bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature and histamine receptor function—what is really happening?
Authors: Cook D. A. , Krueger C. A. , Michalchuk A.
Published: April 2011

Early studies suggested that at low temperatures there was a transition of receptor type from an H1 to an H2 receptor when the temperature was reduced from 37 °C to temperatures below 20 °C. These original observations were based on the development of sensitivity of guinea-pig ileum to the H2 antagonist metiamide as the temperature was reduced. More recently, evidence from a number of laboratories has cast doubt on the existence of a simple H1–H2 receptor transition, but there is abundant evidence that there are major changes in the response of a variety of smooth muscle preparations to histamine at reduced temperatures. The evidence in regard to alterations in histamine response at low temperatures is reviewed, some new evidence presented, and a model which is consistent with most of the observations is suggested.
Mechanisms of action of sodium cromoglycate
Authors: Biggs D. F. , Goel V.
Published: April 2011

The effects of sodium cromoglycate (SCG) on cardiovascular and pulmonary responses to phenylbiguanide, capsaicin, and vagal stimulation were studied in anesthetized guinea pigs. Phenylbiguanide had no bronchospastic activity but induced reflex changes in arterial blood pressure which were reduced or abolished by SCG. Capsaicin induced nonreflex bronchospasm, and decreases in arterial blood pressure that were unaffected by SCG. Sodium cromoglycate, given before or after atropine, had no effect on the bronchospasm and cardiovascular responses to unilateral or bilateral stimulation of the vagus nerves. We conclude that SCG may influence both the afferent and efferent pathways of responses to drugs.
On the metabolism of amygdalin. 1. The LD50 and biochemical changes in rats
Authors: Adewusi S. R. A. , Oke O. L.
Published: April 2011

The mean lethal dose (LD50) of amygdalin in rats was found to be 880 mg/kg body weight (BW) by oral administration. However, when 600 mg/kg BW was administered orally with β-glucosidase, all the rats died. Total and Mg ATPase activities of the heart decreased with increasing levels of administered amygdalin. When 200 mg/kg BW amygdalin was administered 2.3 mg (11.7% of the dose) was excreted intact over 48 h. Amygdalin, 7.4 mg (18.5% of the dose) was excreted when the dose was 400 mg/kg BW, while 7.5 mg (12.4% of the dose) was excreted as intact amygdalin when the dosage was increased to 600 mg/kg BW. Thiocyanate excreted within the same 48-h period was 7.0, 9.1, and 9.5 μmol representing 18, 11.2, and 7.8% of the 200, 400, and 600 mg/kg BW oral dosage, respectively. With 300 mg/kg BW amygdalin administered intraperitoneally, 4.1 mg amygdalin and 3.9 μmol thiocyanate representing 13.7 and 6.5% of the dose, respectively, was excreted. Excretion of intact amygdalin and thiocyanate was uniform when the dose was low (200 mg), but with higher doses over 70% of the excreted products were detected in the urine during the first 24 h.
The in vitro effect of corticosterone on insulin binding and glucose metabolism in mouse skeletal muscles
Authors: Tan M. H. , Bonen A.
Published: April 2011

We studied the in vitro effect of corticosterone on insulin binding, uptake of 2-deoxy-D-glucose, glycolysis, and glycogenesis in the soleus and extensor digitorum longus (EDL) of Swiss–Webster mice. In each experiment, one muscle (soleus/EDL) was incubated with corticosterone (0.1, 1, 50, and 100 μg/mL) and the respective contralateral muscle was incubated without corticosterone, but at the same insulin and pH levels. Corticosterone did not affect insulin binding in both muscles. However, corticosterone decreased the uptake of 2-deoxy-D-glucose and the rate of glycolysis and glycogenesis in both muscles when the dose was pharmacologic (50 and 100 μg/mL), but not when it was physiologic (0.1 and 1 μg/mL). For glycolysis and glycogenesis, the suppression was greater in the EDL when compared with the soleus. This suppression was seen in both basal and insulin-stimulated conditions. In this in vitro system, where the experimental muscle is not exposed to prior hyperinsulinemia as in the in vivo model, corticosterone, at pharmacologic doses, affects postreceptor events without altering the insulin binding in the skeletal muscle.
Dopamine-stimulated parathyroid hormone release in vitro: further evidence for a two-pool model of parathyroid hormone secretion
Authors: Hanley David A. , Wellings Paul G.
Published: April 2011

Bovine parathyroid tissue was placed in an in vitro perifusion system for the study of parathyroid hormone secretion stimulated by low calcium and dopamine. Dopamine caused a transient increase in parathyroid hormone release, while low calcium caused a sustained increase in parathyroid hormone secretion. The dopamine response was similar to that caused by isoproterenol. After parathyroid hormone release had been stimulated by dopamine there was no response to isoproterenol, suggesting they cause the release of the same cellular pool of hormone. Inhibition of protein synthesis with cycloheximide eliminated the response to low calcium, with no effect on dopamine-stimulated parathyroid hormone release. These studies suggest dopamine stimulates the release of a limited quantity storage pool of parathyroid hormone, while low calcium causes a sustained release of hormone by stimulating secretion of newly synthesized hormone. Low calcium has little or no effect on release of the storage granule pool of parathyroid hormone.
The effect of prenatal treatment with busulfan on in vitro androgen production by testes from rats of various ages
Authors: Jansz Gwenderlyn F. , Pomerantz David K.
Published: April 2011

