bluuebunny/crossref_metadata_2025 huggingface dataset:
Possible role of the transverse tubules in accumulating calcium released from the terminal cisternae by stimulation and drugs
Authors: Bianchi C. P. , Narayan S.
Published: April 2011

The sizes of the rapidly exchanging and slowly exchanging Ca2+ pools were estimated in frog sartorius muscles. A new technique using Sr2+ to extract the rapidly exchanging pool was used. The method avoids problems of kinetic analysis. The results showed that stimulation causes Ca2+ to be translocated from a compartment which exchanges with a time constant of 800 min to a compartment that can be washed out in 15 min. This is likely a transfer from the terminal cisternae to the transverse tubule. Calculations show that this would represent 0.9% of the Ca2+ released in each twitch. After 300 twitches produced by a 1-Hz stimulation, this accumulation could have increased the Ca concentration in the transverse tubules to 70 mM. A marked increase of Ca2+ concentration of this magnitude in the transverse tubules would raise the mechanical threshold for excitation–contraction coupling and would decrease the efficiency of coupling between contraction and excitation. This could be the explanation of the fatigue observed during this kind of stimulation.
Pharmacological evidence for the existence of a neuronal amine uptake mechanism in the dog liver in vivo
Authors: Garceau Denis , Yamaguchi Nobuharu
Published: April 2011

The possibility of a neuronal uptake mechanism in the liver was studied in dogs anesthetized with sodium pentobarbital. Plasma catecholamine concentrations in hepatic venous blood were determined by a radioenzymatic assay following injections of tyramine (30–1000 μg) into either the common hepatic artery or the portal vein. Concomitant changes in hepatic vascular parameters and aortic catecholamine concentrations were also investigated. The mean basal values for hepatic venous and aortic catecholamine concentrations were found to be 0.081 ± 0.007 ng/mL and 0.433 ± 0.080 ng/mL, respectively. Injections of tyramine (300 and 1000 μg) into the hepatic artery increased hepatic venous catecholamine concentrations significantly to 0.109 ± 0.017 ng/mL and 0.126 ± 0.023 ng/mL (P < 0.05. n = 7), respectively. Hepatic arterial vascular conductance decreased concomitantly by 29.7 and 44.9% (P < 0.05, n = 7), respectively. Intraportal injections of tyramine did not bring about significant changes in either hepatic venous catecholamine concentrations or portal venous vascular conductance at any dose tested. After inhibition of monoamine oxidase with pargyline (10 mg/kg. i.v.), the effects of tyramine (1000 μg) injected into the hepatic artery were potentiated. The duration of action was approximately 10 min after pargyline pretreatment (control duration: 1 min). The effects of tyramine were absent after inhibition of the neuronal uptake mechanism with desipramine (1 mg/kg. i.v.). No drug tested had a significant effect on aortic catecholamine concentrations. The present results support the presence of the neuronal uptake mechanism in the dog liver.
Effect of salicylate on the fate of [14C]sulfinpyrazone in the rat
Authors: Wong L. T. , Buttar H. S. , Solomonraj G. , Thomas B. H.
Published: April 2011

The effect of acetylsalicylic acid (ASA, 100 mg/kg, po) on the fate of [14C]sulfinpyrazone (50 mg/kg, ip) was studied in male Wistar rats. ASA increased the rate of elimination of [14C]sulfinpyrazone-derived radioactivity from the blood during the first 5 h following drug administration. A tissue distribution study at 4 h showed that ASA increased the concentration of radioactivity in the gastrointestinal tract (GIT) and decreased it in the blood, heart, lung, and testis. ASA had little or no effect on the urinary and fecal excretion of sulfinpyrazone metabolites. Biliary elimination of radioactivity was increased from 54.2 ± 4.7 to 69.6 ± 1.2% of the dose in the 0- to 5-h period by salicylate (SAL), a major in vivo metabolite of ASA. Bile flow rate was also increased by SAL. An in vitro protein binding study showed that SAL displaced sulfinpyrazone from its binding sites. The results suggested that, in the rat, SAL enhanced the rate of sulfinpyrazone elimination by a combination of its choleretic action and displacement of bound sulfinpyrazone from plasma proteins.
Improved carbohydrate tolerance in fibre-fed rats: studies of the chronic effect
Authors: Track Norman S. , Cannon Marilyn M. , Flenniken Ann , Katamay Stefa , Woods Edward F. A.
Published: April 2011

The effect of chronic consumption of diets containing either different sources of dietary fibre (8% guar, 8% pectin, or 8% multifibre) or low carbohydrate upon carbohydrate tolerance was examined in rats. Weight gain was significantly lower throughout the entire 28-day study period with the guar group and after 20 days with the multifibre group. When tested with a liquid meal (1 g sucrose/kg body weight) after 14 days on the diets, only the guar rats had significantly lower fasting and postprandial plasma glucose concentrations. After 28 days, the improved carbohydrate tolerance persisted in the guar rats and started to appear in the multifibre rats. Pectin and low carbohydrate diets had no effect upon either weight gain or carbohydrate tolerance. Consuming the fibre diets did not affect jejunal sucrase activities. Jejunal glucose uptake activity was significantly diminished when measured in fasting guar rats while postprandially activities were similar to controls. Jejunal Na-K-ATPase activities in fasting and postprandial guar rats were not related to changes in glucose uptake. These studies confirm that only certain types of dietary fibre improve carbohydrate tolerance and suggest that reduced weight gain and altered intestinal glucose uptake are factors involved in the chronic fibre effect.
The effects of chronic ethanol consumption on cardiac function in rats
Authors: Chan Thomas C. K. , Sutter Morley C.
Published: April 2011

