bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic and physiological response of the rabbit to continuous and intermittent treadmill exercise
Authors: Meng H. , Pierce G. N.
Published: April 2011

Our knowledge of the effects of exercise on the heart is limited by the predominant use of rats as an animal model. The rabbit has many advantages over the rat as an animal model to study. However, little work has characterized its capacity to exercise. The purposes of the present study were to determine if the rabbit could (i) learn to run on a motor-driven treadmill at relatively high speeds using different exercise protocols, and (ii) characterize the various physiological and metabolic responses of the rabbit to acute bouts of exercise. We found that female New Zealand white rabbits had the capacity to run continuously on the treadmill for up to 21 min at 20 m/min until exhausted. Continuous, endurance-type exercise resulted in significant elevations in body temperature, heart rate, and plasma lactate levels. Plasma triglyceride concentration decreased as a function of this type of running whereas plasma glucose levels were unchanged. Twenty-four hours after a bout of running, plasma creatine phosphokinase activity was significantly elevated. The rabbits also had the capacity to learn to run using an intermittent, higher speed protocol. These physically untrained animals could achieve speeds of up to 70 m/min for 10 bouts of 15 s run/30 s rest. Their metabolic and physiological responses to this protocol were similar to those of continuous running with the following exceptions. The decrease in plasma triglyceride was less marked and the increase in plasma lactate was greater after intermittent exercise. Glycogen content of the rabbit vastus lateralis muscle was also significantly depleted after exhaustive, intermittent exercise. Our results demonstrate that rabbits can learn to run using different exercise protocols on a treadmill and, therefore, could serve as an appropriate model in which to study exercise conditioning. Their ability to run at extremely high speeds and withstand relatively intense exercise bouts will be particularly useful in future investigations of the cardiovascular adaptations of the rabbit to exercise training.Key words: exercise, rabbit, treadmill running, lactate, glycogen.
Effects of inositol 1,4,5-trisphosphate injections into cat spinal motoneurons
Authors: Zhang Liang
Published: April 2011

Inositol 1,4,5-trisphosphate (IP3) was injected iontophoretically into cat spinal motoneurons in pentobarbital-anaesthetized cats and nonanaesthetized, decerebrate cats. Injections of IP3 induced a long-lasting, reproducible hyperpolarization without consistent change in input resistance. The peak amplitude of post-spike afterhyperpolarization (AHP) was significantly increased by IP3 when the membrane potential was adjusted to the control level. Intracellular injections of Ca2+ chelators, which depressed the Ca2+-activated AHP, prevented the IP3-induced long-lasting hyperpolarization, suggesting that IP3 acts by a Ca2+-dependent mechanism. Intracellular injections of myo-inositol did not consistently induce hyperpolarizations. Also intracellular injections of Li+, which blocks IP3 catabolism, did not prevent the IP3-evoked hyperpolarization. These data suggest that IP3 itself, rather than its breakdown product myo-inositol, is mainly responsible for the hyperpolarizing effect. Possible mechanisms for the IP3-induced hyperpolarization are discussed.Key words: afterhyperpolarization, Ca2+ chelators, hyperpolarization, inositol trisphosphate, Li+, myo-inositol, phosphoinositide breakdown, spinal motoneurons.
Effect of naloxone and prolonged preganglionic stimulation on noncholinergic transmission in the superior cervical ganglion of the cat
Authors: Bachoo M. , Yip R. , Polosa C.
Published: April 2011

In cats anesthetized with sodium pentobarbital, a supramaximal 40-Hz, 30-s train to the cervical sympathetic trunk, during block of ganglionic cholinergic transmission with hexamethonium and scopolamine, produced a delayed, slow, small amplitude contraction of the nictitating membrane that persisted for several minutes after the end of the stimulus train. The post-stimulus component of the response was due to afterdischarge of the ganglion cells, since section of the post-ganglionic axons at the end of the train resulted in elimination of this component. The amplitude of the slow nictitating membrane response was enhanced in a dose-dependent manner by i.v. injection of naloxone. The enhancement was detectable at a dose as low as 1 μg/kg and was maximal at 10 μg/kg. During continuous preganglionic stimulation at 40 Hz, the amplitude of the slow nictitating membrane response reached a peak in 2–4 min and then faded with time until it became undetectable. Time for 90% decay was 82 ± 5 min (n = 18). The nictitating membrane response to postganglionic nerve stimulation was not modified by prolonged preganglionic stimulation. In three cats, the cervical sympathetic trunk was split into two bundles and one bundle was stimulated continuously at 40 Hz until the slow response disappeared. At this time stimulation of the unconditioned bundle evoked a slow response of normal appearance. This suggests that the process underlying the fade involves only the conditioned axons. Recovery from the fade was slow, the response approaching control by 24 h post-stimulus. In contrast, the nictitating membrane response mediated by ganglionic nicotinic transmission was of amplitude similar to control within the 1st min after the end of a 2-h period of continuous 40 Hz stimulation. The fade and recovery of the slow response may be the consequence of presynaptic events and reflect the exhaustion followed by slow replenishment of the releasable stores of the noncholinergic transmitter. The enhancement of the slow response by naloxone suggests that an inhibitory noncholinergic transmitter, presumably an opioid, is also released by the preganglionic axon terminals.Key words: peptides, opioids, ganglionic transmission, cotransmitters, synapse.
The effects of furosemide and bumetanide on lung liquid production by in vitro lungs from fetal guinea pigs
Authors: Thom J. , Perks A. M.
Published: April 2011

