bluuebunny/crossref_metadata_2025 huggingface dataset:
Impairment of human antipyrine metabolism by piroxicam
Authors: Battellino Luis José , de Cattoni Susana Tereza Dorronsoro , Ragagnin Carmen
Published: April 2011

The pharmacokinetics of a single oral dose of antipyrine was determined in healthy young volunteers (18–28 years), both 3 days before piroxicam, ketoprofen, or naproxen administration and on the following day of their discontinuation. In all subjects treated with piroxicam (10, 20, and 40 mg daily) for 5 consecutive days, the rate of salivary antipyrine elimination slowed. Antipyrine half-life was prolonged and metabolic clearance was reduced significantly (p < 0.01) proportional to the dose administered. After piroxicam was discontinued, both pharmacokinetic parameters of antipyrine returned toward normal. No significant modification in antipyrine half-life or metabolic clearance rate was demonstrated after pretreatment with ketoprofen (50, 100, and 200 mg daily) or naproxen (250 and 500 mg daily). The impairment on antipyrine disposition produced by piroxicam has been interpreted as a consequence of a reduction in the activity of hepatic microsomal drug-metabolizing enzymes, particularly the cytochrome P-450 system. These results suggest the possibility of drug accumulation and toxicity when certain other therapeutic agents are administered simultaneously with piroxicam. For the same reason, it is recommended to bear in mind the potential danger of long-term piroxicam therapy on the oxidative degradation of steroid hormones and other endogenous compounds that are metabolized by the mixed-function oxidase system.Key words: antipyrine, piroxicam, ketoprofen, naproxen, nonsteroidal anti-inflammatory drugs, drug metabolism.
Quantitative radionuclide assessment of total pulmonary vascular volume changes
Authors: Bell Leonard , Rutlen David L.
Published: April 2011

Current techniques do not permit continuous and noninvasive assessments of changes in total pulmonary intravascular volume. Hence, the present study was undertaken to determine whether quantitative radionuclide imaging can be used to determine the direction and estimate the magnitude of total pulmonary vascular volume changes. The pulmonary circulation was separately perfused at a constant rate via the pulmonary artery and drained at a constant pressure via the left atrium in nine dogs. Changes in pulmonary intravascular volume were recorded as reciprocal changes in extracorporeal reservoir volume during phenylephrine or isoproterenol administration, a 20% increase in pulmonary artery flow or a 5 mmHg (1 mmHg = 133.32 Pa) decrease in left atrial pressure. Erythrocytes were labeled with technetium-99 m and pulmonary volume changes were determined from tissue attenuation, blood radioactivity, and changes in total pulmonary radioactivity obtained with a γ-camera. During each of the interventions, count changes correlated with volume changes (r ≥ 0.75). The technique reliably detected volume changes as small as 10 mL. For all 531 individual pairs of radionuclide- and reservoir-determined volume changes, the correlation between reservoir-determined and radionuclide-estimated pulmonary intravascular volume changes was 0.87. The standard error of the radionuclide estimate was 21 mL. Hence, the present study demonstrates that quantitative radionuclide imaging can be used to continuously and noninvasively determine total pulmonary vascular volume changes.Key words: pulmonary circulation, intravascular volume, radionuclide imaging, capacitance vasculature.
Innervation of interstitial cells of Cajal by vasoactive intestinal polypeptide containing nerves in canine colon
Authors: Berezin Irene , Huizinga Jan D. , Farraway Laura , Daniel Edwin E.
Published: April 2011