Treatment of rats with busulfan in utero severely depletes the germ cell population of the seminiferous tubules. These studies have examined the in vitro capacity of testicular tissue and Leydig cells from such testes to secrete androgens. Leydig cells were identified by staining for 3β-hydroxy steroid dehydrogenase. Rats were studied at several ages to identify any developmental changes in the androgen-secreting capacity of control and treated gonads. At 30 days of age, no effect of treatment on serum androgen was found. At 60 and 90 days of age, treatment caused decreased androgen and increased LH content of the serum. At 12, 30, 60, and 90 days of age, the amount of androgen secreted per milligram of testicular tissue in response to LH was higher in busulfan-treated rats. Leydig cells from 60- and 90-day-old rats which had received busulfan were also hyperresponsive to LH. It was concluded that Leydig cells from testes essentially devoid of germ cells were hyperresponsive to LH. Serum androgen levels were decreased yet androgen production per Leydig cell was increased. A possible explanation of this apparent paradox is that busulfan treatment resulted in decreased numbers of Leydig cells in the gonads.
Evidence for increased hepatic sympathetic nerve activity resulting in hyperglycemia in response to hemorrhage-induced reflex stimulation in anesthetized dogs
Authors: Yamaguchi Nobuharu
Published: April 2011

To investigate the role of the sympathoadrenal system in glucose mobilization by the liver during hemorrhage, catecholamine (CA) output from both adrenal glands was determined in anesthetized dogs. Venous blood draining from both adrenal glands was combined in a Y-tube that was connected to an electromagnetic flow probe to measure total adrenal venous blood flow. Plasma concentrations of norepinephrine (NE), epinephrine (E), dopamine (DA), and glucose (GL) were determined in various vascular regions. Adrenal CA output (nanograms per minute) under basal conditions was 50.2 ± 13.6, 181.4 ± 41.9, and 13.7 ± 4.8 for NE, E, and DA, respectively. These values were found to increase significantly (P < 0.05) in response to 5 min of hemorrhage, reaching a maximum output (nanograms per minute) of 663.6 ± 160.6 (NE), 2503.4 ± 607.8 (E), and 141.7 ± 43.7 (DA). Aortic CAs (nanograms per millilitre) increased significantly with a predominant increase in E (0.33 ± 0.08 to 3.75 ± 1.03, P < 0.05). In contrast, increases in portal and hepatic venous CAs (nanograms per millilitre) were characterized by a predominant increase in NE (0.30 ± 0.06 to 0.64 ± 0.11 and 0.17 ± 0.02 to 0.31 ± 0.07, respectively, P < 0.05). Hepatic venous and aortic GL concentrations also increased significantly during hemorrhage. Among the various correlations between plasma CA and GL concentrations, the strongest correlation was found between hepatic venous NE and hepatic venous GL (r = 0.804, P < 0.001). Correlation coefficients obtained with aortic NE and E were weaker but significant (r = 0.603 and r = 0.608, respectively, P < 0.01). Both the predominant increase in NE observed in hepatic-venous blood and the marked correlation of hepatic venous NE with hepatic venous GL suggest that, in dogs with normal sympathoadrenal systems, hemorrhage-induced hyperglycemia results from increased hepatic glycogenosis, due in large measure to increased activation of hepatic sympathetic nerves.
Characterization of postjunctional adrenoceptor subtypes in isolated rat myocardial cells in culture
Authors: Ettaiche M. , Athias P. , Variot N. , Klepping J.
Published: April 2011

The effects of agonists and antagonists, specific for the different adrenoceptor subtypes on the automaticity of cultured ventricular cells from postnatal rat, were studied. Chronotropic responses were assessed by recording monophasic action potentials using intracellular microelectrodes. Contraction was assessed by an electro-optical procedure. (−)-Isoproterenol, salbutamol, (−)-phenylephrine, and methoxamine increased the spontaneous rate in a dose-dependent manner, but the stimulatory potencies of α-adrenoceptor agonists were weaker than those of the β-alternates. The frequency response to (−)-isoproterenol was inhibited by atenolol but not by butoxamine. Atenolol was also more effective than butoxamine in antagonizing the rate acceleration by salbutamol. The chronotropic effects of phenylephrine and methoxamine were inhibited by prazosin. In contrast, neither clonidine nor yohimbine displayed any chronotropic action. These findings suggest that the postjunctional adrenoceptors present in the sarcolemma of the isolated cardiac muscle cells, which mediate automaticity responses to catecholamines, are of β1, β2, and α1 types, the physiological contribution of the β1-adrenoceptors being predominant. Applicability of these conclusions to the in situ myocardiocytes is discussed with respect to the level of functional differentiation achieved by the rat myocardial cells in culture.
Spontaneous and GABA-induced single channel currents in cultured murine spinal cord neurons
Authors: Mathers David A.
Published: April 2011

Intracellular and patch clamp recordings were made from embryonic mouse spinal cord neurons growing in primary cell culture. Outside-out membrane patches obtained from these cells usually showed spontaneous single channel currents when studied at the resting potential (−56 ± 1.5 mV). In 18 out of 30 patches tested, spontaneous single channel activity was abolished by making Tris+ the major cation on both sides of the membrane. The remaining patches continued to display spontaneous single channel currents under these conditions. These events reversed polarity at a patch potential of 0 mV and displayed a mean single channel conductance of 24 ± 1.2 pS. Application of the putative inhibitory transmitter γ-aminobutyric acid (0.5–10 μM) to outside-out patches of spinal cord cell membrane induced single channel currents in 10 out of 15 patches tested. These channels had a primary conductance of 29 ± 2.8 pS in symmetrical 145 mM Cl solutions. Frequency distributions for the open times of these channels were well fit by the sum of a fast exponential term ("of") with a time constant τof = 4 ± 1.3 ms and a slow exponential term ("os") with a time constant τos = 24 ± 8.1 ms. Frequency distributions for channel closed times were also well fit by a double exponential equation, with time constants τcf = 2 ± 0.2 ms and τcs = 62 ± 20.9 ms.
Relationship between levels and uptake of serotonin and high affinity [3H]imipramine recognition sites in the rat brain
Authors: Hrdina Pavel D. , Pappas Bruce A. , Roberts David C. S. , Bialik Robert J. , Ryan Cathrine L.
Published: April 2011