A pharmacological model of alcoholism in rats was developed by administering ethanol in their drinking water. This model has provided us with a convenient means to study the effects of chronic ethanol consumption on cardiac functional properties. Our "treated" animals consumed, on the average, an equivalent of 11.1 g/kg of absolute ethanol per day and had an average blood ethanol concentration of 26.9 mg/dL at the end of the 12-week treatment period. The Langendorff-perfused hearts from both treatment and control groups performed equally well mechanically when left to beat spontaneously, but under conditions of electrical pacing the contractile ability of hearts from the alcohol-treated animals deteriorated more rapidly. Dose–response relationships for isoproterenol (isopropylnoradrenaline, IPNA) showed that hearts from alcohol-treated animals did not respond as well as hearts from control animals at higher doses of IPNA. This trend was completely reversed in the presence of low external calcium where the hearts from alcohol-treated animals responded better at all IPNA concentrations. Our observations suggest that chronic alcohol consumption may give rise to alterations in calcium ion handling at the level of myocardial plasma membranes.
Photoperiodicity and circannual levels of LH, FSH, and testosterone in normal and castrated male, white-tailed deer
Authors: Bubenik G. A. , Morris J. M. , Schams D. , Claus A.
Published: April 2011

To establish the relation between photoperiodicity and the levels of LH, FSH, and testosterone (T) in plasma, three intact and three castrated adult male white-tailed deer were sampled once a month for 2–3 years. The range of average LH levels in controls varied between 0.8 and 2.0 ng/mL; the levels in castrates were considerably higher, 3.4 to 8.9 ng/mL. Average levels of FSH varied in controls between 25 and 112 ng/mL and in castrates between 141 and 240 ng/mL. A significant correlation between the seasonal time course of LH and FSH was found in castrated, but not in intact bucks. In castrates both gonadotropins exhibit two major elevations coinciding with spring and fall equinoxes in March and September. The seasonal time course of FSH in castrates correlates highly with seasonal levels of FSH in controls. However, the time course of the LH curve in controls is substantially different from the curve in castrates, presumably owing to feedback mechanisms. A possible role of testicular estradiol in this feedback is discussed. In controls, peak T levels are reached in December, i.e., 3 months after maximum levels of FSH and 5 months after peak levels of LH were detected.It appears that male deer undergo two periods of reproductive stimulation (one in the spring, the other in the fall). However, the organism responds with the full range of gonadal and behavioral mechanisms leading to the initiation of the rut only during the fall.
Release of endogenous noradrenaline from the rat tail artery induced by veratridine
Authors: Palatý Vladimír
Published: April 2011

The overflow of endogenous noradrenaline from the isolated rat tail artery was measured using a radioenzymatic method. Veratridine increased the overflow markedly even in the absence of external Ca2+. Modifications of the effect of 5 μM veratridine by tetrodotoxin, pargyline, cocaine, lidocaine, and phenoxybenzamine indicated that interaction of the alkaloid with the sodium channel induces primarily nonexocytotic release of noradrenaline. Ouabain inhibited the effect of 5 μM veratridine on the overflow into Ca2+ -free solution, but it greatly potentiated the effect if external Ca2+ was present. Potentiation of the effect of veratridine in Ca2+-free solution by cyanide was ouabain sensitive. These observations are consistent with the hypothesis that, at low concentrations of veratridine such as 5 μM, the initial cause of enhanced release of noradrenaline may be a consequence of increased activity of the sodium pump, namely increased consumption of ATP by the pump.
Response of blood pressure and cardiac myosin polymorphism to swimming training in the spontaneously hypertensive rat
Authors: Rupp Heinz , Jacob Ruthard
Published: April 2011

Cardiac muscle can adapt to different functional demands, as evidenced by polymorphism of myosin. Pressure load in spontaneously hypertensive rats induced a shift of the myosin isoenzymes towards myosin V3 (18% V1, 27% V2, 55% V3) relative to normotensive Wistar rats (49% V1, 29% V2, 22% V3). A swimming routine with Wistar rats resulted in a shift towards myosin V1 (72% V1, 18% V2, 10% V3). The training effect is not restricted to normotensive rats, since spontaneously hypertensive rats subjected to the same swimming routine exhibited a myosin isoenzyme pattern (38% V1, 31% V2, 31% V3) approaching that of the sedentary Wistar rats. Swimming training can, therefore, prevent the myosin isoenzyme redistribution towards myosin V3 found in sedentary spontaneously hypertensive rats. Furthermore, systolic blood pressure was significantly reduced (130 ± 8 mmHg (1 mmHg = 133.322 Pa)) in the swim-trained compared with the sedentary spontaneously hypertensive rats (157 ± 12 mmHg). The training-induced changes in myosin polymorphism and systolic blood pressure are, at least partially, attributed to substantially normalized sympathetic activity. The functional relevance of swimming training in the spontaneously hypertensive rat is seen in the increased potential of coping with situations requiring fast contraction which may occur during sudden physical exertion or emotional stress.
Antagonism with dibenamine, D-600, and Ro 3-7894 to estimate dissociation constants and receptor reserves for cardiac adrenoceptors in isolated rabbit papillary muscles
Authors: Siegl Peter K. S. , McNeill John H.
Published: April 2011

