bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary toxicity of 1,1-dichloroethylene: correlation of early changes with covalent binding
Authors: Forkert P. G. , Stringer V. , Troughton K. M.
Published: April 2011

Administration of a single intraperitoneal dose of 1,1-dichloroethylene (125 mg/kg,1,1-DCE) to mice resulted in bronchiolar injury with selective necrosis of Clara cells. Degenerative changes were manifest in Clara cells as early as 1 h following 1,1-DCE exposure, and were characterized by marked swelling of mitochondria and aggregation of chromatin against the nuclear membrane. Cell death was apparent at 2 h; by 8 h, areas of the bronchiolar epithelium were devoid of lining cells, and at 24 h, the majority of Clara cells were exfoliated. The residual epithelium consisted of flattened cells which formed a thin lining for the airway. Necrosis of Clara cells early in the course of 1,1-DCE exposure coincided with peak covalent binding of [14C] 1,1-DCE and significant depression of components of the pulmonary mixed-function oxidase system; cytochrome P-450 and aryl hydrocarbon hydroxylase activity were markedly reduced but not depleted. Liver damage involving centrilobular hepatocytes was observed at 24 h in 30% of treated animals, and coincided with significant inhibition of aryl hydrocarbon hydroxylase activity; cytochrome P-450 content, however, remained unchanged. While changes in the liver evoked by 1,1-DCE were less striking, the results in lung demonstrate positive temporal correlations between structural damage, peak covalent binding and disturbances of monooxygenase enzymes.
Heart rate and respiratory patterns in mild hypoxia in unanaesthetized newborn mammals
Authors: Finley John P. , Kelly C.
Published: April 2011

The heart rate and respiratory patterns in hypoxia are not well documented in unanaesthetized intact newborn animals. We studied heart rate and respiratory patterns during quiet sleep in 17% inspired O2 in 31 unanaesthetized newborns of five species: lamb, piglet, puppy, kitten, and rabbit. There was no significant change in mean heart rate and respiratory rate with hypoxia for any species. Brief apneas greater than 5 s were frequent (5–8/h), both in 21 and 17% O2 only in lambs and puppies. No sustained periodic breathing was induced by hypoxia. Thus, mild hypoxia has little steady-state effect on heart rate and respiratory rate and pattern in these unanaesthetized newborns. These findings are compatible with depressed chemoreceptor threshold, but indicate a remarkably mature respiratory pattern in full-term newborns of these species.
Neural control of jejunal and ileal motility and transmural potential difference in the ferret
Authors: Greenwood Beverley , Read N. W.
Published: April 2011

The aim of the present study was to examine the vagal control of motor activity and transmural potential difference in the anaesthetized ferret jejunum and ileum in vivo. The data suggest that in the jejunum fluctuations in transmural potential difference occur secondary to spontaneous bursts of contractions and both are controlled by activity in the vagus nerve. However, in the ileum, spontaneous contractile activity and transmural potential difference are not under the tonic influence of the vagus nerve, although transmural potential difference may be under tonic sympathetic control. Furthermore, it appears that vagally induced motor activity and transmural potential difference responses are independent phenomena. Finally the changes in transmural potential difference and the long latency motor responses to vagal nerve stimulation in the small intestine of the ferret are mediated at least in part by noncholinergic transmitters.
Effect of a volatile anesthetic upon presynaptic excitability in mammalian hippocampus
Authors: Saint D. A. , Quastel D. M. J. , Chirwa S.
Published: April 2011

Changes in presynaptic terminal axon excitability produced by enflurane in the rat hippocampal slice preparation were investigated by stimulation of Schaeffer collateral terminal axons and by recording single unit antidromic action potentials. Stimulating pulses were preceded by conditioning hyperpolarizing or depolarizing current pulses. A plot of net threshold for action potential generation against the conditioning pulse yields an "accommodation curve;" changes in this curve can be used to assess the mechanism by which changes in excitability are produced. Enflurane, at a concentration equivalent to [Formula: see text] times the minimum alveolar concentration, reduced excitability of terminal axons and increased accommodation in a manner consistent with a possible change in the inactivation of gNa.
Maintenance of tone, role of arachidonate metabolites, and effects of sensitization in guinea pig trachea
Authors: Mansour S. , Daniel E. E.
Published: April 2011

A study was made of the mechanisms underlying production of resting active tension in guinea pig tracheal smooth muscle and the changes with active sensitization to ovalbumin. The same types of tissues were also analyzed as to their responses to arachidonate. Responses for each tissue were expressed in relation to a scale between zero active tension and maximum active tension in response to carbachol. A variety of selective and nonselective inhibitors of cyclooxygenase or 5-lipoxygenase were shown to affect active tension in a manner consistent with the conclusion that a cyclooxygenase product, probably prostaglandin F(PGF2α) and not thromboxanes was chiefly responsible. The inhibition of active tension produced by cyclooxygenase inhibition was shown to be related to the initial active tension, such that tissues with greater resting active tension had greater reductions in tone. No differences of major importance were found as to the mechanisms underlying tone production in control and sensitized tissues. The tension changes in response to exogenous arachidonate were also found to be dependent on the initial level of active tension; when this was low, tension increased, when it was high, tension decreased or did not change. Effects of inhibitors on these responses were again consistent with the conclusion that primarily excitant prostaglandins, not thromboxanes, were produced. Some suggestive evidence for production of excitatory and inhibitory nonprostaglandin metabolites was obtained. No difference of major importance between control and sensitized tissues was observed in the magnitude or underlying mechanism of production of active tension.
Interaction of metallothionein and carbon tetrachloride on the protective effect of zinc on hepatotoxicity
Authors: Clarke I. S. , Lui E. M. K.
Published: April 2011