High affinity [3H]imipramine binding, endogenous levels of serotonin and noradrenaline, and serotonin uptake were determined in brain regions of rats with selective destruction of serotonergic neurons by 5,7-dihydroxytryptamine (5,7-DHT), of adrenergic neurons by 6-hydroxydopamine (6-OHDA), and of rats treated with reserpine. Neonatal treatment with 5,7-DHT resulted in a significant decrease of both serotonin levels and density (Bmax) of high affinity [3H]imipramine binding sites in the hippocampus. In contrast, an elevation of serotonin levels and an increase in Bmax of [3H]imipramine binding were noted in the pons–medulla region. No changes were observed in the noradrenaline content in either of these regions. Intracerebral 6-OHDA lesion produced a drastic suppression of noradrenaline levels in cerebral cortex but failed to alter the binding affinity (KD) or density (Brnax) of [3H]imipramine recognition sites. A single injection of reserpine (2.5 mg/kg) resulted in marked depletion of both serotonin (by 57%) and noradrenaline (by 86%) content and serotonin uptake (by 87%) in the cerebral cortex but had no significant influence of the parameters of high affinity [3H]imipramine binding in this brain region. The results suggest that high affinity [3H]imipramine binding in the brain is directly related to the integrity of serotonergic neurons but not to the magnitude of the uptake or the endogenous levels of the transmitter, and is not affected by damage to noradrenergic neurons or by low levels of noradrenaline.
The precision and accuracy of noninvasive measurements of total body calcium in the rat
Authors: Beachey D. J. , Wickham M. , Webber C. E.
Published: April 2011

It has been proposed that the adult castrated male rat may be used as a model of human postmenopausal osteoporosis. If such a model is valid then the total body calcium of castrated rats should progressively decrease compared with normal rats. To search for this age-related difference, it will be necessary to use a measurement technique with a precision which is small compared with the magnitude of the change to be detected. From measurements of total body calcium by neutron activation and by whole body ashing of eight dead rats, it has been shown that total body calcium can be measured with an accuracy and precision which should allow distinction between the expected lifetime changes in normal and castrated rats.
Effects of 6-mercaptopurine treatment on the membrane potentials of rat skeletal muscle fibers
Authors: Clouva-Molyvdas Phyllis , Sperelakis Nicholas , Forbes Michael S. , Alleva Frederic R. , Balazs Tibor
Published: April 2011

6-Mercaptopurine (6-MP), injected daily (2 mg/kg s.c.) into Sprague–Dawley rats during the first 3 weeks of life, causes atrophy in muscles of the hindquarters beginning at 4 months of age. The extensor digitorium longus (EDL) muscles from 24 rats injected with 6-MP and 23 saline-injected controls, 6–18 months of age, were studied. Electron microscopy showed a number of abnormalities in the EDL muscle of 6-MP-treated rats, such as myocytes with atypical ultrastructure (including disorganized myofibrils) adjacent to structurally normal cells. Membrane potentials (Em) were measured in the isolated EDL and in the caudofemoralis (CF) muscle in situ. The mean Em of fibers in the EDL of 6-MP-treated rats (−61.1 ± 0.7 (SE) mV) was lower than that of the control rats (−69.7 ± 0.6 mV). The same was true for the fibers of the CF muscle (−64.9 ± 1.5 mV for 6-MP-treated fibers vs. −71.6 ± 1.3 mV for controls). The contribution of the electrogenic pump potential to Em (± ouabain) was similar in 6-MP-treated and control rats, and therefore could not account for the depolarization observed in 6-MP-treated rats. This depolarization was not due to a decreased intracellular K+ concentration. The Na+:K+ permeability ratio (PNa/PK) was higher in the 6-MP-treated rats and could account for the decrease in Em. The action potentials (APs) of 6-MP-treated rats (elicited from the natural Em of the fiber) had lower maximum rate of rise [Formula: see text] (330 ± 20 vs. 391 ± 17 V/s in controls), and lower amplitude (65.1 ± 2.9 vs. 73.3 ± 1.8 mV). When hyperpolarized to −90 mV before eliciting the AP, fibers from 6-MP-treated rats had depressed [Formula: see text] (382 ± 19 vs. 511 ± 21 V/s in controls), depressed AP amplitudes (97.0 ± 2.1 vs. 105.1 ± 1.6 mV), and prolonged duration at 50% amplitude (APD50) (0.66 ± 0.03 vs. 0.60 ± 0.02 ms). These data demonstrate definite electrophysiological and ultrastructural abnormalities in the EDL muscle of 6-MP-treated rats, resembling those observed in murine muscular dystrophy.
Jejunal uptake of sugars, cholesterol, fatty acids, and fatty alcohols in vivo in diabetic rats
Authors: Hotke C. , McIntyre Y. , Thomson A. B. R.
Published: April 2011