In papillary muscles isolated from reserpinized rabbits, positive inotropic responses to the alpha (α)-adrenergic agonist, (−)-phenylephrine in the presence of 10−7 M timolol and the beta (β)-adrenergic agonist, (−)-isoproterenol were antagonized with the irreversible α-adrenergic antagonist, dibenamine, the irreversible β-adrenergie antagonist, Ro 3-7894, and the calcium blocker, D-600. D-600 was employed as a functional antagonist of both α- and β-adrenoceptor responses. Dissociation constants (KA values) for drug–receptor interactions were calculated by the method of Furchgott and used to estimate fractional receptor occupancy and agonist efficacies. Comparison of responses showed that the receptor reserve for cardiac β-adrenoceptors was greater than for α-adrenoceptors. D-600 was an effective inhibitor of both cardiac α- and β-adrenoceptor responses; however, estimates of KA and receptor reserves were similar to estimates using an irreversible antagonist for α- but not β-adrenoceptors.
Slow inward Ca current in frog heart: theoretical evidence against a voltage-dependent inactivation
Authors: Fischmeister Rodolphe , Horackova Magda
Published: April 2011

The validity of a Hodgkin–Huxley type voltage-dependent inactivation of slow inward Ca current (Isi) was tested in frog heart using a computer simulation. The time course of Isi, was calculated during the development of a frog atrial action potential (AP). With a time constant of inactivation (τf) of 55 ms at a membrane potential (Em) of –15 mV, the variation of Isi was biphasic; after a transient increase followed by a decrease to zero, Isi partially "reactivated" (at the beginning of the AP repolarization phase) and then fully deactivated. The "reactivation" phase of Isi developed whether τf was an increasing, decreasing, U-shaped, or bell-shaped function of Em. The addition of an independent and slower process responsible for the recovery from inactivation only partly suppressed the "reactivation" phase. However, until now there was no experimental evidence supporting such a biphasic variation of Isi during AP repolarization. Thus our results indicate that the Hodgkin–Huxley type model of the voltage-dependence of Isi-inactivation process may not correctly represent the actual behavior of frog cardiac muscle.
Exercise in diabetic man: glucose turnover and free insulin responses after glycemic normalization with intravenous insulin
Authors: Zinman B. , Marliss E. B. , Hanna A. K. , Minuk H. L. , Vranic M.
Published: April 2011

The metabolic response to moderate exercise in postabsorptive insulin-dependent diabetics receiving insulin by constant intravenous infusion was compared with that of normal controls. The diabetics were infused with insulin overnight and were normoglycemic (89 ± 6 mg/dL, controls: 90 ± 6 mg/dL). With exercise, glycemia remained constant in both groups. In the diabetic subjects, glucose production was 166 ± 11 mg/min at rest, increased to 230 ± 27 mg/min with exercise (p < 0.05), and returned to base line during recovery. Glucose disappearance changed in a synchronous and parallel fashion. In the normal controls, insulin concentration was 0.44 ± 0.03 ng/mL at rest and decreased significantly with exercise (p < 0.01) while in the diabetic free insulin was fourfold higher (1.70 ± 0.32) and did not change with exercise. Lactate increased similarly (twofold) with exercise in both groups. In summary, (i) complete normalization of glycemia, glucose turnover, and the lactate response to postabsorptive exercise can be achieved by the intravenous infusion of insulin adjusted to obtain normoglycemia before the onset of exercise; (ii) this response was obtained with an associated elevation in circulating free insulin which probably reflects the peripheral intravenous route rather than the physiologic (portal) site of insulin administration.
Effects of indomethacin, acetazolamide, ethacrynate sodium, and atropine on intestinal secretion mediated by Escherichia coli heat-stable enterotoxin in pig jejunum
Authors: Ahrens Franklin A. , Zhu Beilei
Published: April 2011

Intraluminal perfusion of pig jejunum with Escherichia coli heat-stable enterotoxin reversed net absorption of water and electrolytes to net secretion. Addition of atropine (2 × 10−5 M) to the perfusate reduced the secretory response to enterotoxin and enhanced sodium and chloride absorption in control segments. Indomethacin (1.4 × 10−3 M), acetazolamide (2.2 × 10−3 M), or ethacrynate sodium (3.1 × 10−4 M) had no effect. Mucosal disaccharidase activity and Na-K-ATPase activity were not altered by enterotoxin. The results suggest that blockade of cholinergically mediated secretion in the small intestine attenuates the enterosorptive effects of heat-stable enterotoxin and may be useful therapeutically in the management of secretory diarrhea.
Divalent ion transport in dogs with experimental chronic renal failure
Authors: Wong Norman L. M. , Quamme Gary A. , Dirks John H. , Sutton Roger A. L.
Published: April 2011

Micropuncture studies were performed to examine the segmental reabsorption of sodium, calcium, and magnesium in the normal dog kidney (stage I) and in the remnant kidney both in the presence (stage II) and in the absence (stage III) of the contralateral normal kidney. The protocol consisted of an initial phase of hydropenia, followed by 5% extracellular fluid volume expansion in the second phase, followed by parathyroid hormone administration in the final phase. In stage II dogs during hydropenia, proximal and distal transport of sodium, calcium, and magnesium were similar to those of normal dogs (stage I). Following 5% body weight volume expansion, fractional deliveries to both the proximal and distal puncture sites were increased similarly in stage 1 and stage II, with a slightly greater increase in stage II animals. In stage III dogs, proximal fractional reabsorption was depressed, as reflected by a marked reduction in proximal tubule fluid to plasma inulin ratios during hydropenia, and the response to volume expansion was accentuated. In the loop segment a constant fraction of the augmented load of sodium, calcium, and magnesium was reabsorbed in stage III. The percentage of the delivered load that was reabsorbed by this segment was similar in all three stages. The diminution in proximal reabsorption in stage III resulted in greater delivery to the distal nephron. The distal reabsorption of a constant fraction of delivered solute resulted in an increase in fractional urinary excretion of sodium, calcium, and magnesium in stage III. Parathyroid hormone significantly reduced the renal excretion of calcium and magnesium in the stage III dogs, indicating the preservation of the renal response to parathyroid hormone in azotemia.
Superoxide dismutase protects against paraquat-mediated dioxygen toxicity and mutagenicity: studies in Salmonella typhimurium
Authors: Hassan Hosni M. , Moody Carmella S.
Published: April 2011