To study the influence of hepatic metallothionein (MT) on the hepatotoxic response to carbon tetrachloride (CCl4), adult male rats were pretreated with a 10 mg∙kg−1 dose of zinc (Zn) 24 h prior to CCl4 (i.p., 1 mL∙kg−1) treatment. Zn pretreatment increased the hepatic MT concentrations markedly and reduced the magnitudes of the CCl4-induced reduction of cytochrome P450 concentration as well as elevation of serum alanine aminotransferase and aspartate aminotransferase activities when determined at 4 or 24 h following CCl4 treatment. Treatment of Zn-exposed animals with CCl4 also resulted in significant reduction of the concentrations of hepatic MT (as determined by the cadmium-saturation method) as well as cytosolic Zn. Sephadex G-75 chromatographic study of hepatic cytosols showed that MT-bound Zn was selectively depleted by CCl4 exposure. Moreover, it was demonstrated that CCl4, after metabolic activation, reduced the cadmium binding capacity of Zn-induced hepatic MT in vitro. To examine the possible protective effect of Zn independent of induction of MT synthesis, CCl4 was administered 2 h following Zn pretreatment and the hepatotoxic response was examined 4 h later. This study revealed limited protection by Zn prior to the induction of MT synthesis. These data further support a role of MT in the modulation of CCl4 hepatotoxicity.
Metabolism and disposition of 3,6-dibutanoylmorphine in rat brain
Authors: Tasker R. A. R. , Nakatsu K.
Published: April 2011

In previous studies from this laboratory it was found that dibutanoylmorphine (DBM) was more potent than morphine as an analgesic in rats and that it was less active than acetyl esters of morphine on behaviour. As DBM is a morphine prodrug, the aim of this work was to determine if rat brain homogenates were capable of deacylating DBM and monobutanoylmorphine (MBM) and to determine relative proportions of parent drug to metabolites in the brain in vivo. In 10% (w/v) brain homogenates, DBM was eliminated with a half-life of about 70 min (corrected for dilution), while MBM was eliminated 10 times as quickly. DBM and its metabolites were found in both blood and brain as early as 1 min after i.v. administration of DBM. After 5 min, the predominant form in blood was MBM and in brain it was DBM. Thus, rat brain possesses the capacity to metabolize DBM by deesterification and the parent drug, MBM, and morphine were found in blood and brain in vivo.
Effects of acute and chronic administration of sotalol on the blood pressure and the sympathoadrenal activity of anesthetized deoxycorticosterone acetate – salt hypertensive rats
Authors: Bouvier Michel , Champlain Jacques De
Published: April 2011

Using plasma catecholamine (CA) levels as an index of the sympathoadrenal activity, the effects of chronic and acute beta-blockade on the blood pressure and sympathetic activity were evaluated in deoxycorticosterone acetate (DOCA) – salt hypertensive (HT) rats. The acute administration of one beta-blocker (sotalol, 5 mg/kg) to intact of vagotomized anesthetized HT animals induced a significant decrease in plasma norepinephrine (NE) concentrations and mean arterial pressure (MAP). The amplitude of the decrease of the MAP or NE levels were linearly correlated with the basal NE levels, suggesting that sotalol reduced the blood pressure and sympathetic NE release more efficiently in rats with increased sympathetic activity. Similarly, chronic infusion of sotalol (1.5 mg∙day−1∙rat−1) through an osmotic pump for 12 days in DOCA-salt HT rats significantly reduced NE and epinephrine (E) plasma levels compared with those observed in untreated DOCA-salt HT rats. Moreover, the chronic treatment with sotalol significantly reduced the plasma E elevation induced by bilateral carotid occlusion (CO) in vagotomized normotensive (NT) and HT rats. It therefore appears that acute administration of sotalol to HT rats causes a significant reduction in the sympathetic activity which is associated to a decrease in MAP. Although chronic sotalol treatment causes a significant reduction in the sympathoadrenal basal activity and in the adrenal reactivity, this treatment did not prevent the development of DOCA-salt hypertension.
Dense-cored membrane structures in rat myometrial smooth muscle cells: increase in number during parturition
Authors: Kwan Chiu-Yin , Berezin I. , Daniel E. E. , Lee R. M. K. W.
Published: April 2011

Membrane-bound structures containing electron-dense material were found in the cytoplasm of the smooth muscle cells of rat myometrium. Most of these structures were observed as membrane-bound vesicles with a variable diameter in the range of 50–90 nm. Some of these were present underneath the cell membranes among the clusters of caveolae and some were found deep in the interior of the smooth muscle cell. The number of such structures progressively increased with gestation reaching the maximum during parturition and decreasing to a minimal level 2 days postpartum, suggesting that the occurrence of these structures is of physiological relevance in parturition. Ovariectomy of the pregnant rats had no influence upon the temporal distribution of these structures within the gestation period, indicating that hormones of ovarian origin are not responsible for the maintenance of these structures during their disappearance after parturition.
Nonlinear stiffness–force relationships in whole mammalian skeletal muscles
Authors: Stein R. B. , Gordon T.
Published: April 2011

