bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrophysiological effects of sulfinpyrazone on canine cardiac Purkinje fibers
Authors: Benditt David G. , Grant Augustus O. , Hutchison Amalia B. S. , Strauss Harold C.
Published: April 2011

Sulfinpyrazone, administered prophylactically following myocardial infarction, has been reported to reduce the incidence of sudden death. Because direct antiarrhythmic action may, in part, account for this finding, electrophysiological effects of sulfinpyrazone were studied in isolated superfused canine cardiac Purkinje fibers. Using conventional microelectrode recording techniques and programmed electrical stimulation, transmembrane action potential (AP) characteristics and effective refractory period (ERP) were determined in seven experiments under control conditions and during sequential 30-min periods of tissue exposure to 10−6, 10−5, and 10−4 M sulfinpyrazone (pacing cycle lengths 1000 and 500 ms). In six out of seven experiments, recordings were repeated during a 30- to 45-min drug-free recovery period. In four additional experiments, spontaneously depolarizing Purkinje fibers with low resting membrane potentials (−55 to −65 mV) were superfused with 10−4 M sulfinpyrazone for 45 min following a drug-free control period. AP resting potential, rate of rise of AP phase 0, AP duration, and ERP were not altered significantly from control or recovery values by sulfinpyrazone exposure. Similarly, neither the AP phase 4 slope nor the mean cycle length (678 ± 32 ms vs. control 665 ± 20 ms, N = 4) of spontaneously firing Purkinje fibers was affected by drug. Thus, sulfinpyrazone did not exhibit direct electrophysiological actions comparable to those associated with conventional antiarrhythmic drugs.
Etude de l'interaction aiguë entre l'éthanol et la méthaqualone chez la souris
Authors: Rousseau Jean-Jacques , Rousseau Micheline , Brodeur Jules
Published: April 2011

The pharmacological interaction between acutely administered ethanol and methaqualone was investigated in mice. Data were submitted to analysis of variance according to a 3 × 3 factorial design. When associated at hypnotic doses (ethanol [Formula: see text], orally, and methaqualone [Formula: see text], i.p.), both drugs lengthened sleeping time in a supraadditive manner. At lethal or near lethal doses (ethanol [Formula: see text] and methaqualone [Formula: see text]), complex interactions were observed: an antagonistic effect of ethanol (2 g/kg) against methaqualone toxicity and at least additive effects of both drugs when ethanol was given at 6 g/kg. When methaqualone was replaced by sodium barbital (725 mg/kg, i.p.) ethanol (2 g/kg) failed to exhibit any antagonistic effect. Because methaqualone at near lethal doses possesses convulsant properties, the protection afforded by ethanol (2 g/kg) might be due to its mild anticonvulsant effects. At 6 g/kg the central depressant properties of ethanol appear to be contributory to the lethality of methaqualone; in addition, at high doses, ethanol facilitates the distribution of methaqualone to the brain. This investigation suggests that the ethanol–methaqualone association induces a rather complex set of pharmacological interactions; it especially demonstrates the antagonistic properties of subhypnotic doses of ethanol against the toxicity of methaqualone.
Voltage dependence of chloride current through Xenopus muscle membrane in alkaline solutions
Authors: Vaughan Peter C. , McLarnon James G. , Loo Donald D. F.
Published: April 2011

Three-microelectrode voltage-clamp experiments have been conducted on surface fibres of Xenopus laevis sartorius muscles. When potassium and chloride were substituted by rubidium and sulphate, negligibly small currents were observed. In solutions containing rubidium and chloride at pH 8.4–8.8 normally polarized fibres exhibited instantaneous current–voltage relations that were linear over a wide voltage range. Chloride conductance varied widely from fibre to fibre; the mean resting conductance at −80 mV was 7.4 × 10−4 ± 2.6 × 10−4 S/cm2 (mean ± SE). When hyperpolarizing voltage steps were made, conductance declined from the initial to the steady state; inward currents saturated near 14 μA/cm2. In experiments performed on fibres depolarized by immersion in K+-and Rb+-rich solutions it was found that resting conductance did not increase by as much as would be expected from constant field – constant permeability precepts, by comparison with normally polarized fibres. Despite the low chloride transmembrane concentration ratio, rectification in the steady state was similar in depolarized and normally polarized fibres.When a two-pulse protocol was employed to test the availability of chloride conductance after conditioning of the system at some voltage, it was found that the test current, the initial current at the onset of the test voltage step, depended sigmoidally on the conditioning voltage. The sigmoid relationships had asymptotic limits: after hyperpolarizing conditioning the test current was minimal, after depolarizing conditioning, maximal. Normalized sigmoid relations were superimposable, whether from normally polarized or chronically depolarized cells.When the protocol was repeated using different test potentials and initial currents following a particular conditioning voltage were plotted against the test potential, families of straight lines were obtained. The slopes of the members of these families were dependent on the conditioning voltage: the more negative the conditioning step the lower the slope. The lines projected through a mutual intersection at a voltage slightly more positive than the resting potential. This is interpreted as indicating that there is some voltage, slightly positive with respect to the membrane potential, at which the initial current is independent of the conditioning voltage.It is concluded that the state of the chloride conductance mechanism is a function of the deviation of the membrane from the resting potential rather than of the absolute membrane potential and that relaxations from initial to steady states reflect properties of the permeation mechanism rather than accumulation or depletion of chloride in a confined space, although some contribution by a mechanism such as the latter cannot be completely ruled out.
Effects of bile and pancreatic secretions on intestinal mucosa after proximal small bowel resection in rats
Authors: Gélinas Monique D. , Morin Claude L.
Published: April 2011