The hypothesis was tested, through structural and functional studies, that interstitial cells of Cajal receive and can respond to direct innervation from nerves containing the vasoactive intestinal polypeptide neuromediator. The submucosal network of interstitial cells of Cajal has been postulated to provide pacemaking activity for the circular muscle and to be involved in neurotransmission from noradrenergic, noncholinergic nerves for which vasoactive intestinal polypeptide is a putative mediator. The distribution of vasoactive intestinal polypeptide and substance P immunoreactive material in nerve profiles of the enteric nervous system of the canine colon was examined. In addition, electrophysiological studies were done on the interstitial cells bordering the submucosal side of the circular muscle layer after they were electrically isolated using heptanol. The vasoactive intestinal polypeptide immunoreactivity, located exclusively in nerve large granular vesicles, was found throughout the enteric nervous system (myenteric plexus, submucous plexus, and circular muscle – submucosa interface). The highest proportion (38% compared with 22–24%) of profiles of large granular vesicles with vasoactive intestinal polypeptide immunoreactivity was found in nerve profiles of the circular muscle – submucosa interface. In contrast, substance P immunoreactivity was found in nerve profiles of myenteric plexus (33% of large granular vesicles were positive) but not associated with submucosal interstitial cell nerve network. The vasoactive intestinal polypeptide hyperpolarized interstitial cells by 9 mV when electrically isolated by 1 mM heptanol and markedly reduced (about 50%) their input membrane resistance. We conclude that the distribution of vasoactive intestinal polypeptide immunoreactivity and its action are consistent with a postulated role of the interstitial cells as a major site of neurally mediated inhibition of colonic pacemaker activity.Key words: enteric nervous system, interstitial cells of Cajal, inhibitory junction potential, nonadrenergic noncholinergic nerves.
Inaccuracies in self-reported intake identified by comparison with the doubly labelled water method
Authors: Schoeller Dale A. , Bandini Linda G. , Dietz William H.
Published: April 2011

To test the accuracy of self-reported energy intake, reported intake was compared with measured energy expenditure. Results from nine studies were reviewed in which intake data were obtained by recall or weighed record for at least 7 days. Expenditure was measured for 7 days or more by the doubly labelled water method. Individual differences between reported intake and expenditure were large (range +25 to −76%). Group mean differences were smaller. Lean, nonathletic groups living in industrialized countries demonstrated the smallest mean difference between self-reported energy intakes and expenditure (0 to −20%). Obese populations demonstrated the largest mean differences (−35 and −50%), but women living in the Gambia and elite athletes also demonstrated large mean differences. Most of the difference appears to be due to underreporting, but some subjects lost weight during the reporting period indicating that some of the difference was due to under-eating. Because the greatest bias was observed in obese subjects, current methods for self-reported energy intake are not recommended for use in obesity research.Key words: dietary intake, doubly labelled water, nutritional assessment.
Mycotoxins and toxigenic fungi on cereal grains in western Canada
Authors: Mills John T.
Published: April 2011

Toxins occasionally present on cereal grains in the field in western Canada include ergot alkaloids produced by Claviceps purpurea and trichothecenes produced by Fusarium species, particularly Fusarium sporotrichioides and Fusarium graminearum. HT-2 toxin, T-2 toxin, diacetoxyscirpenol, and deoxynivalenol are the main trichothecenes encountered. During storage of cereals, the predominant toxins and toxigenic fungi are ochratoxin A and citrinin produced by Penicillium aurantiogriseum, P. chrysogenum, and P. verrucosum and sterigmatocystin produced by Aspergillus versicolor. The incidence of toxin-contaminated grains is extremely low relative to the volume of grains produced. Occurrence of toxins is influenced by field moisture, temperature, and bin storage conditions of a particular year. The risk of toxin production is highest in durum wheat and lowest in oats.Key words: ochratoxin A, citrinin, deoxynivalenol, T-2 toxin, ergot alkaloids.
Tetrabutylammonium induces a voltage-dependent block of kainate current in Xenopus oocytes injected with rat brain mRNA
Authors: Randle John C. R.
Published: April 2011