Paraquat is univalently reduced to the relatively stable, but oxygen-sensitive, paraquat radical (PQ∙+). This PQ∙+ can react with dioxygen to generate the superoxide radical, which can further generate other more deleterious species of oxygen free radicals (i.e., hydroxyl radical, OH∙). These oxygen free radicals are known to cause chromosomal breaks; therefore, it was logical to postulate that paraquat is a mutagen. This proved to be the case when tested in a modified Ames test using a liquid incubation assay. Salmonella typhimurium strains TA98 and TA100 were grown in the presence of various concentrations of PQ, as well as in the presence of known mutagenic compounds: mitomycin C, azide, and proflavine. Paraquat was much more toxic and mutagenic in a simple nutritionally restricted medium than in a rich complex medium and these toxic and mutagenic effects were oxygen dependent. Furthermore, cells containing high levels of superoxide dismutase were more resistant to the toxic and mutagenic effects of paraquat than were cells containing a normal level of this enzyme.
Alpha- and beta-adrenergic and muscarinic cholinergic binding sites in the bladder and urethra of the rabbit
Authors: Johns Anthony
Published: April 2011

The affinities of a number of α and β-adrenergic binding sites and muscarinic cholinergic binding sites in rabbit urethra and bladder have been determined, using specific radioligand receptor binding assays. There was a greater density of β-binding sites than α-binding sites in the bladder, while, in the urethra, there was a greater density of α-binding sites than β-binding sites. The number of α-binding sites was fourfold greater in the urethra, whereas there were fewer β-binding sites in the urethra. There were fewer muscarinic binding sites in the urethra than in the bladder. The dissociation constant for [3H]dihydroalprenolol at the β-binding site was 6.4 nM, for [3H]dihydroergocryptine at the α-binding site was 2.11 nM, and for 3H-labelled l-quinuclidinyl benzilate at the muscarinic binding site was 0.22 nM.
Effects of chlordiazepoxide administration on biogenic amines in cat brain
Authors: Vachon Luc , Roberge Andree G.
Published: April 2011

Cats underwent treatment with chlordiazepoxide hydrochloride (0.4, 10.0, and 20.0 mg/kg per os), for 7 consecutive days, and were killed 18 h after the last administration. The endogenous levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), and dopamine (DA) were assayed in 12 brain areas. Few effects on 5-HT, 5-HIAA, and NA content and on the 5-HT:5-HIAA ratio were observed with a 0.4 mg/kg treatment. These changes were localized in the piriform lobe (amygdala), hippocampus, mesencephalon, and mesencephalon raphe nuclei. Moreover, the DA concentration was not affected. The changes produced by 10.0 and 20.0 mg/kg chlordiazepoxide treatments were extended to many more structures, including the limbic system, brainstem, diencephalon, and neostriatum with respect to 5-HT, 5-HIAA, and NA content and also to DA levels. The changes observed after the three doses generally included an increased 5-HT content, a decreased 5-HIAA level, a high 5-HT:5-HIAA ratio, and increased NA and DA concentrations. However, in some structures, a decreased NA content and an increased 5-HIAA level were found. The present results suggest that administration of chlordiazepoxide for 7 consecutive days in cats produces regional changes in the content of endogenous biogenic amines in the central nervous system (CNS) at low doses; much more extended effects are produced at high doses. These findings are in agreement with a reducing effect of benzodiazepines on the turnover and release of biogenic amines in the CNS, but also suggest that certain discrete areas are more involved in these changes, thus dissociating them from the rest of the brain.
Effect of acute changes in the PaCO2 on acid–base parameters in normal dogs and dogs with metabolic acidosis or alkalosis
Authors: Bercovici M. , Chen C. B. , Goldstein M. B. , Steinbaugh B. J. , Halperin M. L.
Published: April 2011

There is a linear relationship between the [Formula: see text] and blood hydrogen ion concentration in normal dogs, but for theoretical reasons to be discussed, we questioned whether this relationship would apply in animals with metabolic acidosis or alkalosis. To study this in more detail, animals were divided into three groups: normal, metabolically acidotic, and metabolically alkalotic. Following anesthesia and bilateral ureteral ligation, dogs were intubated and ventilated to produce acute steady-state [Formula: see text] values corresponding to the range observed during disease states. Changes in the volume and electrolyte composition of the gastrointestinal fluid and urine as well as the concentration and distribution of lactate were evaluated in all experiments. We observed the previously described linear relationship between the [Formula: see text] and blood hydrogen ion concentration in normal dogs, but the slope of the regression line differed significantly from those of dogs with metabolic acidosis and metabolic alkalosis. On the other hand, there was a consistent relationship between the ratio of the [Formula: see text] values, but not the absolute [Formula: see text], and the change in the plasma bicarbonate concentration over a wide range of [Formula: see text] values in all groups of dogs. The chemical basis for these observations will be discussed.
Oxygen uptake and blood flow in canine skeletal muscle during moderate and severe anemia
Authors: Chapler C. K. , Cain S. M.
Published: April 2011