Previous in vitro studies have demonstrated enhanced active and passive intestinal uptake of nutrients in streptozotocin-diabetic rats, but the effect of diabetes on the in vivo absorption of glucose and amino acids remains controversial, and the effect of diabetes on the in vivo uptake of lipids has not been reported. Accordingly, an in vivo perfusion technique was used in rats to examine the uptake of nutrients from the intestinal lumen, their transfer to the body, their mucosal and submucosal content, and the percentage of uptake transferred. Diabetes was associated with reduced uptake of fatty alcohols, indicating that the effective resistance of the unstirred water layer in vivo is higher in diabetic than in nondiabetic control rats. The mucosal and submucosal content of dodecanol was lower in diabetic than in control rats, but the percentage of the dodecanol uptake transferred to the body was higher. Although the uptake of varying concentrations of D-galactose was similar in diabetic and in control animals, kinetic analysis corrected for unstirred layer effects demonstrated lower mean values of the passive permeability coefficients (Pd) for galactose in diabetic than in control animals, with lower values of the Michaelis constant (Km) and higher values of the maximal transport rate [Formula: see text]. The uptake of lauric acid was reduced in diabetic rats, whereas the uptake of deconoic acid and of cholesterol was unchanged. With correction for unstirred layer effects, it was apparent that the jejunum of diabetic rats was in fact more permeable to decanoic and lauric acid as well as to cholesterol. The results suggest that (i) in diabetic rats the effective resistance of the unstirred water layer between the jejunal lumen and the brush border membrane is lower; (ii) the differences in unstirred layer resistance between the diabetic and control animals obscure the changes in the kinetic constants (Pd, Km, [Formula: see text]) describing the uptake of galactose, medium chain length fatty acids and cholesterol; and (iii) the kinetic changes in nutrient uptake observed in vitro may be confirmed in vivo once the effect of intestinal unstirred layers has been taken into account.
In vitro evaluation of a toxic metabolite of sulfadiazine
Authors: Shear N. H. , Spielberg S. P.
Published: April 2011

We have demonstrated the in vitro production of a potentially toxic metabolite of sulfadiazine. Human lymphocytes were incubated with sulfadiazine and a murine hepatic microsomal drug metabolizing system. Toxicity to cells was assessed by trypan blue dye exclusion. Covalent binding of labelled sulfadiazine to microsomes also was studied. Sulfadiazine toxicity to cells was dependent on microsomes and NADPH. Binding and toxicity were decreased when microsomes were boiled or cytochrome P-450 inhibited, and by the addition of N-acetylcysteine or glutathione. The data suggest the production of a toxic intermediate of oxidative metabolism of sulfadiazine which is detoxified by conjugation with glutathione. Covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.
The effect of D600 on tonic tension, Na+ inward current, and Na+–Ca2+ exchange in frog heart
Authors: Horackova Magda
Published: April 2011

Preparations of frog atrial muscle were stimulated at 0.33 Hz under voltage clamp, and the resulting membrane currents and the twitch contractions (phasic and tonic components) were recorded in presence or absence of D600. It has been suggested earlier that the tonic contractions are regulated by an electrogenic Na+–Ca2+ exchange, while the phasic contractions are closely related to the calcium inward current (Isi). In this study we investigated the effect of D600 on (i) the tonic contractions elicited by long depolarizing pulses of high amplitude and (ii) the tonic contractions increased by veratrine and resulting in a positive inotropic effect (PIE). While 1 μM D600 reduced Isi and the corresponding phasic contractions to < 30% of their initial values within 5 min, the inhibitory effect of D600 on tonic contractions developed more slowly or higher concentrations of D600 were needed to achieve similar levels of inhibition within the same time. Furthermore, applications of 5–50 μM D600 inhibited the veratrine-induced increase in INa and in tonic contractions, and both of these effects again fully developed within a few minutes of D600 being removed. The results demonstrate that D600 inhibits not only Isi and phasic contractions, but it also decreases the tonic contractions in frog heart. The effect on the tonic component is associated with inhibition of the tetrodotoxin-sensitive Na+ inward current, and the results are interpreted as an effect of D600 on the electrogenic Na+–Ca2+ exchange. These additional effects of D600 should be considered when using this drug as the "specific" calcium channel blocker.
The interactive effects of fatigue and pH on the ionic conductance of frog sartorius muscle fibers
Authors: Renaud J. M. , Mainwood G. W.
Published: April 2011

The effects of fatigue on the membrane conductance of frog sartorius muscle at the resting potential and during an action potential were studied. When muscles were exposed to an extracellular pH of 8.0 the membrane conductance at the resting potential increased during fatigue by about 20% and returned to prefatigue level in about 20 min. The membrane conductance of muscle fibers exposed to pH 6.4 was about three times less than that of pH 8.0 and decreased further during fatigue. Furthermore, the recovery of a normal membrane conductance was slow at pH 6.4. Both the inward, depolarizing and the outward, repolarizing currents during the action potential are reduced in fatigue. In each case the effect is greater at pH 6.4 than at 8.0 and recovery towards normal values is slower at pH 6.4. It is concluded that the ionic conductance of the sareolemmal membrane at the resting potential and during an action potential are modified by fatigue and that these changes are modulated by pHo.
Role of insulin in regulating hepatic gluconeogenesis in sheep
Authors: Brockman Ronald P.
Published: April 2011