Following injection of rat striatal and cerebrellar mRNA, Xenopus oocytes were voltage clamped and current responses to the excitatory amino acid receptor agonist, kainate, were recorded. This nonspecific cationic current is carried principally by Na+ and K+ and reverses polarity at a membrane potential of approximately −5 mV. When the membrane potential was voltage clamped to −60 mV, bath-applied tetrabutylammonium (0.1–30 mM) produced a rapid, concentration dependent and reversible block of kainate-induced inward current with an IC50 of 1.3 mM. Tetraalkylammonium derivatives having shorter chains (methyl, ethyl, and propyl) were relatively ineffective blockers. Longer alkyl chain derivatives (pentyl, hexyl, and heptyl) were more potent than tetrabutylammonium but limited in their usefulness by their toxicity. The antagonism of kainate-induced current by tetrabutylammonium displayed apparently uncompetitive kinetics, in contrast with the competitive antagonism by γ-D-glutamylaminomethylsulfonate. The block by tetrabutylammonium was strongly voltage dependent; an e-fold change in IC50 was observed for a 27 mV change in holding potential. Replacement of the Na+ in the medium with a more permeant cation (NH4+), a less permeant cation (tetramethylammonium), or an uncharged solute (mannitol) had little effect on the block of kainate-induced current by tetrabutylammonium. The rates of association and dissociation of tetrabutylammonium with the kainate receptor–channel are clearly rapid. These observations suggest that tetrabutylammonium enters and blocks the kainate receptor-associated cation selective channel. Tetrabutylammonium appears to traverse 80–90% of the membrane electrical field to reach a relatively low-affinity binding site that may simply be a narrowing of the channel.Key words: voltage clamp, excitatory amino acid receptor, neurotransmitter-activated ionic currents, striatum, cerebellum.
Effects of in vivo and in vitro treatment with L-carnitine on isolated hearts from chronically diabetic rats
Authors: Rodrigues Brian , Ross John R. , Farahbakshian Sepehr , McNeill John H.
Published: April 2011

The effects of in vivo and in vitro L-carnitine administration on cardiac function were studied in isolated perfused working hearts from control and diabetic rats. Injection of L-carnitine (3 g∙g−1∙day−1,i. p.) for 2 weeks into rats previously diabetic for 6 weeks partially reversed the adverse effects of chronic diabetes on heart function. In a second experiment, a lower dose of L-carnitine (0.5 g∙kg−1∙day−1,i.p.) injected for 6 weeks prevented the onset of heart dysfunction in chronically diabetic rats. The protective action of L-carnitine in the myocardium appeared to be independent of any direct pharmacological effects. In both studies, L-carnitine was a potent lipid-lowering agent. The data suggests that L-carnitine administration at either dose had a protective effect against myocardial damage seen during diabetes. The mechanism(s) underlying these effects remains to be elucidated but are discussed.Key words: diabetes, heart, cardiomyopathy, carnitine, lipids.
Effect of functional adrenalectomy on glucagon secretion and circulating catecholamines during insulin hypoglycemia in the dog
Authors: Yamaguchi Nobuharu , Briand Richard , Gaspo Rania
Published: April 2011

The present study was carried out to determine whether an increase in the pancreatic immunoreactive glucagon (IRG) secretion during the acute phase of insulin-induced hypoglycemia depends on circulating catecholamines of adrenal origin. Hypoglycemia was induced by a bolus insulin injection (0.15 IU/kg, i.v.) in dogs anesthetized with sodium pentobarbital (35 mg/kg, i.v.). Plasma aortic epinephrine (E) and norepinephrine (NE) concentrations increased significantly 30 min after the injection of insulin. At this time point, a functional adrenalectomy (diversion of bilateral adrenal venous blood from the systemic circulation) was performed for 5 min. The increased aortic E and NE concentrations significantly decreased reaching, within 5 min, a level below the corresponding preinjection control value. The basal output of pancreatic IRG (6.58 ± 1.12 ng/min, n = 6) significantly increased (24.93 ± 2.77 ng/min, p < 0.05, n = 6) 30 min after insulin injection. During the functional adrenalectomy, the increased pancreatic IRG output diminished rapidly, within 5 min, to approximately 50% (11.73 ± 3.19 ng/min, p < 0.05, n = 6) of the value observed 30 min after insulin administration. In the other group of dogs receiving sham adrenalectomy, the increased aortic E and NE concentrations and pancreatic IRG output following insulin injection remained elevated above the levels observed immediately before the sham adrenalectomy. The net decrease in IRG output during the adrenalectomy was significant (p < 0.05) compared with the corresponding net IRG output observed in the sham group. The net changes in pancreatic IRG output after insulin administration and during adrenalectomy observed in both groups were correlated with those in aortic E and NE concentrations (r = 0.720, p < 0.05). The study shows that the increase in pancreatic IRG secretion during the early phase of insulin-induced hypoglycemia is due, in part, to the increased circulating catecholamines of adrenal origin.Key words: catecholamine, adrenal, pancreas, glucagon, insulin, hypoglycemia, adrenalectomy.
The effect of atrial natriuretic factor on force development in rat cardiac trabeculae
Authors: Stone James A. , Backx Peter H. M. , Keurs Henk E. D. J. ter
Published: April 2011