The metabolic and cardiovascular adjustments of the whole body and skeletal muscle were studied during moderate and severe acute anemia. In 15 anesthetized dogs, venous outflow from the gastrocnemius–plantaris muscle group was isolated. Cardiac output [Formula: see text], muscle blood flow [Formula: see text], total body and muscle oxygen uptake [Formula: see text] were determined during a control period, and at 30 and 60 min of either (i) moderate anemia (n = 8) in which the mean hematocrit (Hct) was 25% or (ii) progressive anemia (n = 7) in which the mean Hct values were 25% at 30 min and 16% at 60 min of anemia. Muscle [Formula: see text], [Formula: see text], and [Formula: see text] were increased in both groups at 30 min of anemia. By 60 min, [Formula: see text] and [Formula: see text] declined to preanemic control values in the moderate anemia group; whole body [Formula: see text] was maintained at the control level. Arterial oxygen transport was the same in the two groups at both 30 and 60 min of anemia despite the difference in Hct at 60 min. Muscle [Formula: see text] showed a further and similar rise in both groups between 30 and 60 min of anemia. These data show that the rise in muscle [Formula: see text] during acute anemia was not directly proportional to the degree of the hematocrit reduction. Further, the findings suggest that the muscle [Formula: see text] response was related to the decrease in arterial oxygen transport.
The Upjohn Award Lecture 1982/La Conférence Upjohn 1982: Cell membrane receptors: gateway to endogenous medicinals
Authors: LaBella Frank S.
Published: April 2011

Some recent developments in the author's laboratory which rely upon the techniques of radioreceptor assays (RRA) for drugs and hormones are reviewed. These receptor studies have led, for example, to (a) the identification of 17-alpha estrogens that interact with the opiate receptor, (b) the delineation of a unique class of opiate receptor that mediates explosive motor behavior and is resistant to naloxone, (c) the discover of progesterone derivatives and active tissue fractions that compete for specific binding sites for cardiac glycosides, (d) the observation that both the opiate and digitalis RRA's permit discrimination between classes of centrally active compounds that differ only trivially in their physicochemical properties but exert opposing actions on nerve excitability, and (e) the hypothesis that the correlation between lipid solubility and potency of general anesthetics applies to the accommodation of this class of drugs by hydrophobic crypts of membrane proteins and other proteins rather than to an ill-defined hydrophobic interaction with membrane lipid. Examples are given to demonstrate that the radioreceptor technique promises (a) to continue as a major contributing methodology in the design of pharmacological agents of greater specificity with respect to organ systems and neuronal pathways affected and, thus, of potential clinical usefulness, and (b) to expose as yet unidentified physiologically important humoral factors.
Determination of 5-hydroxytryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid in 20 rat brain nuclei using liquid chromatography with electrochemical detection
Authors: Paolo Thérèse Di , Dupont André , Savard Pierre , Daigle Michel
Published: April 2011

High-performance liquid chromatography with electrochemical detection is utilized for the simultaneous determination of serotonin, its precursor 5-hydroxytryptophan, and its major metabolite 5-hydroxyindoleacetic acid in nervous tissue samples. Tissue preparation required only homogenization in acidic solution and centrifugation prior to application to the chromatograph. Detection limits in the low picogram range were obtained for those indoles separated. This assay was used in combination with a micropunch dissection technique of 20 discrete rat brain nuclei to measure serotonin, its precursor, and major metabolite. The specificity of the assay was checked with pharmacological experiments aimed to increase or decrease serotonin levels. Pargyline, a monoamine oxidase inhibitor, led to a marked increase in serotonin and a decrease of 5-hydroxyindoleacetic acid while p-chlorophenylalanine, by blocking the conversion of tryptophan to 5-hydroxytryptophan, selectively depleted 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid.
Patterns of porphyrin accumulation in response to chemicals in chick embryo liver cells
Authors: Marks G. S. , Follows S. B. , Zelt D. T. , Cole S. P. C.
Published: April 2011

Four patterns of porphyrin accumulation were observed by high-pressure liquid chromatography when chemicals were added to chick embryo liver cells. These patterns provide a guide to the site of action of the chemicals. Protoporphyrin accumulated in response to 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), a result consistent with its ability to inhibit ferrochelatase. Uroporphyrin and heptacarboxylic acid porphyrin accumulated in response to 3,3′,4,4′-tetrachlorobiphenyl, 2,2′,4,4′,6,6′-hexachlorobiphenyl, and 3,5-diethoxycarhonyl-2,4,6-trimethylpyridine, a result suggesting inhibition of uroporphyrinogen decarboxylase. Coproporphyrin was the major porphyrin to accumulate in response to allylisopropylacetamide, aromatic amides, and steroids, a result suggesting inhibition of coproporphyrinogen oxidase. A mixture of uroporphyrin, heptacarboxylic acid porphyrin and coproporphyrin accumulated in response to aromatic di- and mono-esters, aliphatic diesters, and aliphatic amides. The pattern observed after addition of excess δ-aminolevulinic acid (ALA) the endogenous substrate of the pathway to the cells was proto- > copro- > uro-porphyrin. This pattern resembled that produced by DDC but by none of the other chemicals. It was concluded that porphyrin accumulation can not be attributed solely to the induction of ALA-synthetase. It appears that porphyrin-inducing chemicals exert an additional effect on one or other of the enzymes of the heme biosynthetic pathway.
Phase locking of the respiratory rhythm in cats to a mechanical ventilator
Authors: Petrillo G. A. , Glass Leon , Trippenbach T.
Published: April 2011