After proximal small bowel resection the remaining small intestine undergoes adaptive hyperplasia. In the present study, the relative contributions of bile and (or) pancreatic juice to adaptive intestinal hyperplasia following proximal resection was studied. Using male Sprague–Dawley rats a 50% proximal intestinal resection was done starting 10 cm distal to the beginning of the jejunum. The animals were also subjected to diversion of bile and (or) pancreatic secretions to the distal ileum at 18 cm proximal to the ileocecal junction. After 8 days gut and mucosal weights, mucosal proteins, and DNA were measured in the duodenojejunum (gut segment proximal to the resection anastomosis) and in the ileum (first half of the small bowel segment distal to the diversion site). The results indicate that (1) in rats fed either chow (Purina rat chow) or a chemically defined diet diversion of pancreaticobiliary secretions to the ileum significantly stimulated ileal mucosa growth whereas no changes were observed in the duodenojejunum, (2) in rats fed a chemically defined diet neither bile nor pancreatic juice affected ileal mucosa when separately diverted to the ileum, and (3) pancreatic juice draining into the duodenum while bile was diverted to the ileum induced hypoplastic changes in the duodenojejunum. The present study suggests that following jejunectomy the regulation of mucosal growth by pancreatic and bile secretions is different in the proximal and distal small intestine. Pancreaticobiliary secretions are trophic for the ileum. However, in the proximal gut bile offers protection against a direct or indirect catabolic action of pancreatic juice.
Ethnic difference in drug metabolism: debrisoquine 4-hydroxylation in Caucasians and Orientals
Authors: Kalow W. , Otton S. V. , Kadar D. , Endrenyi L. , Inaba T.
Published: April 2011

The extent to which debrisoquine (D) is metabolized to 4-hydroxydebrisoquine (4OHD) was found to be influenced by the ethnic origin of the subjects. Following ingestion of 20 mg of debrisoquine sulfate, Orientals excreted, on the average, significantly more D and less 4OHD in 0- to 8-h urine than Caucasians; however, the sums of D + 4OHD did not differ.
Factors influencing the release of labelled γ-aminobutyric acid and acetylcholine evoked by electrical stimulation with alternating polarity from rat cortical slices
Authors: Birsel S. , Szerb J. C.
Published: April 2011

To establish conditions under which electrical stimulation causes Ca2+-dependent and Ca2+-independent release of 3H-labelled γ-aminobutyric acid ([3H]GABA), rat cortical slices were incubated with [3H]GABA and were superfused at either 32 or 37 °C. To release [3H]GABA the slices were stimulated with 2-ms pulses of alternating polarity at either 16 or 64 Hz. For comparison, the release of [3H] acetylcholine ([3H]ACh), after incubation with [3H]choline, was followed under identical conditions. In the presence of Ca2+ maximal release of [3H]GABA was obtained with 64-Hz stimulation at 32 °C whereas maximal release of [3H]ACh was obtained with 16 Hz at 37 °C. In the presence of Ca2+ the release of both [3H]GABA and of [3H]ACh evoked by 64-Hz stimulation was less at 37 than at 32 °C. A second period of 64-Hz stimulation at 32 °C released less [3H]ACh after stimulation at 37 than after stimulation at 32 °C, indicating that 64-Hz stimulation at 37 °C causes an irreversible heat inactivation of release. In the absence of Ca2+ the release of [3H]ACh evoked by 2-ms pulses was much reduced under all conditions but that of [3H]GABA was eliminated only at 32 °C. Tetrodotoxin suppressed the evoked release of both transmitters. Intermittent stimulation with bursts of 128 Hz (average frequency 16 Hz) at 32 °C was as effective in releasing [3H]GABA as 64-Hz continuous stimulation. Stimulation with long (5 ms) pulses at 64 Hz and 32 °C evoked a large release of [3H]GABA both in the presence and absence of Ca2+. However, in the presence of 0.5 mM Ca2+ this release was reduced. Results can be explained by the following. Major differences in the release of [3H]GABA and [3H]ACh induced by low-frequency stimulation, in the presence of Ca2+, may be due to differences in the properties of voltage-dependent Ca2+ channels in the two types of terminals. The Na+-dependent release of [3H]GABA in the absence of Ca2+ is inhibited by small concentrations of Ca2+ by reducing Na+ influx. The effect of temperature on [3H]GABA release can be explained by the temperature dependence of the voltage-dependent Ca2+ channels and of the sodium pump, both of which determine [Na+]i which in turn governs the Na+-dependent efflux of [3H]GABA.
Species differences of amobarbital metabolism: dihydroxyamobarbital formation
Authors: Tang B. K. , Grey A. A. , Reilly P. A. J. , Kalow W.
Published: April 2011

Amobarbital is almost completely metabolized in animals and man. The major metabolite is 3′-hydroxyamobarbital. The second major metabolite in dog, mice, hamsters, guinea pigs, and rats could be identified as 3′,4′-dihydroxyamobarbital. A striking contrast between man and animals is the virtual absence of the diol in man and absence of amobarbital-N-glucoside in animals.
Substrate repletion in rat myocardium, liver, and skeletal muscles after exercise
Authors: Poland James L. , Trowbridge Carolyn , Poland Jerry W.
Published: April 2011