Studies in single cardiac muscle cells have demonstrated that atrial natriuretic factor decreases the L-type calcium current. Recent investigations in human atrial cells have also demonstrated that atrial natriuretic factor causes a voltage-dependent reduction in sodium channel activity and thus may reduce intracellular calcium via decreased activity of the sodium–calcium exchange mechanism. By reducing intracellular calcium, atrial natriuretic factor may have a negative inotropic effect on cardiac muscle. To characterize the effect of atrial natriuretic factor on the development of force, we studied the force – sarcomere length relationship in 11 right ventricular rat trabeculae, both before and after exposure of the muscles to increasing concentrations of atrial natriuretic factor. Sarcomere length was measured by laser diffraction techniques and controlled by a servomotor system. The addition of atrial natriuretic factor to the superfusion solution, at concentrations of 10−9–10−7 M, increased stimulus threshold, reduced peak twitch force in a dose-dependent manner by 38% (maximum), and reduced time to peak twitch force by 15% (maximum). Incubation of muscle preparations with concentrations of atrial natriuretic factor below 10−9 M had no effect on force generation. The negative inotropic effect of atrial natriuretic factor was associated with a change in the shape of the force – sarcomere length relationship, similar to a reduction of the extracellular calcium concentration. ANF (10−7 M) had no effect on the rate of decay of force following post extra-systolic potentiation. These observations are consistent with the assumption that the negative inotropic effect of atrial natriuretic factor is mediated by reduction of calcium entry into the cardiac cell.Key words: ANF, cardiac muscle, calcium, force, sarcomere length.
Microsomal glycerolphosphate acyltransferase inactivation by fatty acids
Authors: Durocher V. , Miller M. , Rodriguez M. A.
Published: April 2011

Glycerolphosphate acyltransferase activity in microsomes from rat adipose tissue is shown to decrease with time upon incubation with adipose tissue cytosolic fraction. The inactivation can be prevented with serum albumin and seems to be caused by an increase in endogenous free fatty acid as a consequence of the action of cytosolic lipase(s) on the membrane lipids. Similar inactivation can be observed after short incubation of microsomes with oleic acid at micromolar concentrations. Diacylglycerol acyltransferase is also inhibited by oleic acid, although to a lesser degree. In contrast, glucose-6-phosphatase and NADPH – cytochrome reductase activities are not changed. The oleic acid effect appears to occur upon binding to the microsomal membranes and can be prevented by bovine serum albumin at protein/fatty acid molar ratios above one. These results suggest that free fatty acids may be involved in the modulation of triacylglycerol synthetic enzymes.Key words: glycerolphosphate acyltransferase, fatty acids, microsomal enzymes, lipid synthesis.
High-affinity prostaglandin E receptors attenuate adenylyl cyclase activity in isolated bovine myometrial membrane
Authors: Lerner Richard W. , Lopaschuk Gary D. , Olley Peter M.
Published: April 2011