Mechanical ventilation of paralyzed, pentobarbital-anesthetized adult cats was performed while recording phrenic nerve activity. The periodic changes in lung volume owing to mechanical ventilation affected the rhythm of central respiratory activity, resulting in a variety of regular and irregular patterns of coupling between respiratory system output, monitored by phrenic activity, and the mechanical ventilator. Phase-locked patterns, in which phrenic burst onset occurred at specific and repetitive phase(s) of the mechanical ventilator, with ratios of ventilator frequency: phrenic burst frequency of 1:2, 1:1,3:2, 2:1, and 3:1 were observed. Regular and irregular patterns occurred over specific ranges of frequency and volume of the mechanical ventilator. A careful study was made of the 1:1 phase locking as the frequency and inflation volume of the mechanical ventilator were changed. The inspiratory time (TI) was defined as the interval between the time when phrenic activity began to rise and the onset of its rapid decline, and the expiratory time (TE) as the time between inspirations. In the 1:1 phase-locking region, as the frequency of the ventilator was increased both TI and TE decreased, and the phase of phrenic onset in the ventilator cycle changed. During ventilation with frequencies higher than the intrinsic phrenic frequency (initial burst frequency of phrenic activity with the ventilator turned off) inspiratory activity was prematurely terminated by lung inflation (Hering–Breuer inspiratory inhibitory reflex). During ventilation with frequencies lower than the intrinsic phrenic frequency, the onset of phrenic activity was delayed (TE was prolonged) by lung inflation (Hering–Breuer expiratory promoting reflex).
Tofisopam, a new 2,3-benzodiazepine. Inhibition of changes induced by stress loading and hypothalamic stimulation
Authors: Yamaguchi K. , Suzuki K. , Niho T. , Shimora M. , Ito C. , Ohnishi H.
Published: April 2011

Effects of tofisopam, a new 2,3-benzodiazepine compound, were investigated on the following: gastric ulceration, induced by water-immersion stress in normal rats and by immobilization stress in olfactory-bulbectomized (OB) rats; and propulsion of the small intestine caused by water-immersion stress in rats and autonomic responses to electrical stimulation of the hypothalamus in rabbits. In the latter, the results were compared with those of diazepam and γ-oryzanol. Tofisopam (30 and 100 mg/kg, po) significantly inhibited the gastric ulceration induced by water-immersion stress in normal rats in a dose-dependent manner. Immobilization-stress loading increased the incidence and average index of gastric ulceration in OB rats, compared with nonstressed rats. Tofisopam (100 mg/kg, po) significantly inhibited the gastric ulceration induced by stress loading in OB rats. Water-immersion stress loading induced a significant increase in intestinal propulsion in rats. This increase was reversed to control levels by tofisopam (100 mg/kg, po). Tofisopam (1.0 mg/kg, iv, or 0.1 mg/kg by intracerebrospinal injection) inhibited the constriction of ear microvessels, the decrease in earlobe temperature, and mydriasis induced by electrical stimulation of the medial hypothalamic area in rabbits. However, diazepam and γ-oryzanol failed to inhibit the autonomic responses to medial hypothalamic stimulation. From these results, it can be concluded that tofisopam restores the autonomic abnormality induced by stress loading possibly via intervention in the central autonomic area, i.e., the hypothalamus, by an action different from that of diazepam.
Steroid modulation of response of plasma bicarbonate concentration to NH4Cl loading: gamma distribution analysis
Authors: Levine David Z. , McLeod Robert A. , Raman S.
Published: April 2011

Studies have been carried out in awake chronically cannulated adrenalectomized rats subjected to steroid replacement protocols. Our objective was to determine the effects of mineralocorticoid or glucocorticoid or combined replacement on acid–base composition of the extracellular fluid compartment in response to an acute ammonium chloride acid load. We obtained six blood samples from each animal over a 26-h period and, with the help of a specially derived mathematical model, we were able to obtain a continuous dynamic assessment of changes of plasma bicarbonate concentration during induction and recovery of the metabolic acidosis. Assessment of minimum values for plasma bicarbonate concentration, time to reach the minima, and time for 90% recovery showed that dexamethasone did not exert as much protection as aldosterone. The approach we have used, in a sense being a continuous display of plasma bicarbonate concentration, should be useful in further exploring the nature of the interrelations between acid production, net acid excretion, and the resultant plasma acid–base composition.
Postreceptorial refractoriness of prolactin release mechanisms
Authors: Collu R. , Ducharme J. R. , Eljarmak D. , Marchisio A. M. , Bertrand J. , Sabbagh I. , Guillaumot P. , Cohen H.
Published: April 2011

Whilc a first injection of the antidopaminergic benzamide drug, sulpiride, induced a large rise in plasma prolactin (PRL) levels in chronically cannulated adult male rats, a second injection given 2 h later was totally inactive although the pituitary content of the hormone was still 76% of the initial value. When the second injection was given 8 h after the first it was slightly effective, but when administered 24 h later it was as effective as the first. The second of two consecutive injections of haloperidol given at 2-h intervals, or an injection of morphine given 2 h after sulpiride, were incapable of inducing a release of PRL. Two hours after an injection of sulpiride, a 30-min period of immobilization stress induced a significant rise in plasma PRL levels. A significant rise in plasma PRL levels was also observed when larger doses of sulpiride were given 2 h after a first injection of the drug. Apomorphine was at least as effective an inhibitor of PRL secretion when given 2 h after sulpiride than when injected after saline. In vitro studies of dopaminergic binding sites revealed the presence, in pituitary glands of sulpiride-treated rats, of receptors not modified by the drug. These data suggest that the only plausible explanation for the ineffectiveness of the second of two consecutive injections of sulpiride is the development of a state of refractoriness of the mechanisms that subserve the release of PRL induced by suppression of the inhibitory dopaminergic tonus.
Estradiol modulation of ovine uterine activity
Authors: Windmoller R. , Lye S. J. , Challis J. R. G.
Published: April 2011