Small, sinusoidal length changes were superimposed on isometric contractions of fast- and slow-twitch mouse muscles, which were stimulated maximally via their nerves. Stiffness increased with increasing frequency of sinusoidal stimulation, but the relative time course of force and stiffness changes during twitch, tetanic, or partially fused contractions was quite invariant over a range of frequencies in both muscles. Typically, stiffness increases more rapidly than force during contraction and decreases less rapidly during relaxation. This pattern was observed at various temperatures and with various numbers of stimuli. It can be described by a nonlinear relation between stiffness and force with some hysteresis. The presence in the muscle of parallel and series elastic elements, whose stiffness varies with force, may account for the nonlinear relation. This nonlinearity can be used to relate the patterns for summation of force and stiffness observed with brief trains of stimuli under a variety of conditions.
Desensitization of the vascular contractile response to cumulative doses of α2-adrenoceptor agonists
Authors: Cheung D. W.
Published: April 2011

Contractile responses to single or cumulative doses of α-adrenoceptor agonists were compared in the tail artery and the saphenous vein of the rat. In the rat tail artery, there were no differences in the dose–response relationships to noradrenaline, methoxamine, and KCl whether the agonists were applied as single or cumulative doses. However, the responses to single doses of clonidine and B-HT 920 were significantly larger than similar doses applied cumulatively. In the rat saphenous vein, responses to single doses of noradrenaline, clonidine, and B-HT 920 were also significantly larger than the corresponding cumulative doses. However, there was no difference in the responses to KCl. It was suggested that desensitization of α2-adrenoceptors in these vessels may result in the diminished responses to cumulative doses of the agonists. Desensitization appeared to be specific to α2-adrenoceptors, since the effect was not observed in responses mediated by the α1-adrenoceptors and KCl.
Adult ventricular myocytes isolated from CHF 146 and CHF 147 cardiomyopathic hamsters
Authors: Hunter E. G.
Published: April 2011

Single ventricular myocytes have been isolated from normal and cardiomyopathic hamsters using a collagenase method. The procedure produces calcium-tolerant myocytes that are viable and appear on light and electron microscopic examination to be healthy. These cells respond to electrical stimulus and have normal intracellular resting and action potentials.
L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl]-γ-oxo-benzenebutanoate: a leukotriene D4 receptor antagonist
Authors: Jones T. R. , Guindon Y. , Young R. , Champion E. , Charette L. , Denis D. , Ethier D. , Hamel R. , Ford-Hutchinson A. W. , Fortin R. , Letts G. , Masson P. , McFarlane C. , Piechuta H. , Rokach J. , Yoakim C. , DeHaven R. N. , Maycock A. , Pong S. S.
Published: April 2011

L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]-γ-oxo-benzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (KB value of 4.0 μM) and to a lesser extent [3H]leukotriene C4 (Ki value of 36.7 μM) binding in guinea pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotrienes C4, D4, E4, and F4 in concentrations that did not antagonize contractions induced by acetylcholine, histamine, serotonin, prostaglandin F2α, or U-44069 (endoperoxide analogue). Schild plot analysis indicated that L-648,051 competitively antagonized contractions of guinea pig ileum induced by leukotriene D4 (pA2 7.7) and contractions of trachea induced by leukotrienes D4, E4, and F4 (pA2 7.3, 7.4, and 7.5, respectively). Contractions of guinea pig trachea induced by leukotriene C4 were inhibited in a noncompetitive fashion (Schild plot slope, 0.45). Developed contractions of trachea induced by the leukotrienes were rapidly reversed by L-648,051 > FPL-55712 > L-649,923. Intravenous L-648,051 selectively blocked bronchoconstriction induced in anaesthetized guinea pigs by intravenous leukotrienes C4, D4, and E4 but not that induced by arachidonic acid, serotonin, U-44069, or acetylcholine. The compound displayed poor activity following intraduodenal administration. The profile of activity for L-648,051 indicates that it may be a useful topical agent for studying the role of leukotrienes in diseases such as bronchial asthma.
Comparative effects of rauwolscine, prazosin, and phentolamine on blood pressure and cardiac output in anesthetized rats
Authors: Tabrizchi Reza , Pang Catherine Cheuk Ying
Published: April 2011

The endogenous role of the α-adrenergic system in the maintenance of mean arterial pressure (MAP), total peripheral resistance (TPR), cardiac output (CO) and its distribution, and plasma norepinephrine and epinephrine release was investigated by the administration of selective α-adrenoceptor antagonists to halothane-anesthetized rats. The blockade of α1, α2-, and both α1 and α2-receptors was accomplished by i.v. infusions of prazosin, rauwolscine, and phentolamine, respectively. The microsphere technique was used for the determination of CO and its distribution. Since the infusions of the three antagonists caused similar decreases of MAP and heart rate, the results suggest that postjunctional α1 and α2-receptors are both important in the control of MAP. During the infusion of prazosin, TPR was decreased but CO was not changed. In contrast, CO was decreased but TPR was not changed during the infusions of rauwolscine and phentolamine. Thus, CO was reduced after the blockade of α2-but not α1 receptors. All three antagonists caused an increase in percent distribution of CO to the lungs and muscle, suggesting that the sympathetic nervous system plays the greatest vasoconstrictor influence in the lungs and muscle via stimulations of both subtypes of α-adrenoceptors. The administration of either prazosin or rauwolscine caused little change in plasma catecholamine levels. In contrast, phentolamine caused large increases in both epinephrine and norepinephrine levels. Therefore catecholamine release was only increased after concurrent blockade of both α1 and α2-adrenoceptors.
Stereospecific binding of a new benzazepine, [3H]SCH23390, in cortex and neostriatum
Authors: Brière Richard , Diop Laurent , Gottberg Estela , Grondin Louise , Reader Tomás A.
Published: April 2011

