017. By contrast, aortic epinephrine, norepinephrine, and dopamine concentrations rapidly diminished (p < 0.05) to their initial control levels reaching 0.051 ± 0.014, 0.252 ± 0.023, and 0.031 ± 0.005 ng/mL, 5 min after ADRX. The present results indicate that during the early phase of insulin-induced hypoglycemia, circulating norepinephrine in aortic blood significantly increases due, primarily, to the enhanced adrenal norepinephrine output.Key words: insulin, plasma norepinephrine, adrenal catecholamines, functional adrenalectomy, hypoglycemia.
Immunopharmacology: A new frontier
Authors: Pope Barbara L.
Published: April 2011

Immunopharmacology is a hybrid science which has been founded upon the principles, theory, and technical developments of both immunology and pharmacology, but which has a unique identity incorporating both basic and applied areas of research. Basic immunopharmacological research is concerned with the underlying mechanisms by which endogenous and synthetic chemicals interact with the cells of the immune system. Important areas of research include the actions of chemicals such as lymphokines, cytokines, complement, kinins, autacoids, drugs, and even neuropeptides on immune function. Applied immunopharmacology is concerned with the development and testing of new immunomodulatory drugs which will be of benefit to clinical medicine but also as basic research tools. In the past, the two fields of immunology and pharmacology have contributed to each other in many significant ways. Immunology has contributed to pharmacological research by the development of antibodies which are frequently used today as specific probes for the quantitative and qualitative analysis of many different classes of chemicals of interest. Pharmacology has contributed to the field of immunology by providing basic pharmacological information on subjects such as the mediators of hypersensitivity reactions and inflammation. In the future, the truly hybrid field of immunopharmacology promises to have an expanding role in clinical medicine and basic research. This prediction is based on the observation that recombinant lymphokines and newly discovered immunomodulatory substances have begun to enter the clinic in ever increasing numbers. Future immunopharmacological research will include the study of the pharmacology of these lymphokines but also the rational development of new drugs that act as antagonists or agonists for the endogenous lymphokines that normally regulate the immune response. These studies will require scientists well versed in the fundamentals of both pharmacology and immunology. Our universities must be prepared to play their role in educating these individuals.Key words: immunopharmacology, immunomodulators.
Cardiac function in spontaneously diabetic BB rats treated with low and high dose insulin
Authors: Rodrigues Brian , McGrath Gail M. , McNeill John H.
Published: April 2011

Cardiac abnormalities observed in animals with drug-induced diabetes may be due to the direct cardiotoxic effect of the drugs or factors not related to the diabetic state. The purpose of this investigation was to examine cardiac sarcoplasmic reticular (SR) calcium transport and heart function in the BB rat, a strain in which diabetes occurs spontaneously and clearly resembles insulin-dependent diabetes in humans. Complete insulin withdrawal for 2 or 4 days from BB diabetic rats leads to a spectrum of metabolic derangements including a loss of body weight, hyperglycemia, and elevated triglyceride levels confirming the insulin dependence of this model. The present study involved treating BB diabetic rats with a low (hyperglycemic) and high (normoglycemic) insulin dose for 12 weeks after the detection of glycosuria. The hearts from these animals were then isolated, and SR Ca2+ transport and heart function (using isolated perfused working hearts) were examined and compared with BB nondiabetic littermates or Wistar controls. Strain-related differences were found in ATP-dependent SR Ca2+ transport between the Wistar and BB rats. There were, however, no significant diabetes-related differences in SR Ca2+ transport between the low dose insulin treated diabetic group (LD) and the high dose insulin treated diabetic group (HD) or the nondiabetic littermates. Plasma lipid concentrations of the LD and HD BB rats and nondiabetic littermates were also generally higher than those of control Wistar rats indicating strain-related but not diabetes-related differences. In addition, there were no differences in cardiac function between the LD and BB nondiabetic littermates or Wistar controls. These studies suggest that since persistent hyperglycemia in the LD BB rat produced no significant physiological abnormalities in the heart, other factors must be contributing to the depression of heart function noted during diabetes.Key words: diabetes, BB rat, sarcoplasmic reticular calcium transport, heart function.
Effect of chronic dietary treatment with L-tryptophan on the maintenance of hypertension in spontaneously hypertensive rats
Authors: Fregly Melvin J. , Sumners Colin , Cade J. Robert
Published: April 2011