The effects of continuous estradiol-17β (E2) infusion (100 μg/24 h and 1 mg/24 h) on spontaneous myometrial activity and uterine responsiveness to oxytocin (OT) and prostaglandin (PG) F2α were measured in nonpregnant sheep. Continuous recordings were made of intrauterine pressure (IUP) and uterine electromyographic (EMG) activity. Continuous E2 infusion resulted in an accentuated pattern of uterine quiescence alternating with periods of high activity lasting 6–8 h. Short (3–10 min) periods of elevated resting IUP and intense EMG activity increased in frequency after E2. E2 also increased the rate of rise of IUP cycles. Within 30 h of commencement of E2 infusion the uterine response to a bolus challenge of OT or PGF2α increased significantly; dose-related responses to OT and PGF2α were measured after 4 days E2 infusion. The response to OT was not abolished by infusing meclofenamic acid. We conclude that: (i) continuous E2 infusion results in a pattern of uterine activity characterized by alternating high activity and quiescence, and increased frequency of occasional rises in basal IUP; (ii) E2 induced increases in OT and PGF2α responses are consistent with other reports that E2 increases OT and PGF2α binding to myometrium; (iii) the E2 effect on OT response is probably independent of enhanced PG synthesis.
Transfer of habituation between stimulation sites of the siphon withdrawal reflex in Aplysia californica
Authors: Goldberg Jeff I. , Lukowiak Ken
Published: April 2011

Habituation of the siphon withdrawal reflex (SWR) can be evoked by iterative tactile stimuli presented to one of several sites, including the siphon and gill. The SWR evoked at an arbitrary "test" site did not habituate when stimuli were presented at 20-min intervals. However, there was a large decrease in the reflex evoked at the test site when the trial was preceded by 10 repetitive stimuli (interstimuli interval = 30 s) presented to the opposite "habituation" site. Transfer of habituation occurred from gill to siphon stimulation sites, and vice versa. There was a concomitant decrease in the excitatory input evoked in the central siphon motor neurons LDS1 and LDS3. Moreover, transfer of habituation occurred after the abdominal ganglion (central nervous system) was removed. There was little change in the magnitude of the control responses or transfer of habituation after deganglionation. Since transfer of habituation between stimulation sites of the SWR was similar to that reported previously for the gill withdrawal reflex, it was suggested that a common mechanism may underlie the two behaviors.
Inhibition of hepatic aldehyde dehydrogenases in the rat by calcium carbimide (calcium cyanamide)
Authors: Loomis C. W. , Brien J. F.
Published: April 2011

Oral administration of 7.0 mg/kg calcium carbimide (calcium cyanamide, CC) to the rat produced differential inhibition of hepatic aldehyde dehydrogenase (ALDH) isozymes, as indicated by the time-course profiles of enzyme activity. The low-Km mitochondrial ALDH was most susceptible to inhibition following CC administration, with complete inhibition occurring at 0.5 h and return to control activity at 96 h. The low-Km cytosolic and high-Km mitochondrial, cytosolic, and microsomal ALDH isozymes were inhibited to a lesser degree and (or) for a shorter duration compared with the mitochondrial low-Km enzyme. The time course of carbimide, the hydrolytic product of CC, was determined in plasma following oral administration of 7.0 mg/kg CC to the rat. The maximum plasma carbimide concentration (102 ng/mL) occurred at 1 h and the apparent elimination half-life in plasma was 1.5 h. Carbimide was not measurable in the liver during the 6.5 h time interval when carbimide was present in the plasma. There were negative, linear correlations between plasma carbimide concentration and hepatic low-Km mitochondrial, low-Km cytosolic, and high-Km microsomal ALDH activities. In vitro studies demonstrated that carbimide, at concentrations obtained in plasma following oral CC administration, produced only 19% inhibition of low-Km mitochondrial ALDH and no inhibition of low-Km cytosolic and high-Km microsomal ALDH isozymes. These data demonstrate that carbimide, itself, is not primarily responsible for hepatic ALDH inhibition in vivo following oral CC administration. It would appear that carbimide must undergo metabolic conversion in vivo to inhibit hepatic ALDH enzymes, which is supported by the observation of no measurable carbimide in the liver when ALDH was maximally inhibited following oral CC administration.
Increased mortality with cardiotoxic doses of Adriamycin after verapamil pretreatment despite prevention of myocardial calcium accumulation
Authors: Rabkin Simon W. , Often Maureen , Polimeni Philip I.
Published: April 2011