Carbohydrate and lipid substrates were measured in rats during recovery following exercise or a 24-h fast and compared with values from time-matched control (rested, fed) rats. After exercise muscle glycogen recovered at the expense of liver glycogen repletion. Myocardial glycogen supercompensated whereas soleus, red vastus lateralis (RVL) and white vastus lateralis glycogen merely returned to control levels. A similar recovery pattern occurred after fasting with refeeding promoting glycogen synthesis in the liver, skeletal muscles, and even in the myocardium, where glycogen had already been elevated by the fast. Both soleus and RVL muscles, along with the myocardium, exhibited glycogen supercompensation. Both exercise and fasting increased plasma free fatty acid (FFA) levels which favor myocardial glycogen synthesis. Unchanged tissue triglycerides and relatively stable blood glucose levels suggest that these are unlikely influences on glycogen recovery. It is concluded that exercise per se is unlikely to induce glycogen supercompensation in skeletal muscles though myocardial glycogen supercompensation readily occurs, that food restriction prior to exercise quantitatively affects substrate recovery though its impact could go unnoticed because of the qualitative similarities between substrate recovery following exercise or fasting, and that FFA is the only major energy substrate concurrently changing with glycogen after exercise or fasting which could facilitate glycogen synthesis.
Evidence of environmental influence on the development of thermoregulation in the rat
Authors: Ferguson A. V. , Veale W. L. , Cooper K. E.
Published: April 2011

Sprague–Dawley rats were raised in an environmentally controlled room at 33 °C. Thermoregulatory responses of animals reared in this way were compared with those of control and warm-acclimated rats. Warm-reared animals demonstrated a significantly greater fall in colonic temperature during cold exposure when compared with both warm-acclimated (p < 0.01) and control (p < 0.001) animals. Warm-reared animals also show a modified response to central infusion of noradrenaline; they produce a hyperthermia in contrast with the hypothermia observed in control and warm-acclimated rats. These results suggest that the early thermal environment may modify the development of temperature regulation in the Sprague–Dawley rat in a way different from the normal acclimation process.
The degradation of bradykinin (BK) and of des-Arg9-BK in plasma
Authors: Marceau F. , Gendreau M. , Barabé J. , St-Pierre S. , Regoli D.
Published: April 2011

The metabolism of bradykinin (BK), des-Arg9-BK, and two analogues of the latter was studied in human, rat, and rabbit plasma, using bioassays and high pressure liquid chromatography (HPLC) for measuring the concentrations and characterizing the types of metabolites. A solution of BK containing 100 μg/mL was added to 20% (v/v) plasma and incubated for up to 75 min at 37 °C. The concentration of BK, measured by the rabbit isolated jugular vein assay, decreased progressively whereas that of the fragment des-Arg9-BK, measured on the rabbit mesenteric vein, increased. This was taken as an indication that a carboxypeptidase is present in the plasma of the three species and transforms BK into des-Arg9-BK. Solutions of BK (3 mg/mL) containing 20% human plasma were incubated for 1 – 18 h and then analyzed by HPLC in order to identify the metabolic fragments resulting from the action of peptidases in human plasma. This assay confirmed that des-Arg9-BK is the principal metabolite and the first fragment to appear; this compound is further transformed into des-(Phe8, Arg9)-BK. No other fragments were found to be present in significant amounts. The addition of Captopril (100 ng/mL), an inhibitor of the converting enzyme, did not change the pattern of appearance or the quantities of metabolites.The degradation of synthetic des-Arg9-BK was measured by bioassay after incubation with the plasma of the three species. The fragment is inactivated, although more slowly than BK, and is presumably transformed into des-(Phe8, Arg9)-BK by the action of a carboxypeptidase. This conclusion is supported by the finding that the two analogues, [Phe-OMe8]-des-Arg9-BK and [D-Phe8]-des-Arg9-BK, are more resistant to degradation than des-Arg9-BK. As des-Arg9-BK is a strong stimulant of the B1 receptor for kinins, the generation and degradation of des-Arg9-BK is discussed in view of a possible involvement of this receptor in pathological states.
Maternal steroid changes after fetal death until delivery of the dead sheep fetus
Authors: Carson George D. , Challis John R. G.
Published: April 2011

Progesterone, estrone, and estradiol have been determined during late pregnancy and at parturition in the maternal plasma of sheep bearing live and dead fetuses. Mean concentrations of the steroids at days 125–130 after mating were lower after fetal death, although the differences were not significant. The mean interval between fetal death and delivery was 11.8 ± 5.8 days. The concentration of progesterone in plasma did not fall abruptly after fetal death, although it declined to very low values (0.02 ± 0.001 ng/mL) on the day of delivery. There was no preparturient rise in maternal estrogen levels in animals with dead fetuses. The ratios of progesterone:estradiol and progesterone:estrone fell from 130 and 140 to 2.9 and 1.2, respectively, during the 5 days prior to delivery due entirely to the fall in progesterone. In normal animals the ratios of progesterone:estradiol and progesterone:estrone decreased from 186.1 and 81.7 at 5 days before parturition to 9.4 and 2.0 on the day of birth. This was attributable partly to a fail in progesterone but largely to the preparturient rise in estrone and estradiol. We conclude that some placental steroid output continues after fetal death in the sheep but that deliveries of both dead and live fetuses are associated with an abrupt change in the ratio of progesterone:estrogens in maternal blood.
Effect of hemorrhage on fever: the putative role of vasopressin
Authors: Kasting N. W. , Veale W. L. , Cooper K. E. , Lederis K.
Published: April 2011