Purified bovine myometrial plasma membranes were used to characterize prostaglandin (PG) E2 binding. Two binding sites were found: a high-affinity site with a dissociation constant (KD) of 0.27 ± 0.08 nM and maximum binding (Bmax) of 102.46 ± 8.6 fmol/mg membrane protein, and a lower affinity site with a KD = 6.13 ± 0.50 nM and Bmax = 467.93 ± 51.63 fmol/mg membrane protein. Membrane characterization demonstrated that [3H]PGE2 binding was localized in the plasma membrane. In binding competition experiments, unlabelled PGE1 displaced [3H]PGE2 from its receptor at the same concentrations as did PGE2. Neither PGF2α nor PGD2 effectively competed for [3H]PGE2 binding. Adenylyl cyclase activity was inhibited at concentrations of PGE2 that occupy the high-affinity receptor. These data demonstrate that two receptor sites, or states of binding within a single receptor, are present for PGE2 in purified myometrial membranes. PGE2 inhibition of adenylyl cyclase activity support the view that cAMP has a physiological role in the regulation of myometrial contractility by PGE2.Key words: myometrium, PGE2 receptor, adenylyl cyclase.
Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle
Authors: Rhoades R. A. , Packer C. S. , Roepke D. A. , Jin N. , Meiss R. A.
Published: April 2011

Reactive oxygen species alter pulmonary arterial vascular tone and cause changes in pulmonary vascular resistance. The objective of this investigation was to determine direct effects of oxygen radicals on the contractile properties of pulmonary arterial smooth muscle. Isolated pulmonary arterial rings from Sprague–Dawley rats were placed in tissue baths containing Earle's balanced salt solution (gassed with 95% O2 – 5% CO2, 37 °C, pH 7.4). Vessels were contracted with 80 mM KCl to establish maximum active force production (PO). All other responses were normalized as percentages of PO for comparative purposes. Reactive oxygen metabolites were generated enzymatically with either the xanthine oxidase (XO) reaction or me glucose oxidase (GO) reaction, or hydrogen peroxide (H2O2) was added directly to the muscle bath. Exposure to XO, GO, or to H2O2 resulted in a contractile response that was sustained during the 30-min exposure period. The muscle fully relaxed following removal of the reactive oxygen species. Resting tension remained unchanged throughout the experimental period, suggesting no functional change in membrane potential. The contractile response was dose dependent and was not prevented by either cyclooxygenase or lipoxygenase inhibition, or by removal of the endothelium. Pretreatment of vessels with superoxide dismutase (SOD) partially blocked the XO-induced contraction, while mannitol or deferoxamine had no effect on the response to XO. However, pretreatment with catalase (CAT) completely blocked the XO-induced contraction. These data suggest that superoxide ions and hydrogen peroxide are the major causative agents. Following O2-radical exposure, vessels showed a decrease in contractile responsiveness to 80 mM KCl (recovery response), suggesting damage to the smooth muscle cells. Administration of SOD or CAT alone significantly improved the recovery response to 80 mM KCl, while SOD plus CAT offered complete protection resulting in final responses to high K+ that were 100% of PO. Vessels precontracted with a submaximal dose of KCl or 5-hydroxytryptamine and then exposed to O2 radicals produced contractile responses that were more than additive, suggesting that "priming" the vessel potentiated reactive oxygen-mediated contraction. These data show that reactive oxygen species can act directly as vasoconstrictors, while simultaneously damaging the arterial smooth muscle such that subsequent contractility is impaired.Key words: oxygen radicals, pulmonary circulation, pulmonary artery, vascular smooth muscle.
Lack of effect of oral L-carnitine treatment on lipid metabolism and cardiac function in chronically diabetic rats
Authors: Rodrigues Brian , Seccombe David , McNeill John H.
Published: April 2011

L-Carnitine is necessary for the transfer of long-chain fatty acids into the mitochondrial matrix where energy production occurs. In the absence of L-carnitine, the accumulation of free fatty acids and related intermediates could produce myocardial subcellular alterations and cardiac dysfunction. Diabetic hearts have a deficiency in the total carnitine pool and develop cardiac dysfunction. This suggested that carnitine therapy may ameliorate alteration in cardiac contractile performance seen during diabetes. In this study, heart function was studied in streptozotocin diabetic rats given L-carnitine orally. Oral L-carnitine treatment (50–250 mg∙kg−1∙day−1) of 1- and 3-week diabetic rats increased plasma free and total carnitine and decreased plasma acyl carnitine levels. In both groups, myocardial total carnitine levels were increased. However, L-carnitine (200 mg∙kg−1∙day−1) treatment of diabetic rats for 6 weeks had no effect on plasma carnitine levels. Similarly, plasma lipids remained elevated whereas cardiac function was still depressed. These studies suggest that in the chronically diabetic rat, the route of administration of L-carnitine is an important factor in determining an effect.Key words: L-carnitine, lipid metabolism, cardiac function, diabetic rats.
Mechanisms underlying anoxic hyperpolarization of hippocampal neurons
Authors: Krnjevlć K. , Xu Y.
Published: April 2011