Lungs from fetal guinea pigs of 61 ± 3 days of gestation were supported in vitro for 3 h, and lung liquid secretion rates were measured by a dye dilution technique based on Blue Dextran 2000. Ten preparations that had received no treatment showed an average secretion rate of 1.12 ± 0.28 mL∙kg−1 body weight∙h−1 during the first hour, and there were no significant changes over the following 2 h. In studies of 54 fetal lungs, furosemide, bumetanide, control ethanol carrier, or saline alone were placed in the supporting medium during the middle hour of the 3-h incubations (ABA design). Furosemide at 10−3 M reduced secretion 83.4 ± 16.8%; at 10−4 and 10−5 M it produced smaller reductions. Bumetanide at 10−3 M usually produced reabsorption (129.9 ± 23.0% reduction), at 10−4 M it reduced secretion 30.9 ± 11.8%, but at 10−5 M it was ineffective. Control carrier and saline were without effect. The ability of the loop diuretics to produce reabsorption of fluid in some preparations suggests the unmasking of an active reabsorptive process. The results also suggest that lung liquid secretion in the fetal guinea pig, as in the sheep, is dependent on a Na+ and Cl− cotransport system.Key words: fetus, lung fluid, bumetanide, furosemide.
Hepatic effects of ketoconazole in the male Swiss Webster mouse: temporal changes in drug metabolic parameters
Authors: Whitehouse L. W. , Pakuts A. P. , Paul C. J. , Mueller R. W. , Thomas B. H.
Published: April 2011

There have been conflicting observations regarding the effects of ketoconazole on hepatic metabolism. The objectives of these studies were to determine whether ketoconazole was an enzyme inducer or inhibitor in the mouse and then to establish the time frame of these ketoconazole-induced enzyme changes. Ketoconazole was administered (150 mg/kg p.o. × 4 days) to male Swiss Webster mice. Biochemical observations over a period of 6 days following treatment indicated that ketoconazole had a temporal biphasic effect on the liver. Although liver weight and microsomal protein were elevated, all other parameters monitored were lower at 2 h following ketoconazole treatment. At 24 h after the last dose of ketoconazole, hepatic biochemical parameters (liver wt., % liver wt./body wt., microsomal protein, and cytochrome P-450) were statistically elevated, while enzyme activities (benzphetamine N-demethylation, 6β- and 7α-hydroxylation of testosterone, formation of androstenedione and UDP-glucuronyltransferase) were inhibited. At 72 h the ketoconazole-induced changes in the hepatic biochemical parameters were comparable to those observed at 24 h, and enzymatic parameters generally appeared to be induced by ketoconazole, with the exception of benzphetamine N-demethylase and UDP-glucuronyltransferase, which exhibited lower enzyme activities. Ethoxyresorufin O-deethylase, 7α-hydroxylation of testosterone and glutathione S-transferase, on the other hand, were unaltered by ketoconazole treatment. The opposing effects of ketoconazole on benzphetamine N-demethylase and ethylmorphine N-demethylase at 72 h were further examined. Enzyme kinetics studies indicated that ketoconazole did not effect the Michaelis constants (Km) of the two substrates, but the maximum velocity (Vmax) of the reactions was altered. Six days after drug administration all monitored parameters had returned to control values, indicating the hepatic effects of ketoconazole in the male mouse were temporal.Key words: ketoconazole in mice, hepatic effects, biphasic effects, temporal effects, enzymic effect, enzyme inhibition, enzyme induction.
Potentiation of the halothane-cooling contractures of mammalian muscles by denervation
Authors: Trachez Margarete M. , Sudo R. Takashi , Suarez-Kurtz G.
Published: April 2011

Denervation potentiated the cooling-induced contractures and the halothane-cooling contractures of isolated extensor digitorum longus and soleus muscles of the mouse. These effects were more striking in extensor digitorum longus than in soleus muscles. Significant increases in the peak amplitudes of the halothane-cooling contractures of both muscles and of the cooling contractures of soleus muscle were observed within 2 and 7 days of denervation. The potentiation of the contractures persisted for 90 days, the period of this study. Denervation (>2 days) endowed extensor digitorum longus with the ability to generate cooling contractures in the absence of halothane. The rate of tension development of cooling-induced contractures in the absence or presence of halothane was significantly greater in denervated (2–90 days) than in innervated muscles. Denervation also reduced the effectiveness of procaine in inhibiting the halothane-cooling contractures. It is proposed that the potentiation of cooling-induced contractures in denervated muscles results primarily from an increase in the rate of efflux and in the quantity of Ca2+ released from the sarcoplasmic reticulum, upon cooling and (or) when challenged with halothane.Key words: denervation, excitation–contraction coupling, halothane, cooling-induced contractures, skeletal muscle.
Evaluation of experimental combined toxicity by use of dose–frequency curves: comparison with theoretical additivity as well as independence
Authors: Pöch G. , Dittrich P. , Reiffenstein R. J. , Lenk W. , Schuster A.
Published: April 2011