Ruminant animals, as a result of the fermentative nature of their digestion, ordinarily absorb little or no hexose sugar from the gut. Their glucose needs must be met by gluconeogenesis, even postprandially. The role of insulin in regulating hepatic gluconeogenesis in ruminants has not been assessed, in this study the effect of insulin on net hepatic removal of the major glucose precursors was determined, insulin was infused with glucose matched to maintain euglycemia. The insulin concentrations attained in plasma were within the physiological range, insulin at low concentrations reduced the hepatic removal of lactate, glutamine, and glycerol. At higher concentrations of insulin the hepatic extractions of pyruvate and alanine were also reduced. Thus, in sheep insulin at physiological concentrations may reduce hepatic glucose output by altering the uptake of glucose precursors.
Antagonist actions of bicuculline methiodide and picrotoxin on extrasynaptic γ-aminobutyric acid receptors
Authors: Barolet A. W. , Li A. , Liske S. , Morris M. E.
Published: April 2011

The effects of picrotoxin and bicuculline methiodide to block depolarizing responses of extrasynaptic receptors for γ-aminobutyric acid (GABA) are compared using excitability testing of myelinated axons in amphibian peripheral nerve. The actions of the antagonists appear both complex and dissimilar. Picrotoxin (10–1000 μM) produces large reversible depressions of the maximal response to GABA (0.01–10 mM) and increases the EC50 from 0.33 to 12.6 mM. With high concentrations of agonist and antagonist an insensitive component is apparent. The action of picrotoxin is not classically noncompetitive: it may represent a mixed antagonism (competitive and noncompetitive) or a noncompetitive one, masked by the presence of receptor reserve and (or) secondary depolarizing influences (e.g., GABA-evoked [K+]o accumulation). Bicuculline methiodide (10–200 μM) shifts the GABA concentration–response curve to the right; maximal responses persist and are even enhanced. The impression that bicuculline methiodide has a competitive action is supported by analysis of its inhibition of responses to low concentrations of the agonist. It is suggested that the enhancement of GABA responses by bicuculline methiodide and their apparent resistance to block by picrotoxin may be due to a common secondary effect of the antagonists such as a decrease in membrane conductance to K+ and (or) block of transmitter uptake.
Mechanism of action of nicotine on crab-eating monkey isolated bronchial smooth muscle
Authors: Kizawa Yasuo , Takayanagi Issei
Published: April 2011

Monkey (crab-eating monkey) was used as an experimental animal in this study since the pharmacological properties of isolated monkey bronchial smooth muscle were reported to be qualitatively similar to human muscle. Nicotine (10−5–10−3 M) induced a phasic contraction in the isolated monkey bronchial smooth muscle preparation. The contractile response to nicotine was abolished by hexamethonium and atropine and potentiated by physostigmine but not influenced by tetrodotoxin. These results suggest that the response to nicotine was mediated through the release of acetylcholine, and that the nicotine-induced response may be produced through a sodium action potential independent process. In addition, the mechanisms of action of nicotine on the bronchial preparation of crab-eating monkey were similar to those of nicotine on the rabbit bronchial preparation but not to those on the isolated guinea-pig bronchus.
Evidence for the pharmacological relevance of benzodiazepine receptors to anticonvulsant activity
Authors: Fisher T. E. , Johnson D. D. , Tuchek J. M. , Crawford R. D.
Published: April 2011

Each of a series of benzodiazepines was found to be effective in preventing convulsions evoked by intermittent photic stimulation of epileptic chickens. There was a high correlation between the anticonvulsant potencies (mean effective dosages) and the affinity of the agents for the putative benzodiazepine receptor as measured by displacement of [3H]diazepam from binding sites on chicken synaptosomal membranes. This correlation in a genetic model of epilepsy provides further evidence that benzodiazepines exert their anticonvulsant effects by interacting with the benzodiazepine receptor.
Variations in plasma motilin, somatostatin, and pancreatic polypeptide concentrations and the interdigestive myoelectric complex in dog
Authors: Poitras P. , Lemoyne M. , Tasse D. , Trudel L. , Yamda T. Y. , Taylor I. L.
Published: April 2011

We have looked at the plasma concentrations of motilin, pancreatic polypeptide (PP), and somatostatin (STS) during the various phases of the interdigestive motor complex (IDMC) in dogs. As expected, motilin cyclical increase was always associated with the phase III of the IDMC. Statistical analysis of PP variations revealed a significant rise 10 min before duodenal phase III; however, in individual animals, this relationship was inconsistent. Although a dose-related increase in PP blood levels was induced by administration of synthetic canine motilin (0–200 ng kg−1 iv), fasting plasma levels of PP were not correlated with the concentrations of circulating endogenous motilin. After truncal vagotomy, while motilin release and the intestinal motility pattern remained unaltered, the phase III associated cyclical increases of PP disappeared. Infusion of physiological amounts of PP (1 μg kg−1 h−1 for 3 h) mimicking the postprandial release failed to reproduce a fed pattern type of intestinal motility and of motilin secretion. No statistical correlation could be established between STS plasma levels and the motor activity of the intestine. STS plasma levels were not correlated with circulating concentrations of motilin and the exogenous administration of physiological doses of synthetic canine motilin failed to modify STS plasma levels. Morphine (200 μg kg−1 iv) stimulated only the release of motilin. These data suggest that the role played by circulating concentrations of PP and STS in the control of the IDMC in dog is at most minimal.
Inactivation of atrial natriuretic factor in blood
Authors: Veress Anthony T. , Chong Chee K. , Sonnenberg Harald
Published: April 2011