The outward current evoked in CA1 neurons by brief anoxia is strongly voltage dependent and is abolished by an atropine-sensitive action of carbachol (and also when recording with a GTPγS-containing microelectrode). In this respect, it closely resembles the M-type K current, but the involvement of other, voltage-independent, carbachol-sensitive K channels has not been excluded. When the anoxic outward current is eliminated, an anoxic inward current is revealed, which may be Cl− mediated. It is suggested that an early release of Ca2+ from a dantrolene (and perhaps GTP)-sensitive internal store activates Ca-sensitive Cl channels, as well as carbachol-sensitive (mainly M-type?) K channels. The opposing Cl− and K currents would account for the variable depolarizing and hyperpolarizing effects of anoxia.Key words: carbachol, atropine, GTPγS, rat hippocampal slices, M current, Cl current, intracellular Ca2+.
Characterization by saturation studies of the in vivo binding of [3H]flunitrazepam in mouse brain
Authors: Wong Peter T.-H.
Published: April 2011

The in vivo binding of [3H]flunitrazepam ([3H]Fln) was characterized in seven regions of the mouse brain. The binding showed saturability and linear Scatchard plots. Hill coefficients were close to unity. Data fitting to a hyperbola by least squares yielded consistent Kd values for all regions studied (0.36–0.6 pmol/mg protein). Bmax values ranged from 0.14 to 0.89 pmol/mg protein, a sixfold regional variation. The order of binding is as follows: cortex > hippocampus > midbrain = thalamus/hypothalamus > striatum ≥ cerebellum > brainstem, consistent with that obtained by in vitro binding. The in vivo receptor density and affinity are apparently lower in comparison with in vitro parameters. This is consistent with the observation that the Kd increases and Bmax decreases in vitro when the incubation temperature is increased from 0 °C. Non-specific binding has been estimated by displacement of in vivo binding by unlabelled ligand in vitro as well as by pretreatment with unlabelled ligand. The two alternative methods were compared and evaluated. It is concluded that the displacement method provides more reliable estimates of the nonspecific binding. Diazepam-sensitive mice did not differ from the control mice in the in vivo [3H]Fln binding. However, mice pretreated with diazepam 1 or 2 days before have binding reduced by 70 or 30%, respectively. The reduced binding may be explained by receptor occupancy by residual oxazepam. However, the low concentration of the residual oxazepam is an unlikely cause of the phenomenon of "acute tolerance" observed in these mice.Key words: benzodiazepines, in vivo binding, characterization, diazepam-sensitive mice, acute tolerance.
The effect of long-term, voluntary ethanol consumption on hepatic regeneration in rats
Authors: Minuk G. Y. , Rockman G. E. , Gauthier T. , Markert L. , Gibson J. , Benarroch A.
Published: April 2011