Dose–frequency curves of toxic effects of a substance A were evaluated in the absence and in the presence of a fixed dose of a second substance B. Data were fitted by the curve–fitting program ALLFIT. Observed combined frequencies of A + B were compared statistically with the expected frequencies of additivity and (or) independence by the χ2-square goodness-of-fit test. The theoretical dose–frequency curves expected for an additive response were obtained by a solely graphical procedure and the theoretical curves for independent effects were calculated from the effects of B and A at certain doses. In rotarod tests with trained mice, the combined deteriorating effect of ethanol and benzodiazepines were significantly over-additive. However, their lethal interaction appeared underadditive in mice. The lethal underadditive interaction of ethanol and phencyclidine (PCP) can be ascribed largely to independent actions of these compounds. Loss of righting reflex was additively enhanced by PCP, whereas PCP overadditively enhanced the effect of ethanol. The insecticidal action of the cholinesterase inhibitors malathion and parathion appeared additive and significantly different from independent interaction. A comparison of results from dose–response curves with isoboles showed good agreement. The method appears as an attractive alternative or as a complementary procedure to the isobolographic analysis. Combination experiments as described can be carried out and evaluated rather simply, with a minimum of expenditure and a maximum of information.Key words: combined toxic effects, statistical evaluation, dose–frequency curves, additivity, independence.
Sex differences in spironolactone induction of rat intestinal and hepatic p-nitrophenol UDP-glucuronyltransferase
Authors: Catania Viviana A. , Luquita Marcelo G. , Carrillo María C. , Mottino Aldo D.
Published: April 2011

In the present study we analyzed the effect of spironolactone administration on hepatic and intestinal p-nitrophenol-UDP-glucuronyltransferase activity. We used microsomal preparations from male and female Wistar rats to establish whether or not this effect was sex dependent. Enzyme activity was measured in the presence of UDP-N-acetylglucosamine, a presumed physiological activator of the enzyme. Female but not male microsomes showed an increase in enzyme activity of both hepatic and intestinal tissue preparations in response to the inducer pretreatment. In addition, the inducer effect observed in female rats showed a tissue-related difference, since percent increase in the intestinal enzyme activity was greater than that in the liver (127 and 52%, respectively). These results suggest that factors regulating enzyme activity or mechanisms involved in the inducer effect of spironolactone could be different in the intestinal mucosa in comparison to the liver. A possible explanation of sex-related response to spironolactone administration was discussed.Key words: p-nitrophenol, UDP-glucuronyltransferase, spironolactone induction, sex differences.
Prevention of Dahl salt-induced hypertension by chronic dietary tryptophan
Authors: Lark Lisa A. , Becker Kathryn B. , Park Ruth E. , Weyhenmeyer James A.
Published: April 2011

Four-week-old inbred Dahl salt-sensitive (DS/JR) and Dahl salt-resistant (DR/JR) rats were placed on an 8% salt diet with or without a supplemental 2.5% tryptophan (Trp). Blood pressures were monitored for the next 5 weeks. Urine volumes and ion concentrations were measured during the 6th week. Blood pressures of DS/JR rats on control diets elevated rapidly and markedly, whereas pressures of DS/JR rats on the Trp-supplemented diet were not significantly elevated over those of DR/JR rats. Pressures of DR/JR rats were unaffected by Trp supplementation. Urinary sodium was significantly greater in DR/JR rats compared with DS/JR rats and was unaffected by Trp supplementation. This suggests that the antihypertensive effect of Trp was not at the level of the kidney. We conclude that dietary Trp blocks the development of hypertension in DS/JR rats maintained on a high salt diet.Key words: hypertension, tryptophan, dietary sodium, Dahl rats.
Clinical application of breath hydrogen measurements
Authors: Perman Jay A.
Published: April 2011

Breath hydrogen (H2) measurements are applied in clinical medicine for the detection of carbohydrate malabsorption. H2 in expired air results when dietary sugars escape absorption in the small intestine, thereby becoming available for bacterial fermentation. H2 produced by bacterial metabolism of the carbohydrate is absorbed into the portal circulation and excreted in breath. Relatively simple collection, storage, and analysis methodologies have been developed in recent years. They permit convenient and noninvasive testing of patients in most age groups for common clinical disorders of digestion and absorption, including lactase deficiency and other disorders of di- and mono-saccharide malabsorption, starch malabsorption, and small bowel bacterial overgrowth. Limitations of breath hydrogen testing are few. Developmental considerations constrain the ease of interpretation of breath H2 measurements in early infancy, and factors affecting intraluminal H2 production by the intestinal flora may occasionally affect the H2 signal. Despite these factors, breath H2 testing has repeatedly been demonstrated to be the most accurate indirect indicator of lactase deficiency, and breath H2 measurments have been widely applied in studying digestion of the entire spectrum of dietary carbohydrates.Key words: breath test, hydrogen, carbohydrate, lactose, bacterial overgrowth.
A comparison of the biological activities of authentic rat GRF(1–43)OH with the analogue rat GRF(1–29)NH2
Authors: Kraicer J. , French M. B. , Lussier B. T. , Moor B. C. , Brazeau P.
Published: April 2011

The purpose of this study was to characterize the biological activity of the synthetic rat growth hormone releasing factor analogue rGRF(1–29)NH2 and to compare its action on growth hormone (GH) release to that of authentic rGRF(1–43)OH. We first compared the concentration–response characteristics of the two peptides in static incubation, and then examined the reversibility and repeatability of the GH response in a perifusion system. Authentic rGRF(1–43)OH was significantly more potent in static incubation (EC50 = 3 × 10−11 M) than the analogue (5 × 10−11 M), whereas the reverse held true in perifusion. The shapes of the GH responses were similar for both peptides in the perifusion system. However, while the GH response to authentic rGRF was repeatable, the prior administration of rGRF(1–29)NH2 significantly reduced (>50%) the GH response to the subsequent administration of either rGRF(1–29)NH2 or rGRF(1–43)OH. Thus authentic rGRF and the synthetic fragment may have different actions at the level of the GRF receptor or at a postreceptor (second messenger) step.Key words: growth hormone, growth hormone releasing factor, adenohypophysis.
Characterization of a high-affinity choline uptake mechanism in the cestode Hymenolepis diminuta
Authors: Webb Rodney A.
Published: April 2011