The binding of the D1 antagonist SCH23390 to membrane preparations from rat cerebral cortex was examined using enantiomers of dopamine agonists and antagonists to compete with the bound [3H]SCH23390 at its Kd value. The competition curves were compared with those obtained with preparations from the neostriatum. The results demonstrate that specific [3H]SCH23390 binding in the cerebral cortex has the same pharmacological profile as in the neostriatum, so that this radioligand can be used to label dopamine D1 receptors in brain regions with a sparse dopaminergic innervation.
Sarcoplasmic reticulum Ca2+ transport and long chain acylcarnitines in hyperthyroidism
Authors: Black Shawn C. , McNeill John H. , Katz Sidney
Published: April 2011

Male Wistar rats were treated with L-3,5,3′-triiodothyronine (T3) (500 μg∙kg∙−1∙day−1) for 3 days. Cardiac sarcoplasmic reticulum (SR) was isolated at several time points during the induction of the hyperthyroid state and calcium transport and the levels of carnitine derivatives were determined. Calcium transport was augmented at all free calcium concentrations assayed (0.1–5.3 μM) 24 h following a single dose of T3; at 48 and 72 h, calcium transport was further augmented. Calcium-dependent phosphoprotein levels were increased in the SR of the 48- and 72-h T3-treated groups. Total SR carnitine was reduced after 24, 48, and 72 h of treatment. Long chain acylcarnitine (LCAC) levels were decreased in T3-treated SR at 48 and 72 h. This study shows that calcium transport is increased in T3-treated rat heart SR and that this increase may be related to a reduction in the endogenous level of LCAC in the SR membrane.
Patterns of isosorbide dinitrate and glyceryl trinitrate metabolites formed by selected segments of the rabbit gastrointestinal tract
Authors: Tam Glen S. , MacMillan Heather , Bennett Brian M. , Marks Gerald S. , Brien James F. , Nakatsu Kanji
Published: April 2011

Homogenates of selected segments of the rabbit gastrointestinal tract (GIT) were studied for their ability to biotransform isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) to their mono- and di-nitrate metabolites, respectively. In addition, preferential formation of certain metabolites was investigated by examination of the patterns of metabolites formed by the various homogenates. After a 30-min incubation of ISDN with GIT homogenates (pH 7.4, 37 °C), the percent disappearance of ISDN and the ratio of isosorbide-2-mononitrate (2-ISMN) to isosorbide-5-mononitrate (5-ISMN) were as follows: stomach, 32%, 0.8; duodenum, 65%, 0.1; jejunum, 59%, 0.2; ileum, 38%, 1.2; cecum, 33%, 2.7; and colon, 32%, 3.4. After a 5-min incubation of GTN with GIT homogenates, the percent disappearance of GTN and the ratio of glyceryl-1,3-dinitrate (1,3-GDN) to glyceryl-1,2-dinitrate (1,2-GDN) were as follows: duodenum, 54%, 0.65; ileum, 73%, 0.68; and colon, 61%, 0.17. Incubation of 2 × 10−7 M ISDN with mucosal and muscularis homogenates of duodenum, jejunum, and ileum resulted in significant losses of ISDN with an equimolar formation of the mononitrate metabolites. Most of the metabolic activity for ISDN resided in the mucosal layer of each section. The ratio of 2-ISMN to 5-ISMN varied in each section (stomach to colon) and cross section (mucosal versus muscularis) of the GIT. We conclude that the metabolism of ISDN and GTN by the GIT may contribute to the high clearance of these organic nitrates, and the low oral bioavailability of ISDN. Also, multiple mechanisms appear to be involved in the biotransformation of ISDN and GTN in the rabbit GIT.
Effect of reduced Na gradient on electrical activity in isolated bovine and feline ventricular myocytes
Authors: Horackova Magda , Beresewicz Andrzej , Isenberg Gerrit
Published: April 2011

We have studied changes in electrical activity resulting from abrupt alterations of the Na gradient, using ventricular myocytes isolated from feline and bovine hearts. Attempting to investigate the ionic current possibly generated by Na–Ca exchange, we studied the effects of the changes in [Na]o in the presence of 20 mM CsCl to inhibit K currents. To facilitate the effect of Cs, we also used a K-free solution and a patch electrode filled with 150 mM cesium glutamate. The application of 20 mM Nao resulted in hyperpolarization and the action potential duration was reduced. Under voltage clamp, 20 or 45 mM Nao generated an outward current at all membrane potentials investigated. The initial part (100–200 ms) of this current was only partially inhibited by 5 mM NiCl2 which is known to fully block the Ca inward current. However, the outward current generated by the reduced [Na]o was fully inhibited by 20 mM MnCl2 (which presumably inhibits Na–Ca exchange). Our observations extend the work on multicellular cardiac preparations indicating that the outward current elicited by a sudden decrease in Na gradient could be generated by Na–Ca exchange. Although the characteristics of this outward current support certain concepts of the Na–Ca exchange in cardiac muscle, we cannot at present exclude a contribution of other membrane current(s).
Sensorimotor transformations underlying the organization of arm movements in three-dimensional space
Authors: Soechting J. F. , Terzuolo C. A.
Published: April 2011