The purpose of this investigation was to determine whether the calcium blocking agent, verapamil, could modify Adriamycin cardiotoxicity, and if so, whether or not such modification is mediated by a mechanism involving myocardial electrolyte distribution. The mean survival time of female New Zealand white rabbits administered Adriamycin was reduced by pretreatment with verapamil. Myocardial cellular calcium concentration, [Ca]i, in animals pretreated with verapamil before receiving Adriamycin was lower than in animals receiving Adriamycin alone (1.49 ± 0.11 vs. 2.22 ± 0.35 mmol/kg cell water, respectively; P = 0.05). Myocardial [Ca]i in control animals was 1.68 ± 0.10 mmol/kg cell water. Myocardial [Mg]i in animals receiving Adriamycin alone was lower than that for animals receiving verapamil alone (15.6 ± 1.4 vs. 19.2 ± 0.8 mmol/kg cell water, respectively). When these drugs were combined, [Mg]i approached the control value of 17.3 ± 0.6 mmol/kg cell water. Cellular concentrations of the monovalent electrolytes were little affected by these drugs, except for a reduction of [Cl]i by verapamil. Neither myocardial water distribution nor plasma concentrations of these electrolytes were altered by either drug. The data indicate that verapamil pretreatment increases the mortality associated with Adriamycin in rabbits despite the continued efficacy of verapamil as a Ca-blocking agent after injection of Adriamycin. Particular caution must be exercised if clinical combination of Ca-blocking agents and anthracyclines is contemplated.
Comparative effects of adenosine and nifedipine in rabbit vascular smooth muscle
Authors: Young M. A. , Merrill G. F.
Published: April 2011

The calcium channel blocker nifedipine attenuates the coronary response to adenosine infusion and reactive hyperemia in dogs. Other evidence indicates adenosine may dilate vascular smooth muscle with a mechanism similar to the calcium channel blockers. In isolated rabbit femoral arterial rings, we studied the interaction of adenosine and nifedipine in mediating vascular relaxation. We also compared the actions of adenosine and nifedipine in relaxing norepinephrine- and K+-stimulated tension, and Ca2+-free contractions in an effort to elucidate differences in the specificity of the two agents. Nifedipine (10–25 μg/L) was without effect on adenosine-mediated relaxation of femoral arteries. Adenosine exhibited a greater ability to relax NE-induced contractions and contractions in Ca2+-free medium than did nifedipine. Conversely, nifedipine attenuated K+-induced contractions more effectively than adenosine. These results suggest that adenosine and nifedipine have different cellular actions and that part of adenosine-mediated relaxation may operate intracellularly. Furthermore, the negative interaction of nifedipine and adenosine in vivo suggests that these agents might act differently in an in vitro setting.
Calcium efflux from amphibian sciatic nerve
Authors: Snyder R. E. , O'Brien D. W.
Published: April 2011

Eight Xenopus laevis were injected intraperitoneally with 45CaCl2 and 16–18 h later an unbranehed section from each sciatic nerve was removed. Efflux measurements of nerve from which the perineurial sheath had been removed could be described by three compartments of approximately eqvial size with half-lifes of 2.37 ± 0.76 (SD), 30.3 ± 17.3, and 196 ± 61 min, the shortest lived compartment representing diffusion from the extracellular space with a coefficient of diffusion of 2.1 ± 0.7 × 10−6 cm2/s. Efflux from nerve in which the perineurium remained intact was characterized by a half-life of 862 ± 399 min resulting from the sheath acting as a diffusion barrier of permeability 3.4 ± 1.6 × 10−7 cm/s. The perineurium was found to bind or sequester a quantity of calcium 1–2 times that contained in an equal volume of plasma.
Digoxin–amiodarone interaction: in vivo and in vitro studies in rats
Authors: Koren G. , Soldin S. , Macleod S. M.
Published: April 2011

Amiodarone is a new antiarrhythmic drug, commonly coadministered with digoxin in various cardiac disorders. Amiodarone caused a 10-fold increase of serum digoxin in rats, when the two drugs were simultaneously administered. Amiodarone significantly reduced digoxin uptake by renal cortical slices in the rat, and failed to reduce digoxin uptake by either heart or diaphragmatic muscle. The inhibition of the renal tubular uptake of digoxin caused by amiodarone may explain in part the increased serum digoxin concentration observed in vivo. Close resemblance was found between the mechanisms involved in the amiodarone–digoxin interaction, and those of digoxin interaction with either quinidine or verapamil.
Effect of temperature and pH on phosphate transport through brush border membrane vesicles in rats
Authors: Brunette Michèle G. , Beliveau Richard , Chan Meanthan
Published: April 2011

The kinetics of sodium gradient dependent phosphate uptake by the renal brush border membrane vesicles of the rat have been studied under various conditions of temperature and pH. From 7 to 30 °C the Lineweaver-Burk plots are linear, and the apparent Km progressively increases from 54 to 91 μM. Above 30 °C, the apparent Km continues to increase to reach 135 μM at 40 °C, but a break is observed in the Lineweaver-Burk plots at the substrate concentration of 300 μM. The existence of this break, confirmed by the Eadie-Hofstee plot supports the hypothesis of a dual mechanism of phosphate transport, one for low concentrations of substrate with a Km of 100 μM and the other for high concentrations with a Km of approximately 240 μM. When the two components of the Eadie-Hofstee plot are analyzed according to a nonlinear regression program, these two values of Km become 70 μM and 1.18 mM, respectively. The Vmax continuously increases with temperature. However, the Arrhenius plot (In Vmax vs. 1/Tk) shows an abrupt discontinuity at 23 °C. pH experiments were performed at 35 °C. In the absence of a proton gradient, increasing the pH from 6.5 to 7.5 and 8.5 decreases the apparent Km from 341 to 167 and 94 μM, respectively. When only the divalent form of phosphate is considered as the substrate, the apparent Km does not vary anymore with the pH and remains around the mean value of 105 μM. The uniformity of the apparent Km for the total phosphate uptake, when only the divalent phosphate is considered as being the substrate, suggests that this divalent form is the only one which is transported. Whatever the substrate considered, total phosphate or divalent phosphate, the highest Vmax is obtained at pH 7.5 which probably approximates the optimum pH inside the vesicles for the phosphate uptake.