Radiolabelled choline was taken up by tissue slices of the cestode Hymenolepis diminuta by a sodium-dependent and a sodium-independent mechansim. The sodium-dependent uptake was saturable, against a concentration gradient, displayed structural specificity, and was inhibited, in part, by hemicholinium-3. Kinetic analysis of the sodium-dependent choline uptake showed an apparent Kt = 2.0 μM and a Vmax = 0.146 pmol∙mg−1 wet weight tissue∙min−1, which is consistent with a high-affinity choline uptake (HAChU) mechanism. The rate of uptake or release of choline depended on the magnitude and direction of the sodium gradient, was diminished by high- or low-potassium, but was not chloride or sulphate dependent. A homoexchange mechanism for HAChU was not demonstrated. Evidence was obtained to suggest that HAChU or release of endogenous ACh is regulated by autoreceptors. The choline taken up by the HAChU mechanism was but slowly converted to ACh and other products.Key words: high-affinity sodium-dependent choline uptake, sodium-independent choline uptake, cestode tissue slices, choline metabolism, high-affinity choline transporter.
Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms
Authors: Jin N. , Packer C. S. , Rhoades R. A.
Published: April 2011

Reactive oxygen species (at least relatively high doses) cause contraction of pulmonary arterial smooth muscle. The objective of the present study was to elucidate the possible cellular mechanisms involved in reactive oxygen-mediated contraction. Isolated arterial rings from Sprague–Dawley rats were placed in tissue baths containing Earle's balanced salt solution. The maximum active force production (Po) in response to 80 mM KCl was obtained. All other responses were normalized as percentages of Po for comparative purposes. Exposure to reactive oxygen (generated from either the xanthine oxidase reaction (XO) or the glucose oxidase reaction) resulted in pulmonary arterial muscle developing mean active tension of 17.1 ± 3.0% Po. This contraction was independent of extracellular calcium, since it was not affected by verapamil (a calcium channel blocker) or by placement of the arterial muscle in calcium-free media. Phentolamine (an α1-receptor blocker) and propranolol (a β-receptor blocker) did not diminish the response to XO. Ryanodine (a SR calcium release inhibitor), while reducing the response to norepinephrine, did not affect the response to XO. However, H-7 (an inhibitor of protein kinase C) decreased the XO-mediated contraction by 49%. These results indicate that while Ca2+ may not be involved as a second messenger, protein kinase C activity appears to play a role in the transduction pathway of reactive oxygen species mediated contraction of pulmonary arterial smooth muscle.Key words: muscle calcium, α1-receptor, ryanodine, protein kinase C, vascular smooth muscle, oxygen radicals, verapamil.
Unimpaired induction of drug-metabolizing enzymes in hepatocytes isolated from rats with micronodular cirrhosis
Authors: Wu Zhenqiang , Piché Daniel , Vallières Sylvie , Huet Pierre-Michel , Gascon-Barré Marielle
Published: April 2011

To test further the competence of the cirrhotic liver to metabolize xenobiotics, hepatocytes were isolated from control and CCl4-induced cirrhotic male or female rats. Histologically micronodular cirrhosis was present in all CCl4-treated rats, while control rats had normal livers. Portal perfusion pressure and intrahepatic collagen content were also significantly increased by CCl4 administration. In male rats, no significant differences in levels of circulating transaminases nor in alkaline phosphatase was observed between cirrhotic and control rats, while CCl4-treated females had slightly higher than normal serum transaminase levels at the time of the studies. Hepatocytic cytochrome P-450 and basal xenobiotic biotransformation were unaffected by micronodular cirrhosis in both genders; calculation of the aminopyrine and 7-ethoxycoumarin intrinsic clearances (Cli) revealed, however, a slightly decreased transformation potential in hepatocytes obtained from cirrhotic females, a phenomenon not observed in cirrhotic male rats. It is speculated that the observed reduction in Cli may have been independent of cirrhosis per se, owing to the perduring cytotoxic effect of CCl4 as evidenced by the higher than normal level of transaminases in female rats. Finally, male rats were subjected to in vivo administration of phenobarbital or 3-methylcholanthrene; both compounds led to significant induction of the mixed-function oxidase system, which was similar in magnitude and in selectivity in control and cirrhotic rats as illustrated by calculation of the Michaelis–Menten kinetic parameters for aniline p-hydroxylation, aminopyrine-N-demethylation, 7-ethoxycoumarin-O-deethylation, and p-nitrophenol UDP-glucuronyl transferase. We conclude mat in well-established but compensated and hepatolysis-free micronodular cirrhosis, hepatocytes are fully able to transform xenobiotics and to respond normally and selectively to inducers of drug metabolism.Key words: micronodular cirrhosis, hepatocytes, drug metabolism, intact hepatocyte hypothesis, phenobarbital, 3-methylcholanthrene.
I. Introductory remarks: Basic mechanisms of pain associated with deep tissues
Authors: Dubner Ronald
Published: April 2011