The effects of hemorrhage on the febrile response of the sheep was examined because hemorrhage is a potent stimulant for arginine vasopressin (AVP) release into cerebrospinal fluid and blood. Removal of 20% of the estimated blood volume of the conscious sheep led to small physiologic changes and significantly decreased fevers in response to bacterial endotoxin. Mean arterial blood pressure decreased in hemorrhaged febrile sheep to a siginificantly greater extent than in nonhemorrhaged febrile sheep. AVP levels were considerably greater in the blood of hemorrhaged febrile sheep than in nonhemorrhaged febrile sheep and the concentrations correlated with the magnitude of the decrease in fever. Sheep hemorrhaged in the cold had changes in body temperature similar to control sheep. These experiments support the hypothesis that AVP may be an antipyretic neuromodulator.
Placental transfer of indomethacin in the rabbit and sheep
Authors: Harris W. H. , Petten G. R. Van
Published: April 2011

The placental transfer of indomethacin was studied in the rabbit at 30 days of gestation and in the sheep between 120 and 135 days of gestation. Plasma concentrations of indomethacin reached a maximum of 13.7 ± 1.6 and 10.9 ± 1.5 μg/mL in the doe and fetuses, respectively, at 1 h following a maternal subcutaneous injection of 10.0 mg/kg. The maternal plasma concentration of drug decreased rapidly but the fetal plasma concentration of drug remained elevated and exceeded that of the doe before decreasing. Indomethacin became detectable in the amniotic fluid after 2 h, reached a maximum of 3.2 ± 0.8 μg/mL at 4 h, and then gradually decreased. The intravenous infusion of 10.0 mg of indomethacin per kilogram over 30 min into a pregnant ewe resulted in a maximal plasma concentration of 13.5 ± 0.7 μg/mL in the ewe and 0.6 ± 0.1 μg/mL in the fetus at the termination of the infusion. The concentration of indomethacin in the amniotic fluid increased to a maximum of 3.5 ± 0.5 μg/mL 150 min after the infusion stopped. There was an increase in the percentage of drug bound by the fetal plasma proteins as gestation advanced. Thus there exists the possibility that the fetus would be exposed to increasing amounts of indomethacin as term approached.
Brown adipose tissue and carnitine in cold-adapted rats
Authors: Hahn P. , Laury C. , Portet R.
Published: April 2011

Cold-adapted (CA) and warm-adapted (WA) rats (5 and 28 °C) were infused with noradrenaline (4 μg∙kg−1∙min−1) for 15 min. Blood was collected from Sulzer's vein coming from brown adipose tissue and analyzed for total carnitine, free carnitine, and β-hydroxybutyrate content, before and up to 45 min after the infusion. Acylcarnitine (total minus free carnitine) levels increased more and total carnitine levels decreased more in the CA group than in the WA group. β-Hydroxybutyrate content increased to the same extent (from about 0.16 to 0.8 mM) in both groups. Brown fat was found not to release carnitine into the circulation after NA infusion. Twenty minutes after the end of infusion brown fat retained both ketones and acylcarnitine in the CA rats only.
Pharmacological studies of kinins in venous smooth muscles
Authors: Gaudreau P. , Barabé J. , St-Pierre S. , Regoli D.
Published: April 2011

The myotropic effects of bradykinin (BK) and other kinins in two isolated veins, the rabbit jugular and the guinea pig anterior mesenteric, have been studied. The effects of degradation on the biological activities of these compounds and the receptor types mediating their myotropic effects have been determined.It has been found that contractions elicited by kinins in these veins result from direct actions on specific receptors. Both veins contain active kininase II (but not active carboxypeptidases A or B) which interferes with the measurement of the myotropic effects and can be blocked by 1-(D-3-mereapto-2-methyl-3-oxopropyl)-L-proline (SQ 14225). The slopes but not the maxima of the concentration–response curves of BK and other kinins measured in the presence of SQ 14225 are different from those recorded in its absence whereas no significant changes are observed in concentration–response curves obtained with the analogue [D-Phe8]-BK, which resists degradation by kininase II.BK is more potent than its fragment sequence des-Arg9-BK and the effects of kinins are antagonized by dihydrochlorprothixene and β-phenylalanine hexyl ester. These findings suggest that the rabbit jugular and the guinea pig anterior mesenteric veins contain receptors of the B2 type.The findings presented in this paper indicate that the rabbit jugular vein and the guinea pig anterior mesenteric vein are sensitive preparations for kinins and they can be useful for structure–activity studies of these peptides. A correct evaluation of the relative affinities of various kinins is, however, only possible by eliminating the interference of kininase II.
Ketamine potentiates catecholamine responses of vascular smooth muscle by inhibition of extraneuronal uptake
Authors: Lundy Paul M. , Frew Robert
Published: April 2011