Chronic dietary administration of L-tryptophan at 2.5 and 5.0% by weight reduced the elevated systolic blood pressure of spontaneously hypertensive (SH) rats. Blood pressure was reduced significantly by 3 weeks after initiation of treatment and continued to fall during the course of the 15 weeks of treatment. Body weights of the treated rats were not affected significantly by treatment, nor were daily food and fluid intakes and urine outputs. SH rats, treated with the higher dose of tryptophan, also significantly reduced their urinary outputs of epinephrine and norepinephrine compared with SH controls, while both doses of tryptophan increased urinary outputs of dopamine significantly above that of SH controls. Treatment with tryptophan increased significantly the specific binding of [125I]angiotensin II (Ang II) to membranes from the diencephalon in a dose-dependent manner. Measurement of catecholamine concentration of the supernatant from homogenates used for the Ang II binding assay revealed a significant correlation between the specific binding of Ang II to brain membranes of the two tryptophan-treated groups and the concentration of norepinephrine in the supernatant. There was also a significant correlation between the specific binding of Ang II and the concentratiion of dopamine in the supernatant of the control group and the group treated with the higher dose of tryptophan. These results show that chronic dietary administration of tryptophan can reduce the elevated blood pressure of SH rats and support the possibility that this neutral amino acid may act via its effect on the concentration of the neurohormones, norepinephrine and dopamine, in the diencephalon to regulate the binding of Ang II to its receptors.Key words: tryptophan, spontaneous hypertension, brain angiotensin binding, urinary catecholamines.
Platelet-activating factor: lack of direct action on guinea pig myocardium and possible transmitter release from cardiac sympathetic nerve endings at high concentrations
Authors: Shigenobu Koki , Mori Tatsuya , Kamata Katsuo , Kasuya Yutaka
Published: April 2011

Microelectrode and mechanical studies were performed with isolated guinea pig myocardium (right ventricular free walls and papillary muscles) to examine the effects of platelet-activating factor (PAF) and lysophosphatidylcholine (LPC). Low concentrations of PAF (10−8 to 10−6 M, a range equivalent to the blood concentrations that produce marked hypotension in vivo) had no effects on action potential configuration and contractile force. High concentrations (10−5 to 10−4 M) of PAF and LPC per se elicited slow response action potentials with concomitant contraction (restored contraction) in the myocardium depolarized with elevated K+ (25 mM); they also augmented slow responses and restored contractions produced by a low concentration of isoproterenol (10−8 M). Although these results suggested there was an increase in slow Ca current, the slow responses and restored contractions thus produced were greatly suppressed or abolished by the addition of a β-adrenoceptor blocking agent, sotalol (10−5 M), and by pretreatment with reserpine (5 mg/kg i.p., 24 h prior). In accordance with our previous conclusions, the present results suggest that direct cardiac action is not involved in the mechanisms of hypotension produced by PAF. It was also shown that high concentrations of PAF and LPC may act nonspecifically as amphiphilic compounds to induce transmitter release from sympathetic nerve endings, which may in turn augment the Ca current channels in the myocardial cell membrane.Key words: platelet-activating factor, cardiac action potential, slow response, Ca2+ channel, sympathetic nerve ending.
Effects of GABA, THIP, and potassium on excitability of myelinated axons of isolated amphibian spinal roots
Authors: Liske S. , Morris M. E.
Published: April 2011

The effects of direct applications of GABA (γ-aminobutyric acid) and the GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) on the excitability of myelinated axons of individual dorsal and ventral spinal roots (lumbar VI and (or) VII) of the isolated bullfrog peripheral nerve are reported. Increases evoked by the GABA agonists (0.01–10 mM) in the amplitude of half-maximal A-fiber compound action potentials indicate the presence of depolarizing responses with apparently greater localization to the dorsal roots, and a sensitivity to GABA twofold greater than that for THIP. The changes evoked by GABA and THIP, as well as potassium have components that closely resemble those of sensory and motor fibers in the more distal, desheathed nerve bundle but are smaller and delayed, differences attributable to a closely attached root sheath that acts as a diffusion barrier. These results confirm the likely existence of GABAA receptors on both dorsal and ventral spinal roots.Key words: GABAA receptors, dorsal root fibers, ventral root fibers, depolarization, hyperpolarization.
Nuclear magnetic resonance monitoring of sodium in biological tissues
Authors: Boulanger Yvan , Vinay Patrick
Published: April 2011