Coordinated movements in three-dimensional space involve sensorimotor transformations between extrinsic and intrinsic coordinates. It is hypothesized that a key aspect underlying the organization of such movements is the need to simplify these transformations by means of suitable approximations and the imposition of constraints. Motor tasks involving the drawing of circles and ellipses in different planes were analyzed from this perspective, and some rules are presented whereby the plane of motion and the slant of an ellipse can be specified in a simple way in terms of intrinsic parameters. It is shown that these rules can be generalized to hold for more complicated wrist motions if one assumes that they consist of segments of elliptical arcs.
Relationship between transmural potential difference and smooth muscle slow waves and contractility in the rabbit small intestine in vitro
Authors: Greenwood Beverley , Huizinga Jan D. , Chow Edwin , Dodds Wylie J.
Published: April 2011

The relationship between transmural potential difference (PD) and smooth muscle electrical and mechanical activity was investigated in the rabbit ileum in vitro. Transmural PD was monitored using agar salt bridge electrodes connected via calomel half cells to an electrometer. Force displacement transducers recorded predominantly longitudinal smooth muscle activity. Concurrently, predominantly circular muscle activity was recorded at three sites using intraluminal pressure probes. At the same sites, suction electrodes monitored electrical activity of the smooth muscle. In all experiments, fluctuations in transmural PD were temporally linked to smooth muscle mechanical and electrical activity. The frequency of PD oscillations, electrical slow waves, and cyclic pressure changes were identical within each segment. Adrenaline abolished smooth muscle electrical spiking, all mechanical activity, and transmural fluctuations in PD. However, the slow waves were not abolished, though their frequency was increased. Phentolamine but not propranolol reversed the effects of adrenaline, thus slow wave frequency is influenced by α-adrenergic stimulation in the rabbit ileum. In conclusion, oscillations in transmural PD are unrelated to the ionic processes associated with the slow wave. However, they are in some way linked to smooth muscle contractile activity, possibly via an intrinsic neural mechanism as observed in the guinea pig.
Increased retinoic acid metabolism following 3,3′,4,4′,5,5′-hexabromobiphenyl injection
Authors: Spear P. A. , Garcin H. , Narbonne J.-F.
Published: April 2011

Young male Wistar rats received single i.p. injections of 3,3′,4,4′,5,5′-hexabromobiphenyl. In rats dosed with 40 mg/kg, food consumption and growth as well as liver retinol and retinyl palmitate concentrations decreased, while serum retinol and liver weight increased within 28 days following the injection. In rats receiving a 20-mg/kg dose, food consumption, growth, liver weight, and serum retinol were not affected, although liver retinol and retinyl palmitate concentrations declined to 23 and 21% of their respective control values. Vitamin A metabolism was studied in liver microsomes prepared from rats sacrificed 7 days after the 20-mg/kg injection. The rate of retinoic acid hydroxylation via the cytochrome P-450 system to 4-hydroxyretinoic acid plus the subsequent oxidation to 4-ketoretinoic acid was significantly elevated. Retinoic acid conjugation by UDP-glucuronyl transferase was also significantly increased. These changes corresponded with increased activities of cytochrome P-450-dependent aryl hydrocarbon hydroxylase and UDP-glucuronyltransferase conjugation of p-nitrophenol. These results provide a direct link between enzyme induction due to xenobiotics and specific steps in the vitamin A metabolic pathway.
Hepatic blood flow: estimation from clearances of very low dose infusions of ethanol in cats
Authors: Greenway C. V. , Lautt W. W. , Sitar D. S.
Published: April 2011

Experiments were carried out to determine the accuracy and validity of estimations of hepatic blood flow from systemic clearances of ethanol during very low dose (8 μmol∙min−1∙kg−1) infusions of ethanol in anesthetized cats. Systemic clearances were compared with directly measured hepatic blood flow using a hepatic venous long-circuit technique. This technique allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. In 18 cats, Vmax for ethanol was 93 ± 7 μmol∙min−1 per 100 g liver or 21 ± 2 μmol∙min−1∙kg·body weight−1 and Km was 144 ± 19 μM in terms of logarithmic mean sinusoidal concentration. At the dose of 8 μmol∙min−1∙kg body weight−1 used for estimation of hepatic blood flow, extraction was 0.95 ± 0.07 (mean ± SD). Systemic clearance of ethanol overestimated directly measured hepatic blood flow by 15 ± 16%. Hepatic blood flow changes expressed as percentages of the control level were accurately estimated from systemic ethanol clearance (100 ± 10%). Since 73 ± 12% of the infused ethanol was eliminated by the liver and 83 ± 11% was eliminated by the splanchnic bed, an extrasplanchnic uptake of 17% accounted for the overestimation of hepatic blood flow. Estimation of hepatic blood flow from systemic clearances of ethanol during very low dose infusions may have advantages over other clearance methods. Its use in cats was illustrated in a separate series of experiments and it was shown that surgery significantly reduced hepatic blood flow. The method may merit trial for estimation of hepatic blood flow in humans.
Cardiac excitation–contraction coupling: new developments
Authors: Bose D.
Published: April 2011