Effects of ketamine on responses to sympathomimetic amines were studied using isolated aortic and pulmonary artery strips from the rabbit. Ketamine (1.1 × 10−5 to 3.7 × 10−4 M) potentiated adrenaline-contracted strips. Potentiation was not impaired in tissues from animals pretreated with reserpine, with 6-hydroxydopamine, or in tissues pretreated with cocaine. Pretreatment of the strips with the catechol O-methyltransferase (COMT) inhibitors tropolone or pyrogallol or the inhibitor of extraneuronal uptake 17β-estradiol blocked the potentiation by ketamine; in addition, potentiation by the COMT and extraneuronal uptake inhibitors was abolished or greatly reduced by ketamine. In rabbit aorta, ketamine potentiated responses to the catecholamines (adrenaline > nordefrine > noradrenaline) but not to the noneatecholamines phenylephrine, methoxamine, and synephrine; instead a slight relaxant effect was observed. Ketamine potentiated, whereas cocaine inhibited, responses to tyramine. Experiments using the technique of oil immersion demonstrated that ketamine reduced the rate at which aortic strips inactivate adrenaline even when monoamine oxidase (MAO) and neuronal uptake processes were fully inhibited. Uptake studies showed that ketamine and 17β-estradiol reduced extraneuronal accumulation of [3H]adrenaline in aortic strips. We conclude that ketamine is an inhibitor of extraneuronal uptake in the vascular smooth muscles studied and the importance of this mechanism in producing its known cardiovascular effect is discussed.
Interactions between the jaw-opening reflex and mastication
Authors: Lund J. P. , Rossignol S. , Murakami T.
Published: April 2011

Electrical stimulation of the anterior hard palate or upper lip was used to evoke the jaw-opening reflex in rabbits lightly anesthetized with urethane. The amplitude of each excitatory response recorded in the digastric electromyogram during mastication was compared with the mean amplitude of 10 prior control responses. When weak stimuli were used, the mean amplitude of the reflex dropped markedly during mastication and was smallest when the digastric muscle was inactive (closing and occlusal phases of the masticatory cycle). As the stimulus strength was increased, the size of the response during closing rose progressively until it exceeded values obtained during the control period or the jaw-opening phase.In addition, strong stimuli altered the total cycle length and the duration and amplitude of muscle activity in a phase-dependent manner. Stimuli given during closing were particularly effective in causing inhibition of jaw-closing muscle activity and in reducing the velocity and amplitude of closure.It is concluded that the cyclical gain changes of the reflex response to noxious stimuli are controlled to a large extent by premotoneuronal mechanisms and that the overall effect on the masticatory cycle structure is phase dependent.
The coactivation of antagonist muscles
Authors: Smith Allan M.
Published: April 2011

Since Sherrington's convincing demonstration of the reciprocal innervation of opposing muscles, it has generally been thought that antagonist muscles are inactive during most voluntary movements. However, more recent evidence suggests that excitation of Renshaw cells may facilitate antagonist coactivation whereas excitation of Ia inhibitory neurons can induce reciprocal inhibition. A body of evidence has accumulated to indicate some of the circumstances which particularly favour the co-contraction of antagonist muscles. Isometric prehension, either in the precision grip or the power grip, can be shown to be one of the most important examples of antagonist coactivation. Studies of the discharge of single Purkinje cells of the intermediate cerebellar cortex in awake monkeys during performance of a maintained grip revealed that the majority of these neurons are deactivated during antagonist co-contraction. In contrast, other, unidentified neurons of the cerebellar cortex were as a group activated during grasping. It is suggested that the Purkinje cells act to inhibit antagonist muscles during reciprocal inhibition but are themselves inhibited during antagonist coactivation. These results support a suggestion made by Tilney and Pike in 1925 that the cerebellum plays an important role in switching between the coactivation and reciprocal inhibition of antagonist muscles.
Antagonism of calcium-induced contraction in potassium-depolarized rabbit detrusor muscle strips by dicyclomine hydrochloride and rodverine
Authors: Downib J. W. , McGuire R. P.
Published: April 2011

The musculotropic action of dicyclomine hydrochloride in bladder muscle has been attributed to its local anesthetic activity. In this study rabbit detrusor strips were depleted of calcium by incubation in a Ca2+ -free solution containing ethylene glycol bis(β-aminoethyl ether)-N,N′-tetraacetic acid (EGTA). Contractions elicited by replacement of Ca2− during depolarization with 80 mM K+ were only slightly affected by atropine or scopolamine but were antagonized in a noncompetitive manner by dicyclomine and rociverine (pD2′ = 4.89 and 4.61, respectively). These contractions were also blocked with greater potency by nifedipine (pD2′ = 8.50) and with lesser potency by lidocaine (pD2′ = 2.52). Procaine was ineffective up to 1 mM. Comparison of the antagonism produced by dicyclomine and rociverine with that produced by nifedipine or lidocaine did not help to define the mechanism of the musculotropic drugs. However, as rociverine is not a local anesthetic and procaine was not effective, it appears that the "local anesthetic" property is not sufficient to explain the action of these musculotropic drugs.
Hering–Breuer inflation reflex in young and adult mammals
Authors: Gaultier C. , Mortola J. P.
Published: April 2011

The apnea following lung inflation (Hering–Breuer expiratory promoting reflex) is a vagally mediated reflex which is initiated by the activation of pulmonary stretch receptors (PSR) and terminated by the interaction of several factors, which include adaptation of PSR, chemical stimuli, level of anaesthesia, and body temperature. Since PSR activity is determined by the changes in airway tension, the interpretation of the strength of vagal reflexes on the basis of changes in lung volume rather than transpulmonary pressure can be misleading when the mechanical properties of the respiratory system are not constant. In this study we compared the reflex apnea resulting from lung inflation of young and adult mammals, the respiratory system of which have very different mechanical properties. If the response is compared on the basis of similar changes in lung volume, it can be considered weaker or stronger in the young depending upon the normalizing parameter used. However, when considered on the basis of the relative changes in transpulmonary pressure, which better reflects the activation of PSR, the reflex is weaker in young rats and rabbits than in their adult counterparts and similar in dogs. The analysis of the underlying mechanisms suggests a weaker vagal contribution in the young animal, but a satisfactory conclusion requires a better knowledge of the factors which, in the younger animals, result in the termination of the apnea.
The effect of age on the unfolding of elastin lamellae and collagen fibers with stretch in human carotid arteries
Authors: Samila Zenon J. , Carter Stefan A.
Published: April 2011