Tissue extracts of rat heart atria contain a family of peptides with natriuretic and vasorelaxant properties. It has been shown by others that inactivation of this atrial natriuretic factor may involve endogenous peptidases. The present experiments demonstrate that incubation in blood in vitro reduces the natriuretic activity of the factor. Specifically, inactivation was associated with a white cell/platelet fraction, indicating that these blood elements may play a physiological role in the metabolism of this new putative hormone.
Pharmacological evaluation of GABAergic and glutamatergic inputs to the nucleus basalis–cortical and the septal–hippocampal cholinergic projections
Authors: Wood Paul L.
Published: April 2011

The presence of different receptor populations within a given brain area can be effectively evaluated via the local injections of defined receptor agonists and antagonists. Using this approach, it has become evident that the nucleus basalis – cortical cholinergic pathway possesses an inhibitory GABAergic input to the nucleus basalis from the nucleus accumbens as well as a positive glutamatergic feedback from the cortex. The septal–hippocampal cholinergic pathway also possesses an inhibitory GABAergic regulation which consists of a large GABAergic interneuron population in the septum. A glutamatergic feedback from the hippocampus is also present. These regulatory inputs to cholinergic cells are not tonically active but appear to function as phasic modulators of cholinergic transmission in both pathways.
Choline mustard: an irreversible ligand for use in studies of choline transport mechanisms at the cholinergic nerve terminal
Authors: Rylett R. Jane
Published: April 2011

It has been shown in our laboratory that choline mustard aziridinium ion is a potent and irreversible inhibitor of choline transport into rat brain synaptosomes; this compound showed selectivity for the sodium-dependent, high affinity carrier in that it was 30 times more potent as an inhibitor when compared with the effect on sodium-independent, low affinity choline uptake. In the present study, this mustard analogue did not inhibit synaptosomal uptake of 5-hydroxytryptamine, noradrenaline, or gamma-aminobutyric acid, thereby confirming further the specificity of this compound for the choline carrier. Studies of the effect of depolarization of the nerve terminals on the inactivation of choline carriers by choline mustard were performed. It was determined that alkylation of the carrier was significantly increased in nerve endings previously depolarized. The enhancing effect of depolarization on choline transport velocity and on the alkylation of choline carriers by choline mustard was dependent upon the presence of sodium in the external medium. Possible mechanisms for the enhanced inactivation of choline carriers by choline mustard aziridinium ion are proposed, and kinetic interactions of choline mustard with the high affinity choline carrier and with choline acetyltransferase are reviewed and discussed.
Choline analogues: their use in studies of acetylcholine synthesis, storage, and release
Authors: Collier B.
Published: April 2011

The objective of this article is to illustrate how choline analogues might provide insight into mechanisms that regulate the synthesis, storage, and release of acetylcholine (ACh). Studies with false neurotransmitters provide information about the origin of releasable transmitter. Thus, false esters that distribute like ACh to vesicle-bound stores are as releasable as is ACh, but esters that poorly localize to synaptic vesicles are poorly releasable. Studies of choline analogue uptake provide information about the structural specificity of that transport process and, also, show that choline uptake is regulated in response to activity. Thus, stimuli that normally release transmitter increase the rate of choline transport, presumably to provide more precursor for ACh synthesis. However, the relationship between precursor delivery and product formed can be dissociated, suggesting that some factor in addition to choline delivery is involved in ACh synthesis regulation. Studies with a compound (AH5183), which inhibits ACh uptake by synaptic vesicles, provide information about the relationship of ACh stores and releasable transmitter. In the presence of AH5183 some 15% of nerve terminal ACh is released in response to nerve impulses, suggesting the existence of a small population of vesicles that contain readily releasable ACh. In presence of AH5183, ACh synthesis is activated even when ACh release is depressed, showing that transmitter synthesis can be regulated by some factor other than nerve terminal ACh levels.
Multiple conductance states of the acetylcholine receptor channel complex
Authors: Morris Catherine E. , Montpetit Madeleine
Published: April 2011

The acetylcholine-activated channel of vertebrate skeletal muscle, as manifested in cultured, developing cells, is able to adopt more than one conductance state. This paper briefly reviews the evidence for such multiple conductance channels and presents results showing that the amplitude of subconductance states does not depend on agonist size and (or) valence. This seems to rule out the possibility that subconductances occur during partial occlusion of the channel (by agonist molecules) and supports the idea that subconductances represent discrete, allosterically activated channel conformations.
Possible destruction of cholinoceptive neurons by overstimulation of cholinergic tracts
Authors: McGeer Edith , McGeer Patrick L.
Published: April 2011

It is well established that intracerebral injections of kainic acid may cause not only neuronal cell destruction at the injection site, but also losses in some distant regions. The mechanisms are different. The distant, but not the local, destruction can be produced by folic as well as by kainic acid and prevented by pretreatment of the animal with diazepam. Overexcitation of excitatory projections is believed responsible for the distant damage and evidence is presented that in some instances the projections involved are cholinergic. Thus, for example, injections of kainic acid or folic acid into the substantia innominata of rats destroy neurons in areas such as the pyriform cortex and amygdala which receive cholinergic projections from the injected area. Some of the destroyed neurons are GABAergic. That the distant toxicity in these areas can be partially blocked by scopolamine and is accompanied by decreases in the number of muscarinic binding sites is consistent with a cholinergic mechanism. Distant damage also occurs in the thalamus but this appears to be mediated by a noncholinergic projection. Similar injections of folic acid or kainic acid into the rostral pontine tegmentum, another area with cholinergic cells, cause destruction of both dopaminergic and GABAergic neurons in the substantia nigra. The effect on the GABAergic but not that on the dopaminergic cells is blocked by scopolamine. The results are discussed in relation to possible mechanisms of epilepsy and of selective neuronal losses in diseases such as Parkinson's disease.
An antihypertensive extract of erythrocytes: effects on 45Ca uptake and efflux
Authors: Wright G. L. , Rankin G. O. , McCumbee W. D.
Published: April 2011