Over 100 years have elapsed since Sidney Ringer made the serendipitous discovery that calcium played a crucial role in amphibian cardiac contraction. Since then we have learned that this ion is an obligatory requirement for cardiac muscle of all species, and that the regulation of intracellular calcium levels is considerably more complex in the mammalian heart than previously thought. Part of this complexity is due to the involved design requirements of mammalian physiological processes. Another element of complexity is introduced by the quantitative differences in the involvement of various regulatory processes in different species. Finally, many significant technological advances in methods for investigating cardiac cellular functions have provided exciting experimental data. However, these data must be integrated into a unifying framework of knowledge of cardiac functions. Among the exciting recent developments are the use of a patch clamp technique to discover different kinds of calcium channels, a highly refined skinned fiber technique to study calcium-induced calcium release, and calcium indicator dyes and laser diffraction and scattering techniques to study the dynamics of calcium handling by the cell. These studies have not only provided clues about the normal functioning of the myocardial cell but have also reinforced the notion that altered function of the sarcoplasmic reticulum during intracellular calcium overload can influence sarcolemmal electrical function.This symposium, organized by the Pharmacological Society of Canada, examined some of the more recent technological advances in the field to provide a glimpse not only of the "state of the art" but also of future directions.This symposium was made possible by generous financial assistance from Boehringer Ingelheim (Canada) Ltd., Bristol-Myers Pharmaceutical Group, Canadian and Manitoba Heart Foundations, Ciba-Geigy Canada Ltd., Du Pont Canada Inc., Hoffmann LaRoche Ltd., Merck-Frosst Canada Inc., Miles Laboratories Inc., Nordic Laboratories Inc., Pfizer (Canada) Inc., Rhône-Poulenc Pharmaceuticals Inc., G. D. Searle of Canada, Ltd., Squibb Canada Inc., Sterling Drugs Ltd./Winthrop Laboratories, the Upjohn Company of Canada, and the University of Manitoba Pharmacology Department.
Scattered light intensity fluctuation in the canine ventricular myocardium: correlation with inotropic drug effect
Authors: Bose D. , Kobayashi T. , Bouchard R. A. , Hryshko L. V.
Published: April 2011

Scattered light intensity fluctuation (SLIF) of coherent light by a strip of ventricular muscle during diastole is believed to be due to asynchronous cellular motion within the myocyte as a result of spontaneous release of Ca from the sarcoplasmic reticulum. Previous studies have shown a correlation between inotropic agents, such as ouabain and elevated extracellular Ca or decreased extracellular Na, and SLIF. The purpose of this study was to see if this correlation could be extended to other inotropic agents. The digitalis genin, ouabagenin, produces inotropy by increasing intracellular free Ca. In toxic concentrations the drug produces abnormal aftercontractions by spontaneous Ca release from the sarcoplasmic reticulum. On the other hand, the Ca channel agonist BAY k 8644 is also positively inotropic, but its effect is associated with a decrease in Ca release from the sarcoplasmic reticulum, manifested by conversion of "rest potentiation" to "rest depression." The effects of these inotropic agents on the power spectra of SLIF were dissimilar. Both frequency and amplitude of SLIF were increased after ouabagenin (1 μM), but these changes were most marked after the onset of toxicity, at which time contractility was decreased, rather than during the positive inotropic response. In contrast, BAY k 8644 (1 μM) decreased SLIF at all levels of inotropic response. The β-adrenoceptor stimulant drug, dobutamine, and the adenylate cyclase activator, forskolin, produced minimal increase in SLIF at inotropic concentrations but caused a large increase in SLIF only after the onset of toxicity. These results suggest that SLIF is a better indicator of intracellular Ca overload and toxic oscillatory contractions in the presence of an inotrope and not of increased inotropy, per se.
Hepatocellular water and electrolyte secretion
Authors: Bear Christine E. , Shaffer Eldon A.
Published: April 2011

The study of hepatocellular water and electrolyte secretion has been hampered because of the inaccessibility of the hepatobiliary secretory lumen, the canaliculus. The advent of novel experimental models has allowed the application of electrophysiological techniques to investigate the ionic basis of hepatocellular secretion. The "hepatocyte couplet" isolated from the liver in primary monolayer cultures consists of two hepatocytes which enclose a single canalicular unit. The canaliculus of the couplet appears to behave as it would in vivo, exhibiting both secretory and contractile activity. Intracellular microelectrode recordings from this functional unit have permitted direct electrophysiological assessment of cellular and canalicular potentials and measurement of individual ion conductances across the basolateral membrane surface. Further, the application of patch-clamp electrophysiology to study hepatocellular ion transport pathways has characterized individual channel proteins. Intracellular and (or) patch-clamp electrophysiology has elucidated the ion conductance changes activated by bile salts like taurocholate, neurotransmitters like adrenaline, and hormones such as glucagon. These innovative approaches hold much promise in the future study of the ionic basis of hepatocellular secretion.
Voltage-dependent blockade in Na+-dependent action potentials after β1- and H2-receptor stimulation in mammalian ventricular myocardium
Authors: Gillis A. M. , Kohlhardt M.
Published: April 2011

In isolated papillary muscles of guinea pigs, the influence of isoproterenol, histamine, theophylline, and phenylephrine on the maximal rate of rise [Formula: see text] of Na+-dependent action potentials and on isometric contractile force was studied under rested state conditions. Isoproterenol (1 × 10−7 mol/L), histamine (2 × 10−5 mol/L), and theophylline (2 × 10−3 mol/L) shifted the voltage dependence of [Formula: see text] into the hyperpolarizing direction and, consequently, led to a voltage-dependent [Formula: see text] blockade. The α-adrenoceptor agonist phenylephrine, on the other hand, proved to be ineffective in depressing [Formula: see text]. The β-receptor blocker pindolol (4 × 10−6 mol/L) or the H2-receptor blocker cimetidine (4 × 10−5 mol/L) abolished the inhibitory effects of isoproterenol and histamine, respectively, and caused [Formula: see text] to return to the initial control value. A concentration–response relationship analysis at −65 mV revealed that isoproterenol exerted only a weak inhibitory effect on [Formula: see text] compared with its positive inotropic action. The IC50 value of the former effect amounted to approximately 5 × 10−6 mol/L, but the EC50 value of the latter effect was 4 × 10−8 mol/L. It is, therefore, concluded that, in physiologically relevant concentrations, β-adrenergic agonists are unlikely to significantly modulate Na+-dependent excitability even in partially depolarized myocardium.
Recovery from heart failure: structural and functional analysis in a canine model
Authors: Howard Robert J. , Stopps Terrance P. , Moe Gordon W. , Gotlieb Avrum , Armstrong Paul W.
Published: April 2011