We measured folding of elastin lamellae and collagen fibers in human carotid arteries and correlated the results with the elastic properties of the vessels. Specimens cut into circumferential strips were stretched to various degrees, fixed, and stained for elastin and collagen. Folding was measured on photographic projections. Elastin lamellae unfolded quickly with initial stretch. In old vessels they did not straighten as much as in the young suggesting that the content of the interlamellar space may interfere with the unfolding. Collagen fibers straightened more during stretch in stiffer older vessels than in the young, already at low degrees of stretch. Young's modulus at extension of 5% appeared to correlate with unfolding of elastin lamellae in young extensible vessels. The modulus correlated significantly with unfolding of collagen fibers at extensions of 15% and greater, and the slope of the regression of the modulus on folding increased with stretch. Our findings provide for the first time morphologic evidence for the role of elastin lamellae in the determination of the elastic properties at low extensions, for the importance of collagen fibers in increasing stiffness with further stretch, and for the relationship between increased stiffness with age and the earlier recruitment of the collagen fibers.
A problem associated with the measurement of ketone body kinetics in vivo
Authors: Hall Susan E. H. , Bolton T. M.
Published: April 2011

[3–14C]acetoacetate (AcAc) and [2–14C]acetate were infused in separate experiments into nine paired rats. The specific activity (SA) ratio SAβOHB/SAAcAc was 0.23 ± 0.02 when [3–14C]AcAc was the tracer and 0.78 ± 0.1 when [2–14C]acetate was infused. These experiments demonstrate the inadequacy of the common practice of using only one labelled ketone body to calculate the turnover rate of both AcAc and β-hydroxybutyrate (βOHB) simultaneously.
2-Chloroadenosine inhibits brain acetylcholine turnover in vivo
Authors: Haubrich Dean R. , Williams Michael , Yarbrougii George G. , Wood Paul L.
Published: April 2011

Intracisternal administration of 2-chloroadenosine (10 μg) to rats inhibited the apparent turnover rate of acetylcholine in the hippocampus and cortex but not the striatum. The regional variation in this inhibition did not correlate with the apparent density of adenosine receptors as determined by receptor binding techniques. The results indicate that while purinergic mechanisms may be involved in the regulation of specific central cholinergic neurons, the physiological actions of the purine may not be unique to this transmitter system.
The effects of imidazole-4-acetic acid on cerebral indole amine metabolism
Authors: MacMillan V.
Published: April 2011

The effects of imidazole-4-acetic acid (IMA, 100–400 mg/kg) on indole amine metabolism were studied by measurement of the cerebral hemisphere and brain stem contents of tryptophan, 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). The results indicated that IMA does not alter the steady-state contents of brain indole amines. Furthermore, IMA failed to alter the levels of 5-HTP, 5-HT, or 5-HIAA in animals pretreated with 3-hydroxybenzyl hydrazine (a decarboxylase inhibitor), pargyline (a monoamine oxidase inhibitor), or probenecid (a compound which blocks 5-HIAA transport out of brain). These results suggest that altered serotonin metabolism is not a factor in the genesis of the behavioral or electroencephalographic changes produced by IMA.
The metabolism of cyanide and the gastrointestinal circulation of the resulting thiocyanate under conditions of chronic cyanide intake in the rat
Authors: Okoh P. N. , Pitt G. A. J.
Published: April 2011

A study of the distribution of 14C-labelled cyanide was carried out in rats exposed to a regular intake of cyanide in the diet for 3 weeks. All tissues contained radioactivity 9 h after injection of 14CN− but very high amounts were found in the stomach, which accounted for 18% of the total injected radioactivity. Most of this was in the contents of the stomach, of which over 80% was in the form of thiocyanate. When a small amount of S14CN− was given by mouth to rats with elevated plasma thiocyanate levels, most of the activity was excreted in the urine and only small amounts were found in the faeces. This indicated the existence of a gastrointestinal circulation of thiocyanate, in which a substantial amount of this substance secreted into the stomach contents of the rat was reabsorbed by the intestine into the body fluid to be partly excreted in the urine and partly resecreted into the gastric contents. The likely implications of this are discussed.
Intracellular Ca2+ transients in the cat papillary muscle
Authors: Morgan J. P. , Blinks J. R.
Published: April 2011

Intracellular Ca2+ transients in cat papillary muscles were detected with the calcium-sensitive bioluminescent protein aequorin and correlated with tension development. The effects of a variety of inotropic interventions are interpreted in terms of their probable effects on Ca2+ entry, Ca2+ release, Ca2+ sequestration, and the Ca2+ -sensitivity of the contractile apparatus. In contrast to results reported in dog Purkyně strands, the aequorin signals in cat papillary muscles appear to be dominated by release of Ca2+ from intracellular stores.
Differential response of rat cardiac and skeletal muscle glycogen to glucocorticoids
Authors: Poland James L. , Poland Jerry W. , Honey Richard N.
Published: April 2011