There are important differences in pain arising from deep tissues in comparison to cutaneous pain. These differences can be partially explained by the unique organization of nociceptive systems activated by stimulation of muscle, joint, or viscera. Recent evidence also indicates that stimulation of deep tissues can produce long-lasting changes in central nervous system excitability and, therefore, may play a prominent role in persistent or chronic pain conditions. These findings have important implications for the treatment of chronic deep tissue pain conditions.
II Arthritis and headache
Authors: Besson Jean-Marie
Published: April 2011

Pain researchers are committed to designing new experimental models as close as possible to the physiopathological conditions encountered in humans, with due concern for ethical considerations. Some current questions related to inflammation and headache are discussed, along with the approaches used to address them. These approaches are essential for a better understanding of the physiology, pharmacology, and treatment of various pain syndromes.Key words: pain models, arthritis, headache.
III. Chronic muscle pain syndromes: an overview
Authors: Widmer Charles G.
Published: April 2011

This introduction reviews the current classification of chronic muscular pain conditions and the evidence leading to the conclusion that several of the current diagnostic categories may be simply variations of a single disease.
Can the use of physical modalities for pain control be rationalized by the research evidence?
Authors: Chapman C. Elaine
Published: April 2011

Physical modalities, including cold and heat, are widely used in the conservative management of pain associated with musculoskeletal disorders. This review has critically appraised the literature supporting the use of these modalities in the treatment of musculoskeletal pain. It was concluded that, apart from a few exceptions and in a few types of disorders, existing evidence does not support the use of these modalities in long-term pain control. There was, however, evidence that several modalities, specifically cold and a form of deep heat (shortwave diathermy), do have short-lived analgesic effects and so may contribute to more painfree function in the short term. Further research is clearly warranted to define the short- and long-term therapeutic efficacy of physical modalities in the treatment of musculoskeletal pain to justify their continued use in clinical practice.Key words: pain control, cold, heat, ultrasound, low-power laser.
The pharmacological control of musculoskeletal pain
Authors: Kantor Thomas G.
Published: April 2011

The modern therapy of the pain of inflammatory rheumatic disease and osteoarthritis is based on several advances in molecular biology, which are reviewed in this paper. Inhibition of the ubiquitous enzyme cyclooxygenase by the nonsteroidal anti-inflammatory drugs including the salicylates prevents the production of endoperoxides, which are pro-inflammatory, and prostaglandins E2 and I2, which sensitize peripheral pain receptors. In addition, a fundamental understanding of neural tracts that inhibit the pain signal has introduced the concept of giving low dose tricyclic antidepressants for chronic pain to block the re-uptake of serotonin from the neural cleft of synapses. This amplifies the effect of serotonin and catecholamines, which are neurotransmitters for these inhibitory tracts.Key words: cyclooxygenase, prostaglandins, pain receptors, serotonin.
Voltage-dependent inactivation of the potassium current of embryonic chick hepatocytes
Authors: Hill Ceredwyn E. , Shrier Alvin
Published: April 2011

The whole-cell patch electrode voltage clamp technique was used to study the inactivation properties of the delayed rectifying potassium current of single cultured embryonic chick hepatocytes at 20 °C. The potassium current activates maximally within 250–500 ms of membrane depolarization, after which it decays with a monoexponential time course. Both steady-state activation and inactivation are voltage dependent. Steady-state inactivation declines from 100% at −5 mV to 0 near −70 mV, with half inactivation at −41 mV. At the resting potential (EM) of these cells (−21.5 ± 6.0 mV, n = 36) 6–18% of the IK channels are not inactivated and less than 5% are open. Development and removal of inactivation follow single exponential time courses. The inactivation time constant attains a maximum of around 30 s at −35 mV and is sharply voltage dependent at the EM of these cells. Measurement of EM under current clamp shows random oscillations of 5–10 mV amplitude. We suggest that the voltage- and time-dependent properties of IK, in tandem with a time- and voltage-independent, nonselective current also seen here, would provide the mechanism for a fluctuating EM.Key words: hepatocyte, embryonic, potassium current.
Escherichia coli peritonitis activates thermogenesis in brown adipose tissue: relationship to fever
Authors: Scarpace Philip J. , Bender Bradley S. , Borst Stephen E.
Published: April 2011

Fever is a complex and important nonspecific, host defense mechanism against infection. The generation of the heat necessary to increase body temperature may involve thermogenesis in brown adipose tissue. To investigate whether the febrile response to Escherichia coli peritonitis involves thermogenesis in brown adipose tissue, we assessed whole rat oxygen consumption and brown adipose tissue mitochondrial guanosine 5′-diphosphate binding. Non-lethal doses of E. coli, 1 × 106 to 1 × 108 colony forming units, induced a fever for greater than 8 h. In contrast, a dose of 1 × 109 colony forming units resulted in a progressive hypothermia culminating in death. A 48% increase in oxygen consumption (p < 0.05) in E. coli-infected rats occurred almost immediately, preceded the development of the fever, and was sustained throughout the fever. There was a highly significant correlation (r = 0.736, p < 0.01) between oxygen consumption and body temperature for both control and infected animals. Guanosine 5′-diphosphate binding assessed by multi-point Scatchard analysis of [3H]guanosine 5′-diphosphate binding to isolated mitochondria was increased by 45.4 ± 7.3% at 1.75 h and by 31.9 ± 9.0% at 3.5 h (p < 0.05). The greater increase was during the rising phase of the fever. Unexpectedly, a lethal dose of 5 × 109 colony forming units of E. coli also increased guanosine 5′-diphosphate binding sites by 54.4 ± 14.2% (p < 0.05) despite a hypothermia of −1.71 ± 0.29 °C. These data indicate that peritonitis induces a fever that is correlated with oxygen consumption and increased guanosine 5′-diphosphate binding sites, suggestive of brown adipose tissue thermogenesis activation. This thermogenesis appears to be contributing at least some of the heat necessary for the febrile response in rats.Key words: rat, guanosine 5′-diphosphate binding, oxygen consumption.
The effects of chronic depolarization on L-type 1,4-dihydropyridine-sensitive, voltage-dependent Ca2+ channels in chick neural retina and rat cardiac cells
Authors: Ferrante J. , Triggle D. J. , Rutledge A.
Published: April 2011