In recent years, the 23Na nuclear magnetic resonance (NMR) technique has been applied to the study of biological tissues. The advantages of this method are noninvasiveness and good sensitivity. The resonances of the intra- and extra-cellular sodium can be separated by the addition of shift reagents to the extracellular compartment. The method has been mostly applied to cell suspensions, kidney tubules, glands, and small organs. Owing to line-broadening effects, the NMR visibility of the intracellular sodium is reduced to 40% in most cases but can be lower or higher. Time-dependent measurements are possible with adequate life-supporting equipment, allowing the determination of transport parameters. 23Na relaxation times are short in tissues (below 50 ms) and highly dependent on the medium composition. The application of the 23Na NMR technique to intact organs can be hampered by the difficulty of getting a good distribution of the shift reagent in the extracellular milieu. A summary of the studies performed is presented with specific examples to illustrate typical applications.Key words: 23Na nuclear magnetic resonance, shift reagents, sodium quantitation, sodium transport, 23Na relaxation times.
Studies of the innervation of rabbit myometrium and cervix
Authors: Bulat R. , Kannan M. S. , Garfield R. E.
Published: April 2011

We characterized the innervation of isolated circular and longitudinal-oriented muscle strips from the nulliparous rabbit uterus and cervix by field stimulation (FS). FS with increasing frequency (2.5–50 pps) and voltage (2.5–70 V) caused graded increases in isometric contraction with no relaxation or inhibition of spontaneous activity. Tetrodotoxin(TTX, 3.1 × 10−6 M) significantly reduced the FS response by 75% in all strips at higher stimulus frequencies. Contractile responses to FS were also significantly inhibited by atropine (3.5 × 10−6 M) in circular uterus and in longitudinal cervix. Guanethidine (5 × 10−6 M) reduced the response in all strips, as did phentolamine (3.6 × 10−6 M) in longitudinal uterus and circular cervix. Propranolol (3.9 × 10−6 M) did not significantly change the response in longitudinal uterus or circular cervix. In longitudinal uterus, combined guanethidine and atropine produced significant inhibition, but not statistically different from either drug alone. Similar results were seen in circular uterus. Electron microscopy and glyoxylic acid histofluorescence indicate that both blood vessels and smooth muscle in rabbit uterus are supplied with adrenergic nerves. The results suggest the presence of TTX-sensitive adrenergic and cholinergic excitatory innervation of rabbit uterus and cervix.Key words: uterus, myometrium, cervix, adrenergic innervation.
Biochemistry of the lipoxygenase pathways in neutrophils
Authors: Borgeat Pierre
Published: April 2011

Three mammalian lipoxygenases have been reported to date. They catalyze the insertion of oxygen at positions 5, 12, and 15 of various 20-carbon polyunsaturated fatty acids. In the case of arachidonic acid, the immediate products are hydroperoxyeicosatetraenoic acids (HPETEs). HPETEs can undergo different transformations. One reaction is a reduction of the hydroperoxy group yielding the corresponding hydroxyeicosatetraenoic acids (HETEs). In the neutrophils, the major pathway of arachidonic acid metabolism is the 5-lipoxygenase. In these cells the 5-HPETE undergoes a cyclization reaction leading to a 5(6)-epoxy(oxido)eicosatetraenoic acid or leukotriene A4. The 5(6)-epoxy fatty acid can undergo three additional transformations: (a) a nonenzymatic hydrolysis to epimeric dihydroxyeicosatetraenoic acids (diHETEs); (b) stereospecific enzymatic hydrolysis to a specific diHETE, leukotriene B4; or (c) ring opening by reduced glutathione (GSH) to yield a peptidolipid, named leukotriene C4, in which GSH is attached via a sulfoether linkage. The leukotrienes constitute a group of biologically active substances probably involved in allergic and inflammatory reactions. The 5(6)-epoxy-eicosatetraenoic acid and the products derived from it contain a conjugated triene unit; the term leukotriene also denotes the cells (leukocytes) recognized to form these products, mainly the neutrophils, eosinophils, basophils, monocytes, mast cells, and macrophages. In the present article various aspects of the biochemistry of the lipoxygenase pathways of neutrophils are reviewed.Key words: arachidonic acid, leukotrienes, leukocytes, lipoxygenase, inflammation.