Though glucocorticoids were previously implicated in the support of myocardial glycogen supercompensation after exercise, it was unclear why skeletal muscle glycogen did not simultaneously supercompensate since it was also exposed to the exercise-induced glucocorticoid increases. The current study shows that glucocorticoids differentially affect cardiac and skeletal muscle glycogen. Following dexamethasone administration (400 μg i.p.) myocardial glycogen peaked at 6 h while glycogen in the soleus, red vastus lateralis, and white vastus lateralis increased more slowly and reached the highest values 17 h postinjection. Concurrently, blood glucose, insulin, and glucagon remained at control levels. Liver glycogen increased within 2 h and continued to rise with a peak value at 17 h. Plasma free fatty acid (FFA) levels increased and remained high throughout the 26-h experimental period. High FFA levels inhibit glycogenolysis and thus could be partially responsible for glucocorticoid-induced glycogen increases. It is postulated that glycogen supercompensation does not readily occur in skeletal muscles after exercise because of the brevity of the corticosterone and FFA increases and the slowness of the skeletal muscle glycogen response to glucocorticoids.
Neural control of the intestinal migrating myoelectric complex. A pharmacological analysis
Authors: El-Sharkawy T. Y. , Markus H. , Diamant N. E.
Published: April 2011

A pharmacological analysis of the participation of autonomic nerves in the control of the intestinal migrating myoelectric complex (MMC) was conducted on six conscious fasting dogs with implanted bipolar electrodes. All dogs exhibited regularly recurring MMC's. Hexamethonium (2–10 mg/kg i.v.) or atropine (25–100 μg/kg i.v.) immediately suppressed all spiking activity, stopped the progression of the ongoing complexes, and prevented the initiation of new complexes for 2.5 to 5 h. Phentolamine (2–4 mg/kg i.v.) and propranolol (2 mg/kg i.v.) given separately or in combination had no observable effect on any of the different phases of the complex, its progression, or its frequency. Phenylephrine (0.5–1 mg/kg) inhibited the spiking phases of the complex. Isopropylnoradrenaline had no effect on the complex at doses (up to 30 μg/kg) which produced maximal cardiac chronotropic effect. The effects of these agonists were totally blocked by the doses of respective adrenergic antagonists used. Phenoxybenzamine given in a dose of 10–15 mg/kg i.v. produced effects similar to atropine apparently owing to blockade of cholinergic muscarinic receptors. It is concluded that (a) the regular spiking phases of the migrating complex result from cyclical and sequential activation of preganglionic fibers forming nicotinic synapses on postganglionic cholinergic excitatory neurones; and (b) the function of adrenergic nerves is not normally required for the MMC.
The effect of a benzodiazepine, flurazepam, on the response of in vitro skeletal muscle preparations to muscle relaxants: are purines or their receptors involved?
Authors: Hamilton John T. , Stone Peggy A.
Published: April 2011

Changing trends in the use of anxiolytic agents and recent reassessment of their neuropharmacological activity has prompted this evaluation of the peripheral neuromuscular activity of the benzodiazepine, flurazepam. In previous reports we have documented peripheral neuromuscular activity of chlordiazepoxide and diazepam on the rat phrenic nerve diaphragm preparation. The water soluble benzodiazepine, flurazepam, has been studied on the rat phrenic nerve diaphragm and frog rectus abdominis in vitro. On the former preparation flurazepam enhanced and then blocked the response to indirect electrical stimulation (0.2 Hz) and readily blocked posttetanic potentiation and prevented the preparation from sustaining a tetanic contracture (30 Hz). On the later preparation, flurazepam blocked in a noncompetitive manner the response of the frog muscle to applied cholinergic agonists. Studies on the rat preparation with the neuromuscular blocking drug succinylcholine have shown an unexpected protection against blockade in preparations pretreated with low concentrations of flurazepam. This was not observed when flurazepam was given prior to d-tubocurarinc. The application of adenosine to rat diaphragms during steady-state partial blockade caused by flurazepam or d-tubocurarine showed an inhibiting action of adenosine which was reversed by theophylline. Pretreatment of rat preparations with dipyridamole significantly enhanced the blocking action of standard concentrations of succinylcholine.These results, along with those in the literature, encourage a reassessment of the action of purines and benzodiazepines on skeletal muscle and encourage a consideration of a possible involvement of purinergic neuromodulation of transmission which is unmasked when the safety factor for transmission is altered by muscle relaxants. The possible clinical significance of protection against succinylcholine by benzodiazepines is noted.
Characterization of the β receptor responsible for enhanced histamine release from bovine leukocytes
Authors: Perron R. , Eyre P.
Published: April 2011

The present study was undertaken to determine the beta-receptor subtype responsible for the enhanced anaphylactic histamine release from bovine leukocytes produced by isoprenaline. The selective β1 antagonist practolol competitively inhibited the enhancement of histamine release produced by isoprenaline. The selective β2 agonists salbutamol and terbutaline produce no significant effect on antigen-induced histamine release. This indicates that the receptor responsible for enhancement of histamine release from bovine granulocytes is of the β1 subtype. The question is raised as to whether this is a normal physiological response or an abnormal condition produced by the sensitization procedure.
Investigation of the membrane-fluidizing properties of porphyrin-inducing drugs
Authors: Marks G. S. , Reich T. , Wan J. K. S. , Singer M. A.
Published: April 2011