Chick neural retina cells contain functional L-type voltage-dependent Ca2+ channels sensitive to 1,4-dihydropyridines. To investigate the effects of chronic depolarization, cells were grown in medium containing elevated K+. After 4-h to 4-day treatments with elevated K+ (12–73 mM), there was a concentration-dependent decrease in high affinity [3H]PN200-110 binding. Saturation analysis of cells treated for 4 days with 40 mM K+ showed a reduction in maximum ligand binding with no change in affinity. Control and experimental Bmax values were 70.7 ± 6.4 and 42.2 ± 4.5 fmol/mg protein, respectively, and control and experimental KD values were 70.2 ± 7.4 and 68.6 ± 7.4 × 10−12 M. The effect of chronic depolarization was time-dependent, reversible, and without effect on cellular protein content. Reduction in 45Ca2+ uptake following chronic depolarization correlated well with the reduction in [3H]PN200-110 binding. The calcium ionophore A23187, 10−6 M for 24 h, also decreased the binding site density. The calcium channel antagonist D600 had no effect alone on [3H]PN200-110 binding; however, D600 blocked the down-regulation of calcium channels induced by chronic depolarization. The mechanism for Ca2+ channel down-regulation may involve calcium entry, since the effect was blocked by D600 and mimicked by the calcium ionophore A23187. Chronic depolarization with either elevated K+ or veratridine, or chronic treatment with A23187 had no effect on calcium channels in rat neonatal ventricular myocytes, although these cells express functional channels of the 1,4-dihydropyridine-sensitive class. That apparently similar channels in cardiac cells were not affected by chronic depolarization likely indicates structural or regulatory differences between cardiac and neuronal L-type Ca2+ channels.Key words: calcium channels, calcium antagonists, 1,4-dihydropyridines, channel regulation, retinal neurons.
O-Methylated and sulfoconjugated catecholamines: differential activities at human platelet α2-adrenoceptors
Authors: Lenz T. , Werle E. , Strobel G. , Weicker H.
Published: April 2011

The physiological effects of the sulfoconjugates of epinephrine, norepinephrine, and the 3-O-methylated catecholamines, metanephrine, normetanephrine, and methoxytyramine were examined with regard to their α2-adrenoceptor binding properties and aggregation activity in human platelets. Sulfoconjugation of catecholamines resulted in the loss of both their competitive potency for [3H]yohimbine binding and their influence on platelet aggregation. O-Methyl substituted catecholamines showed attenuation of their α2-adrenoceptor binding affinities when compared with those of the corresponding non-etherified amines. Unlike the free amine epinephrine, which stimulated platelet aggregation, the O-methylated catecholamine derivatives inhibited aggregation. Inhibition was dose-dependent and restricted to the α2-adrenoceptor mediated aggregation response stimulated by epinephrine (1 μM) or potentiated by subthreshold concentrations of epinephrine (30–300 nM) in the presence of subaggregatory doses of vasopressin (10–30 nM). Collagen- and ADP-induced platelet aggregation was not affected. The hydrophilic β-antagonist CGP 12177 displayed no effects. However, high concentrations (0.1 mM) of both isomers of the strongly lipophilic β-adrenoceptor antagonist propranolol inhibited the actions of all aggregators by stabilizing the membrane. Such a nonspecific membrane interaction of the methylated catecholamines could be excluded because of their low lipid solubility calculated in a n-octanol–phosphate buffer system at pH 7.4. We suggest therefore that methylated catecholamines are biological α2-adrenoceptor antagonists acting on α2-adrenoceptor stimulated reactions of human platelets. Whether this receptor antagonism is relevant to other human tissues needs clarification. Sulfated catecholamines, however, are wholly ineffective at this receptor site and may constitute a pathway to control the concentration of the active free catecholamines.Key words: sulfoconjugated catecholamines, methylated catecholamines, α2-adrenoceptors, human platelet aggregation, dopamine receptors.
A role for xanthine oxidase in the loss of cytochrome P-450 evoked by interferon
Authors: Moochhala Shabbir M. , Renton Kenneth W.
Published: April 2011

It has been suggested that the loss of cytochrome P-450, which is mediated by interferon and its inducers, can result from the generation of free radical species by the enzyme xanthine oxidase. Cytochrome P-450, aminopyrine N-demethylase, and ethoxyresorufin deethylase were depressed by 35, 36, and 38%, respectively, in the livers of hamsters 24 h following the administration of a synthetic interferon (IFN-α-Con1) which contains the most frequent amino acid sequences of the human subtypes. Interferon increased the activities of the D and O forms of xanthine oxidase by 65 and 74%, respectively, in the same animals. The induction of the D form of xanthine oxidase, which is the precursor of the O form, preceded the loss in cytochrome P-450. The protein synthesis inhibitor, actinomycin D, prevented the interferon-induced loss of drug biotransformation and the increase in xanthine oxidase. The free radical scavenger, α-tocopherol, and the xanthine oxidase inhibitor, allopurinol, also prevented the loss of cytochrome P-450 mediated by the interferon inducer poly rI.rC. In chickens in which xanthine oxidase cannot be formed, poly rI.rC had no effect on cytochrome P-450 levels. These results suggest that xanthine oxidase induction may play some role in the interferon-mediated loss of cytochrome P-450.Key words: cytochrome P-450, xanthine oxidase, drug metabolism, interferon.
Comparison of interactions of R-(+)- and S-(−)-isomers of β-adrenergic partial agonists, befunolol and carteolol, with high affinity site of β-adrenoceptors in isolated rabbit ciliary body and guinea-pig taenia caeci
Authors: Koike Katsuo , Hagiwara Hisashi , Takayanagi Issei
Published: April 2011