Chronic, rapid ventricular pacing produces congestive heart failure in the dog. Using echocardiography, the features of developing heart failure were analysed and the capacity of this model for recovery was assessed once pacing had been discontinued. Fifteen dogs were studied; nine were paced at 250 beats/min (bpm) to severe heart failure (5.0 ± 1.8 weeks) and six served as sham controls. In the paced animals at severe heart failure, two-dimensional echocardiography demonstrated a significant increase in diastolic cross-sectional cardiac area (from 11 ± 3 to16 ± 2 cm2, p < 0.05), associated with a marked fall in area ejection fraction (54 ± 8 to 21 ± 8%, p < 0.05), and significant left ventricular wall thinning (from 6.0 ± 0.7to4.7 ± 0.9 mm, p < 0.05). In addition, significant increases in heart rate (77 ± 7 to 126 ± 13 bpm, sinus rhythm; p < 0.05), respiratory rate (41 ± 13 to 80 ± 20 cycles/min, p < 0.05), and body weight (21 ± 1 to 24 ± 3 kg, p < 0.05) were noted. Serum sodium fell (146 ± 3 to 140 ± 8 mmol/L, p < 0.05), while blood urea nitrogen (6 ± 2 to 10 ± 2 mmol/L, p < 0.05) and creatinine (86 ± 12 to 101 ± 15 mmol/d, p < 0.05) increased. Recovery was characterized by rapid improvement such that all measured parameters normalized by 1 week, except for cross-sectional cardiac area which remained dilated up to 4 weeks (14 ± 3 cm2, p < 0.05 versus control). Necropsy data obtained from paced dogs after 4 weeks of recovery demonstrated cardiac hypertrophy when compared with sham controls (9.4 ± 1.2 versus 7.7 ± 0.9 g/kg, p < 0.05), but no histologic abnormality was revealed under light microscopy. Left ventricular norepinephrine levels were similar to those of sham controls (617 ± 323 versus 676 ± 177 ng/g wet weight, not significant). The rapid recovery of ventricular systolic performance demonstrated in this heart failure model suggests that reversible substrate depletion is the mechanism responsible. Despite this recovery, there is persistent diastolic enlargement of the left ventricle indicating that structural remodeling has taken place.
Effect of anaesthesia on insulin-induced hypoglycemia in rabbits
Authors: Haynes Fred J. , Cheema-Dhadli Surinder , Halperin Ross M. , Zettle Randy , Robinson Lisa , Halperin Mitchell L.
Published: April 2011

The aim of this study was to determine how anaesthetized rabbits survive much longer than awake rabbits after receiving an insulin overdose. Insulin appeared to act in both groups of rabbits because there was a prompt fall in circulating glucose, free fatty acids, and β-hydroxybutyrate concentrations. Carbohydrate appeared to be the principal energy source for anaesthetized rabbits because their respiratory quotient approached unity. Although the fall in glycemia was similar in both groups of rabbits, the circulating lactate concentration rose only in the anaesthetized group. This rise in lactate in the initial 60 min after insulin was given could account for most of the fall in glycemia if the source of lactate was the glucose pool. The decline in hepatic glycogen was close to 100 μmol/g liver; this would account for about one-third of the total energy turnover and close to one-half of the measured glucose appearance in these anaesthetized rabbits. As judged from the rate of oxygen consumption, muscle glycogen seemed to supply two-thirds of the fuel to be oxidized in these rabbits. However, only one-third of the lactate released from muscle was first converted to glucose and the remainder was oxidized directly to CO2. Although insulin provided the metabolic setting for a rapid rate of glucose oxidation, this rate appeared to be diminished when the overall rate of oxygen consumption was lower during anaesthesia.
Effect of stimulation frequency on intracellular Na+ activity in rat atrial muscle
Authors: Ruch Stuart , Kennedy Richard H. , Seifen Ernst
Published: April 2011

Mean intracellular Na+ activity [Formula: see text] was measured in rat left atrial muscle stimulated at increasing frequencies between 0 and 12 Hz. Low-pass filtered signals from conventional and ion-selective microelectrodes were used to determine [Formula: see text]. Preparations were bathed in a low Ca2+ (0.1 mM) Krebs–Henseleit buffer containing 1.0 mM Mn2+ to abolish contractile motion and permit stable impalements. Under these conditions, [Formula: see text] increased progressively with frequency from 5.8 ± 1.5 mM at 0 Hz to a maximum of 12.7 ± 2.1 mM, which was observed at 10, 11, or 12 Hz. Further increases in frequency exceeded the effective refractory period, and [Formula: see text] tended to decrease. These data suggest that [Formula: see text] can be approximately doubled in rat atrial muscle by increasing the depolarization rate from 0 to 10–12 Hz, a range that has been shown to elicit a two- to three-fold elevation in Na+-pump activity in similar preparations.
Serotonin blocks the facilitatory action of muscarinic and nicotinic agents in the hippocampus in vivo
Authors: Hong Y. , Krnjević K.
Published: April 2011