The objective of this study was to test the hypothesis that porphyrin-inducing drugs act at least in part by disrupting membrane lipids. The porphyrin-inducing steroids, 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) and 3α-hydroxy-5α-pregnan-20-one induce considerably greater fluidity changes in spin-labelled phospholipids–cholesterol bilayers than do the corresponding 3β-hydroxy steroids which are also less potent as porphyrin inducers. The steroids did not cause any significant change in spin-labelled vesicles lacking cholesterol. The porphyrin-inducing compound 3,5-diethoxyearbonyl-1,4-dihydro-2,4,6-trimethylpyridine and a series of analogues caused fluidity changes in phospholipid bilayers in the presence and absence of cholesterol. The porphyrin-inducing nonplanar 2,2′,4,4′-6,6′-hexachlorobiphenyl caused a significant change in bilayer fluidity in phospholipid bilayers in the presence and absence of cholesterol. Since the planar 3,3′,4,4′-tetrachlorobiphenyl, allylisopropylacctamide (AIA), and griseofulvin are potent porphyrin-inducing compounds, but do not fluidize a lipid bilayer, it was clear that the original hypothesis required modification. No evidence could be obtained to support the idea that a subset of porphyrin-inducing drugs exists which are membrane fluidizers and whose common mechanism of action as porphyrin-inducers might be revealed by a common pattern of porphyrin accumulation in chick embryo liver cells. It is suggested that those porphyrin-inducing compounds with membrane-fluidizing properties might fluidize the nuclear membrane, thus facilitating the transfer of an induction specific RNA for δ-aminolevulinic acid synthetase from the nucleus to the cytoplasm.
Metabolism of the perfused rabbit heart. V. Verapamil-induced release of creatine kinase
Authors: Chiong Miguel A.
Published: April 2011

The effects of verapamil (VER), at concentrations of 0, 10−9, 10−8, 10−7, and 5 × 10−7 M (or 0, 0.5, 5, 50, and 250 ng/mL) were studied in the isolated rabbit heart during 70 min of aerobic perfusion with a standard Krebs–bicarbonate medium at 37 °C. The studied variables were left ventricular performance (RPP, heart rate times left ventricular (LV) systolic pressure), coronary sinus flow (CSF), oxygen uptake [Formula: see text], rate of creatine kinase (CK) release, and energy stores (glycogen, creatine phosphate (CP), ATP, and total adenine nucleotides (TAN)).The results show that (i) VER depressed RPP in a dose-related manner; (ii) [Formula: see text] declined as VER concentration increased except in the 5 × 10−7 M group which showed a paradoxical increase in O2 uptake; (iii) CSF was only slightly decreased by VER with the exception of the 5 × 10−7 M group, which showed an increase in flow; (iv) VER was associated with increments in the rates of CK release in a dose-related fashion (2, 4, 15, and 29 times the rate observed in the untreated group), and (v) VER was associated with slight decrease in glycogen levels, but no changes in CP or adenine nucleotides.It is concluded that, in our preparation, VER caused marked increases in the rate of CK loss in the absence of depletion of total energy stores. The data suggest that the drug affects the permeability characteristics of the sarcolemma, perhaps via localized depletion of calcium stores.
Intestinal motility responses to insulin and glucagon in streptozotocin diabetic rats
Authors: Pascaud X. , Ferre J. P. , Genton M. , Roger A. , Ruckebusch M. , Bueno L.
Published: April 2011

Myoelectrical and mechanical activities were chronically recorded by use of nichrome electrodes and miniaturized strain-gage transducers sutured on the serosa of the antrum, the duodenum, and the jejunum, in a first experiment (n = 6 rats) the early (0–6 h) and late (> 4 days) effects of streptozotocin (65 mg/kg i.v.) was recorded. In addition, the effect of insulin (1–5 IU/kg) and glucagon (6–200 μg/kg) administered intravenously were studied separately each in groups of seven normal and streptozotocin-induced diabetic-fed and fasted rats. The results indicated that within the 30 min following streptozotocin administration there was a significant stimulation of the duodenal and jejunal motility lasting 46 ± 8 min. When diabetes was established as shown by the basal blood glucose level obtained in those rats (2.30 ± 0.84 g/L), a progressive decrease of the frequency of the migrating myoelectric complex was observed along with a disorganization of the regular spiking activity phases without disturbing the basal electrical rhythm. Comparing with the basal level, a significant increase in the gastrointestinal motility indexes (MI) appeared both in fasted (p < 0.01) and fed (p < 0.05) normal animals, 13.1 ± 1.6 min after an i.v. injection of 1 IU/kg insulin. Motor effects of glucagon were related to the dose. When used at 25 μg/kg a disorganization of the spiking activity was observed with a stimulation of the contractile activity in the jejunum. At higher dosages, i.e., 100 μg/kg, it induced an immediate and significant decrease of motility at any level tested and lasting up to 20 ± 7 min. The motility responses to both hormones were lower in diabetic than in normal rats.
Cadmium toxicity in the newborn rat
Authors: Klaassen Curtis D. , Wong King-Lit
Published: April 2011

Newborn rats have about a 20-fold higher concentration of metallothionein in the liver than does the adult rat. This marked increase in hepatic metallothionein does not result in a lower acute toxicity to cadmium in newborn rats; it does not markedly increase the distribution of cadmium to the liver, decrease its concentration in other tissues, or produce a slower removal of the cadmium from younger animals. The toxicity of cadmium in the newborn rat appears to be more dependent on other factors such as the development of the blood–brain barrier and the stage of development of the testes than on the amount of metallothionein in the liver. The results of this study suggest that we should probably reevaluate the role of metallothionein in producing tolerance to cadmium.