The stereoselectivities of β-adrenergic partial agonists for the high affinity binding site of β-adrenoceptors in the rabbit ciliary body and the guinea-pig taenia caeci were studied. The pA2 values of the S-(−)-isomers of befunolol and carteolol against S-(−)-isoprenaline, which were calculated from the shift of each concentration–response curve in increasing cyclic AMP levels, were significantly larger than those of the R-(+)-isomers in the guinea-pig taenia caeci, while the pA2 values of the S-(−)-isomers were not significantly larger than those of the R-(+)-isomers in the rabbit ciliary body. The pKi values determined from the binding experiments were in good agreement with the pA2 values from the increases in cyclic AMP levels. These results suggest that the high affinity binding site of β-adrenoceptors in the guinea-pig taenia caeci may be able to discriminate stereoselectively between the R-(+)- and S-(−)-isomers, while in the rabbit ciliary body there is no stereoselectivity between the two enantiomers.Key words: stereoselectivity, β-adrenoceptor, partial agonist, rabbit ciliary body, guinea-pig taenia caeci.
The hypothetical role of potassium conductance on the genesis of R-wave amplitude increase during ischemia in the isolated rat heart
Authors: Ferrara Nicola , Abete Pasquale , Leosco Dario , Caccese Pompilio , Sederino Salvatore , Landino Pietro , Caprio Lorenzo De , Acanfora Domenico , Rengo Franco
Published: April 2011

The effect of increased potassium conductance on the genesis of R-wave amplitude increase during acute myocardial ischemia has been studied in the isolated perfused rat heart by simultaneously recording the R-wave amplitude of epicardial electrograms (VEE), heart rate (HR), coronary flow rate (CFR), left ventricular diastolic pressure (LVDP), and left ventricular systolic pressure (LVSP). The experiments were performed during basal and partial or total ischemic conditions at spontaneous or fixed HR. In some experiments, potassium conductance was increased by means of high-calcium (8 mM) or acetylcholine chloride (10−6 M) perfusion. In the control experiments, partial ischemic perfusion produced an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP; total ischemic perfusion exaggerated these variations. High-calcium perfusion provoked an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP during basal conditions (p < 0.01 vs. control experiment); these modifications increased progressively during partial ischemic perfusion (p < 0.01 vs. control experiment) and during total ischemic perfusion (p < 0.01 vs. control experiment). Perfusion with acetylcholine chloride produced variations similar to those observed in high-calcium solution except that LVDP under basal conditions remained unchanged from control. When the HR was maintained at a constant value by means of atrial pacing the results were similar to those observed in the unpaced hearts. In conclusion, in the isolated perfused rat heart, increasing potassium conductance may influence the genesis of R-wave amplitude increasing during acute myocardial ischemia.Key words: R-wave, acute myocardial ischemia, potassium conductance, high calcium, acetylcholine.
The contribution of non-NMDA and NMDA receptors to graded bursting activity in the CA1 region of the hippocampus in a chronic model of epilepsy
Authors: Simpson Louise H. , Wheal Howard V. , Williamson Robert
Published: April 2011

The selective excitatory amino acid receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonovalerate (D-APV), have been used to investigate the identity of the receptors involved in evoked epileptiform bursting activity in the chronic kainic acid lesioned hippocampus. Comparisons have been made with the acute bursting activity induced by bicuculline. Presented data suggest there are two possible mechanisms contributing to epileptiform bursting activity in the kainic acid lesioned hippocampus. One of these is probably a product of disinhibition, and generates a predominantly non-NMDA receptor mediated burst which is blocked by CNQX (2 μM). The second synaptic mechanism involves a major (or total) contribution by NMDA receptors to the epileptiform burst, and is blocked by D-APV (10 μM).Key words: hippocampus, CNQX, synapses, epileptiform, NMDA.
Action potentials in gastrointestinal smooth muscle
Authors: Huizinga Jan D.
Published: April 2011

Recent investigation of the ultrastracture and electrophysiology of gastrointestinal smooth muscle layers has revealed a fascinating heterogeneity in cell type, cell structure, intercellular communication, and generated electrical activities. Networks of interstitial cells of Cajal (ICC) have been identified in many muscle layers and evidence is accumulating for a role of these networks in gut pacemaking activity. Synchronized motility in the organs of the gut result from interaction between ICC, neural-tissue, and smooth muscle cells. Regulation of cell to cell communication between the different cell types will be an important area for further research. Progress has been made in the elucidation of the ionic basis of the slow wave type action potentials and the spike-like action potentials. The mechanism underlying smooth muscle autorhythmicity seems different from that encountered in cardiac tissue, and evidence exists for metabolic regulation of the frequency of slow wave type action potentials.Key words: pacemaker activity, slow wave, autorhythmicity, interstitial cells of Cajal.
Force–interval relationship and its response to ryanodine in streptozotocin-induced diabetic rats
Authors: Yu Zhen , McNeill John H.
Published: April 2011