The present report describes some aspects of the effects of a recently described antihypertensive extract of erythrocytes (AHF) on calcium uptake and efflux in rat aortae. AHF was found to be present in the erythrocytes of both spontaneously hypertensive rats and normotensive rats. Furthermore, AHF obtained from erythrocytes of SH rats was shown to be equally effective in suppressing lanthanum-resistant calcium uptake in aortae from hypertensive and normotensive rats. AHF treatment prior to incubation of aortae with 45Ca caused an apparent increase in the total 45Ca uptake. The analysis of calcium washout curves obtained for tissue in calcium-free or lanthanum-containing media indicated that AHF had no significant effect on the rate of calcium loss from the slow component of efflux, though this compartment tended to be reduced in size. This indicated that the increase in the 45Ca content of AHF-exposed aortae prior to rinsing was confined to the rapid component of efflux. The loss of calcium from the rapidly exchanging compartment was enhanced in either of the efflux media used. The results suggest that a principal action of AHF involves an increase in the lability and exchangeability of calcium stores. In addition to its effects in resting tissue, AHF abolished the increase in lanthanum-resistant calcium uptake induced in rat aortae by the addition of high K+ or norepinephrine to the incubation media. In a second part of the study, the effect of AHF on blood pressure and in vitro calcium uptake were compared with that of phosphatidylethanolamine (PEA), the probable identity of another endogenous antihypertensive (renin preinhibitor) compound earlier shown to share important functional similarities with AHF. The results reduce the likelihood that the two causal agents are identical. The AHF produced a significant (75 Torr, 1 Torr = 133.32 Pa) fall in the systolic blood pressure (SBP) of spontaneously hypertensive rats within 24 h following injection, whereas PEA had no effect on the SBP in this model. Both AHF and PEA reduced the resting in vitro uptake of "lanthanum-resistant" calcium in rat aortic segments. However, the AHF effect was significantly greater than PEA at each concentration studied.
Presence of somatostatin-like immunoreactivity in rat pancreatic juice: a physiological phenomenon
Authors: Sarfati Patrice D. , Green Gary M. , Brazeau Paul , Morisset Jean
Published: April 2011

These studies were performed to assess the effects of various exocrine pancreatic stimuli on somatostatin-like immunoreactivity (SLI) secretion in pure rat pancreatic juice. Ingestion of a meal and subcutaneous injections of caeruiein (CA), secretin (SE), and their combination (CA + SE) were compared. Basal fasting SLI output over 5½ h averaged 13.7 ng/30 min; the response to feeding resulted in decreased SLI outputs from 9.7 to 1.7 ng/30 min, a reduction of 81%. SLI secretion following CA, SE, and CA + SE was similar to that obtained following feeding but the reductions of 29, 32, and 39% were less marked and of shorter duration. A return to basal SLI levels was observed only 2½ h following CA administration. Increases in pancreatic volume and protein outputs following CA, SE, and CA + SE were comparable to the feeding response although less pronounced. These data indicate that SLI secretion in pure pancreatic juice can be modulated by two peptides and feeding and that its release is reduced when compared with increases in pancreatic volume and protein secretion. The observation that the peptide's response in terms of SLI output as well as protein and volume were in the same range, although less sustained than the response to a meal, indicates that all stimuli used induced a physiological response of the pancreas.
Acid–base and respiratory properties of a buffered bovine erythrocyte perfusion medium
Authors: Lindinger Michael I. , Heigenhauser George J. F. , Jones Norman L.
Published: April 2011

Current research in organ physiology often utilizes in situ or isolated perfused tissues. We have characterized a perfusion medium associated with excellent performance characteristics in perfused mammalian skeletal muscle. The perfusion medium consisting of Krebs–Henseleit buffer, bovine serum albumin, and fresh bovine erythrocytes was studied with respect to its gas-carrying relationships and its response to manipulation of acid–base state. Equilibration of the perfusion medium at base excess of −10, −5, 0, 5, and 10 mmol∙L−1 to humidified gas mixtures varying in their CO2 and O2 content was followed by measurements of perfusate hematocrit, hemoglobin concentration, pH, [Formula: see text], [Formula: see text], [Formula: see text], and percent oxygen saturation. The oxygen dissociation curve was similar to that of mammalian bloods, having a P50 of 32 Torr (1 Torr = 133.3 Pa), Hill's constant n of 2.87 ± 0.15, and a Bohr factor of −0.47, showing the typical Bohr shifts with respect to CO2 and pH. The oxygen capacity was calculated to be 190 mL∙L−1 blood. The carbon dioxide dissociation curve was also similar to that of mammalian blood. The in vitro nonbicarbonate buffer capacity (Δ[HCO3−] × ΔpH−1) at zero base excess was −24.6 and −29.9 mmol∙L−1∙pH−1 for the perfusate and buffer, respectively. The effects of reduced oxygen saturation on base excess and pH of the medium were quantified. The data were used to construct an acid–base alignment diagram for the medium, which may be used to quantify the flux of nonvolatile acid or base added to the venous effluent during tissue perfusions.
Adrenergic–cholinergic interactions in left atria: Interaction of carbachol with alpha- and beta-adrenoceptor agonists
Authors: MacLeod K. M.
Published: April 2011