The inhibitory effect of serotonin, released iontophoretically, on acetylcholine-induced facilitation of population spikes evoked by fimbria–commissural stimulation was studied in the CA1 region of rat hippocampus in vivo. After serotonin was applied for 2.6 ± 0.8 min, acetylcholine's action was inhibited in 39 cases out of 57 (68.4%), by 68.9 ± 23.1%, irrespective of whether serotonin alone increased or reduced the population spike. Spiperone, used as a 5-hydroxytryptamine1A (5-HT1A) antagonist, suppressed the inhibitory action of serotonin in 14 of 21 tests. Serotonin had similar effects on population spike facilitations induced by acetyl-β-methylcholine and dimethylphenylpiperazinium. Thus serotonin, probably acting on 5-HT1A receptors, blocks effectively but indiscriminately all cholinergic facilitations, whether mediated by nicotinic or muscarinic receptors.Key words: serotonin, cholinergic facilitation, hippocampal pyramidal cells, spiperone, muscarinic and nicotinic actions.
Extrarenal production and activation of human plasma prorenin: the evidence after venous occlusion
Authors: Hare Gregory M. T. , Loh Arlene Y. , Osmond Daniel H.
Published: April 2011

Venous occlusion of the left arm in consenting men was induced for 10 or 20 min to stimulate local fibrinolytic and other proteases, thereby favouring the conversion of prorenin to renin. Using the two techniques cryoactivation and tryptic activation, we found that plasma active renin increased significantly after such occlusion (10 and 20 min) while prorenin rose more convincingly and progressively from 10 to 20 min. The renin increase can be partially attributed to hemoconcentration, but in vivo production and (or) local activation of prorenin to renin cannot be excluded. The prorenin rise can apparently be attributed to local extrarenal production, and not to hemoconcentration or influx, since it was progressive and neither prorenin nor renin levels were raised at all in blood circulating outside the occluded arm. Prekallikrein and plasminogen levels were elevated in occlusion plasmas, but responsibility of these enzyme systems for any enhanced activation of prorenin was not established. The trypsin inhibitory capacity was also elevated, increasing the requirement of trypsin to achieve optimal activation of prorenin, but not changing the prorenin estimate itself. Thus, prorenin appears to be released extrarenally, within the vasculature of an occluded arm, while in vitro evidence suggests that the mechanisms for its activation were stimulated. The importance of such extrarenal production and activation of prorenin for renin production under other physiological or pathophysiological conditions remains to be determined.Key words: venous occlusion, extrarenal prorenin, production, activation.
Electrophysiological assessment of putative antagonists of 5-hydroxytryptamine receptors: a single-cell study in the rat dorsal raphe nucleus
Authors: Blier Pierre , Steinberg Suzanne , Chaput Yves , Montigny Claude de
Published: April 2011

The intravenous administration of low doses of lysergic acid diethylamide (LSD) or of the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) depresses the firing activity of dorsal raphe 5-HT-containing neurons, presumably via the activation of 5-HT1A receptors. The present studies were undertaken to determine the effect of different types of 5-HT receptor antagonists on this effect of LSD and 8-OH-DPAT. (−)-Propranolol (2 mg/kg i.v.), methiothepin (2 mg/kg i.p., twice daily for 4 days followed by an additional dose of 2 mg/kg i.p., prior to the experiment), pelanserine (0.5 mg/kg i.v.), and indorenate (125 μg/kg i.v.) failed to block the effects of either LSD or 8-OH-DPAT on the firing activity of 5-HT neurons of the dorsal raphe nucleus. However, spiperone (1 mg/kg i.v.) significantly reduced the effect of both LSD and 8-OH-DPAT. These results indicate that, among the five putative 5-HT receptor antagonists tested, only spiperone can antagonize the suppressant effect of 5-HT receptor agonists on the firing of dorsal raphe 5-HT neurons.Key words: serotonin, dorsal raphe, 5-HT1A receptors, single unit recording.
The effects of propranolol, phentolamine, and atropine on canine coronary vascular gradients
Authors: Klassen Gerald A. , Armour J. Andrew , Garner J. Barry
Published: April 2011

The objective of this study was to measure pressure gradients in the coronary circulation following the administration of three receptor-blocking drugs, propranolol, phentolamine, and atropine when administered singly and in sequence. As well, we examined the responses of these gradients to eight interventions: left stellate ganglion or left vagosympathetic trunk stimulation, administration of isoproterenol, acetylcholine, noradrenaline, adenosine, phenylephrine, or adrenaline. Using a multiple linear regression model we examined the actions and interactions of the receptor-blocking agents on hemodynamic variables and vascular gradients. Propranolol reduced heart rate as expected and blocked the responses to isoproterenol administration. As well, it abolished the epicardial coronary artery diastolic gradient. The gradient was restored when propranolol was the second receptor blocker administered but was abolished when it was the third. Phentolamine induced vasodilation with a decrease in coronary small vessel gradients. This effect persisted without regard to the sequence of administration. When it was the second or third agent it decreased the microcirculation and small vein gradients, an action it did not manifest when given singly. Atropine singly did not alter pressures or gradients; but as the second agent it altered the transmural, outflow tract, epicardial diastolic, and microcirculation and small vein diastolic gradients; and as the third agent the changes were in the transmural, epicardial systolic and diastolic, and small artery systolic and diastolic gradients. The pattern of responses was not predictable and that indicates that unique changes occur in the responses of the coronary circulation when multiple receptor-blocking agents are employed. Adrenergic control tends to dominate in the coronary arterial circulation, and muscarinic control in the coronary microcirculation and veins with considerable overlap.Key words: coronary gradients, propranolol, atropine, phentolamine, neurocontrol.