Post-quiescent potentiation (PQP), an enhanced contraction following a long pause that occurs as a result of increased Ca2+ release from intracellular stores, and post-stimulation potentiation (PSP), an enhanced contraction following a rapid series of contractions that is believed to be related to increased Ca2+ influx, were measured in streptozotocin-treated Wistar, spontaneously hypertensive (SHR), and Wistar–Kyoto (WKY) diabetic heart tissues. Decreased PQP values were found in Wistar and SHR diabetic papillary muscles (PM) in comparison with the same strain controls, which suggests a diminished degree of releasable Ca2+ from sarcoplasmic reticulum (SR) in these tissues. Decreased PSP was found in SHR diabetic PM, which may be related primarily to a depressed sarcolemmal (SL) Na+–Ca2+ exchange in this tissue. PSP was not decreased in diabetic Wistar or WKY cardiac preparations, indicating that Ca2+ entry via channels must be involved in the PSP mechanism. Ryanodine depressed PQP in Wistar and SHR PM, and SHR left atria in both control and diabetic tissues. It abolished PQP in SHR diabetic tissues but had no effect on WKY control and diabetic tissues. The data suggest that the ryanodine effect differs in the various strains of rat. These differences may be due to differences in the SR sensitivity to ryanodine among the strains. Diabetic SR with impaired Ca2+ uptake may contribute to these phenomena. Ryanodine depressed PSP of Wistar and SHR diabetic PM but had no effects on tissues from controls. The influence of ryanodine on diabetic SL Na+–Ca2+ exchange requires further investigation.Key words: diabetes, cardiomyopathy, post-quiescent potentiation, post-stimulation potentiation, calcium release.
Pharmacokinetic–hemodynamic studies of the enantiomers of isoidide dinitrate in conscious rats
Authors: Bennett Brian M. , Kempenaar Jake W. , Hayward L. Douglas , Baur Romy
Published: April 2011

Our objective was to determine the pharmacokinetic properties of the D- and L-enantiomers of isoidide dinitrate (IIDN) in relation to their hemodynamic effects. Conscious male Sprague–Dawley rats were administered a bolus i.v. dose of 2 mg∙kg−1D- or L-IIDN and simultaneous blood samples and blood pressure recordings were taken at various times. The elimination half-life of D-IIDN was significantly shorter than that of L-IIDN (10 vs. 16 min) owing to a larger Vd area of the L-enantiomer (5.8 vs. 3.8 L∙kg−1). The plasma clearance of either enantiomer was approximately 250 mL∙min−1∙kg−1 a value equal to plasma cardiac output. The pharmacokinetic data indicates that IIDN is distributed extensively and that significant extrahepatic biotransformation of the drug occurs. After intravenous administration of D-IIDN, there was an initial decrease in mean arterial pressure (MAP) of 29% compared with 15% for L-IIDN (p < 0.05). For L-IIDN, the decrease in MAP was short lived (less than 2 min), while for D-IIDN, MAP remained significantly decreased for up to 60 min. The oral bioavailability of both enantiomers was low (ca. 7%). However, decreases in MAP occurred after oral administration of D-IIDN, suggesting that the mononitrate metabolite of IIDN was pharmacologically active. We conclude that, despite a faster rate of elimination from the central compartment, D-IIDN exhibits a greater vasodilator effect in the intact animal compared to L-IIDN. This is consistent with previous observations of a 10-fold greater potency of D-IIDN for relaxation of isolated vascular smooth muscle.Key words: organic nitrates, isoidide dinitrate, enantiomers, pharmacokinetics, hemodynamics.
Consistent activation of prorenin mRNA in renal hypertensive rats
Authors: Morishita Ryuichi , Higaki Jitsuo , Nagano Masahiro , Mikami Hiroshi , Ogihara Toshio , Tanaka Toyoo , Ishii Kenji , Okunishi Hideki , Miyazaki Mizuo
Published: April 2011

To investigate the mechanism of maintaining hypertension in chronic two-kidney, one-clip (2K1C) rats, we studied the expression of the kidney renin gene. Total cellular RNA was extracted by the guanidine thiocyanate–CsCl method. Kidney renin messenger RNA was quantified by densitometric Northern blot analysis using 32P-labeled rat renin genomic DNA as a hybridization probe. Sixteen weeks after clipping, plasma renin concentration and plasma angiotensin II concentration did not differ between 2K1C and sham-operated rats (plasma renin activity, sham rats 16.2 ± 4.2 vs. 2K1C rats 8.9 ± 1.3 ng angiotensin I∙mL−1∙h−1; plasma angiotensin II, sham rats 14.7 ± 7.5 vs. 2K1C rats 6.8 ± 1.3 pg/mL), while plasma angiotensin concentration in 2K1C rats was higher than that of sham rats (p < 0.05). Renin gene expression in the ischemic kidney was 2.2 times higher than that in the kidney of sham-operated rats (p < 0.05), and decreased to 80% of those in the kidneys of sham-operated rats. These results suggest that overexpression of the kidney renin gene in the chronic phases of 2K1C rats may contribute to the sustained high blood pressure, and the kidney renin gene may be inhibited by posttranscriptional factors, i.e., suppressed activation of prorenin to renin.Key words: prorenin, renin, two-kidney, one-clip hypertensive rats, chronic phase, gene expression.