The purpose of the present investigation was to determine the nature of the functional interaction of muscarinic agonists with cAMP-generating and cAMP-independent agonists in left atria. Negative inotropic responses of rabbit isolated left atrial strips to the muscarinic agonist, carbachol were measured in the absence and presence of equi-active inotropic doses of the β-adrenoceptor stimulant isoproterenol (Iso), the mixed α- and β-adrenoceptor stimulant phenylephrine (PE) plus 1 μM timolol to block the β-receptor mediated component of its response, and elevated extracellular Ca2+. Carbachol produced dose-dependent negative inotropic responses in left atrial strips, which were much greater than control in the presence of either Iso, or PE plus timolol. However, carbachol responses were of a similar magnitude to the control in the presence of elevated extracellular Ca2+. In the presence of timolol, PE had no significant effect on cAMP levels in left atrial strips, and inotropic responses to carbachol alone and in combination with PE plus timolol were accompanied by significant increases in cGMP levels but no change in cAMP levels. Carbachol attenuated Iso-induced increases in cAMP levels, but decreases in left atrial tension were proportionally greater than the decreases in cAMP levels produced by carbachol in the presence of Iso. These results suggest that the antiadrenergic effects of muscarinic receptor stimulation may occur by a different mechanism in left atria than has been previously reported in ventricular muscle. While the nature of this mechanism is unknown, it may involve antagonism by muscarinic agents of both α-and β-adrenoceptor mediated increases in Ca2+ influx.
Effects of the ionophore grisorixin on myocardial function and metabolism in isolated perfused working rat heart under normoxic and hypoxic conditions
Authors: Chollet-Debord Françoise , Moins Nicole , Renoux Monique , Gachon Pierre
Published: April 2011

The effects of grisorixin, a monocarboxylic ionophore, were studied on isolated working rat hearts perfused with a suspension of washed pig erythrocytes (10% hematocrit). Grisorixin (2.5 μM) induced a transient stimulation of heart work, maximal at 5 min, expressed by an increase in heart rate (+21%) and aortic flow (+17%) and by an increase in coronary flow, maximal at 10 min (+47%). Concomitantly, myocardial [Formula: see text] was slightly enhanced and the myocardial creatine phosphate level dropped (2 min). The lactate production increased by 82% (5 min) then dropped to the control value (10 min) and increased again till the 45th min (+211%), indicating a cardiac metabolic drift towards anaerobic glycolysis due to partial inhibition of the oxidative metabolism. Owing to its properties as an ionophore, grisorixin also induced a strong and rapid increase of potassium concentration in the perfusate and a decrease of sodium. Grisorixin was tested on hearts submitted to 20 min of hypoxic conditions. The hypoxia was rather mild and induced only very slight modifications of the ultrastructure. In the control series, heart rate and aortic flow decreased regularly while coronary flow and lactate production increased. Upon reoxygenation, the heart performances were rapidly restored. Grisorixin was administered according to four different protocols. When injected at the onset of hypoxia or 5 min later, it was able to maintain the aortic flow during the first minutes and induce a higher coronary dilation. These beneficial effects were short-lasting and no deleterious effects were found on the ultrastructure of hearts subjected to grisorixin whether after hypoxia or after reoxygenation.
Synthesis and biological activity of analogs of dynorphin-A(1–13) substituted in positions 2 and 4: Design of [Ala2,Trp4]-Dyn-A(1–13) as a putative selective opioid antagonist
Authors: Lemaire Simon , Turcotte André
Published: April 2011

Mono- and di-substituted analogs of dynorphin-A(1–13) (Dyn-A(1–13)) were synthesized by the solid-phase procedure. The products were purified and analyzed for their ability to inhibit the electrically evoked contractions of the guinea pig ileum (GPI) and mouse vas deferens (MVD) and to compete with the binding of [3H]etorphine ([3H]ET) and [3H]ethylketocyclazocine ([3H]EKC) to homogenates of rat brain (μ-, δ-, κ2-receptors) and guinea pig cerebellum (κ-receptor), respectively. Introduction of Ala in position 2 caused a drastic decrease in the activity of the peptide on the smooth muscle preparations (IC50 of 104 and 2.250 nM in the GPI and the MVD as compared with 0.7 and 21 nM for the parent peptide, respectively). Conversely, this analog retained much of the opioid binding activity of Dyn-A(1–13) (relative binding potencies of 15 and 72% for the displacement of [3H]ET and [3H]EKC, respectively). The replacement of Phe4 by Trp also caused drastic decreases in the activity of the peptide in the smooth muscle preparations (relative potencies of 0.8 and 8.8% on the GPI and MVD) while much of the binding potency to the opioid receptors was retained (31 and 67% for the displacement of [3H]ET and [3H]EKC, respectively). [Ala2,Trp4]-Dyn-A(1–13) was the least potent peptide tested in the smooth muscle assays (relative potencies: 0.1 and 0.6%). However, this latter analog still retained some opioid binding activity in the displacement of [3H]ET to rat brain homogenates (3%). Finally, the disubstituted peptide selectively antagonized the activity of Dyn-A(1–13), β-endorphin, and the σ- and (or) κ2-selective ligands SKF-10047 and cyclazocine in the GPI when applied prior to the addition of the opioid agonist. However, this compound did not display any antagonist activity against phencyclidine, a σ-ligand, and any other selective ligands for μ-, δ-, or κ-receptors. These data indicate that specific modifications in positions 2 and 4 of Dyn-A(1–13) can abolish most of its agonist potency while retaining its binding capacity to specific receptor types, presumably κ2 for [Ala2,Trp4]-Dyn-A(1–13), thus providing a putative selective antagonist for the endogenous peptide.