Previous studies have reported conflicting results regarding the effect of ethanol on hepatic regeneration. The purpose of the present study was to determine whether long-term, voluntary consumption of ethanol, within the range reported in humans, has an effect on hepatic regenerative activity in rats following partial hepatectomy. Ninety-four adult male Sprague–Dawley rats (n = 3–9/group) were studied. Based on the amount of 9% ethanol consumed over a 50-day period, low ethanol intake (0.1 –1.9 g∙kg−1∙d−1) and high ethanol intake (2.0 – 4.0 g∙kg−1∙d−1) groups were identified. Control groups consisted of rats provided with propylene glycol in equivalent caloric amounts to the ethanol consumed by high ethanol intake rats (isocaloric group) and rats served water only (ad libitum group). An additional two groups from which ethanol was removed 5 days prior to surgery were also studied (low ethanol grace and high ethanol grace). Hepatic regeneration was determined by restitution of liver weight, [3H]thymidine incorporation into DNA, and [14C]leucine incorporation into protein 24, 48, and 72 h following partial (70%) hepatectomy. The results of the study revealed no significant differences in the rate of hepatic regeneration between low and high ethanol consuming rats or between either of these groups and isocaloric or ad-libitum fed control groups. Regeneration in low ethanol grace and high ethanol grace groups were also similar to each other and controls. Moreover, there was no correlation between mean ethanol consumption per rat and restitution of liver weight, [3H]thymidine incorporation into DNA, or [14C]leucine incorporation into protein by the regenerating liver (r = 0.0716, −0.1637, and 0.1395, respectively). These findings suggest that voluntary consumption of ethanol by rats, within the range reported in humans, does not significantly influence the rate of hepatic regeneration following partial hepatectomy.Key words: ethanol, liver regeneration, alcohol, liver disease.
Enhanced arterial contractility to noradrenaline in diabetic rats is associated with increased phosphoinositide metabolism
Authors: Abebe Worku , MacLeod Kathleen M.
Published: April 2011

The purpose of this study was to investigate whether the increased contractile responsiveness of aortae from male rats with 12 – 14 week streptozotocin-induced diabetes to noradrenaline is associated with alterations in phosphoinositide metabolism. The contractile response to noradrenaline (10 μM) in both the presence and absence of extracellular calcium was significantly enhanced in aortae from diabetic rats. No significant differences were found between control and diabetic arteries in the basal incorporation of 32P and [3H]myo-inositol into phosphoinositides, or in the basal accumulation of [32P]phosphatidic acid and [3H]inositol phosphates. However, noradrenaline (10 μM) caused significantly greater breakdown of [32P]phosphatidylinositol 4,5-bisphosphate and formation of [32P]phosphatidic acid and [3H]inositol phosphates in diabetic aortae than in control preparations. The production of [3H]inositol phosphates induced by noradrenaline was selectively reduced by the α1-adrenoceptor antagonist, prazosin, in both control and diabetic tissues. These results indicate that phosphoinositide metabolism in response to noradrenaline via stimulation of α1-adrenoceptors is enhanced in aortae from chronic streptozotocin-diabetic rats. The increase in inositol 1,4,5-trisphosphate and 1,2-diacylglycerol production that presumably results could be responsible, at least in part, for the enhanced contractile response of aortae from diabetic rats to noradrenaline.Key words: diabetes, aortae, phosphoinositide metabolism, noradrenaline, contractile responses.
The characteristics of the microsomal hydroxylation of tolbutamide
Authors: Bélanger Pierre M. , St-Hilaire Serge
Published: April 2011

The in vitro metabolism of tolbutamide to the hydroxymethyl derivative was studied using hepatic microsomal homogenates. The hydroxymethyl metabolite was quantitated by HPLC. The hepatic microsomal hydroxylase was completely inhibited by carbon monoxide and was NADPH dependent. Metyrapone, α-naphthoflavone, phenelzine, mercuric chloride, and nitrogen significantly inhibited the reaction indicating the involvement of the cytochrome P-450 monooxygenase. Species variation showed that the order of hepatic microsomal activity was rat > rabbit >> guinea pig >> mouse and hamster. The reaction increased with time up to 40 min and followed Michaelis–Menten kinetics in rat liver microsomes with apparent Km and Vmax values of 224.4 μM and 359.9 pmol∙mg−1∙min−1, respectively. The reaction was induced by phenobarbital but was depressed after pretreatment with 3-methylcholanthrene and isosafrole. However, expression of the hydroxylase activity per nanomoles of cytochrome P-450 showed that the activity was much higher in liver microsomes of isosafrole pretreated rats. These results indicate the involvement of different isozymes of cytochrome P-450 in the microsomal hydroxylation of tolbutamide.Key words: tolbutamide metabolism, tolbutamide hydroxylation, microsomal hydroxylation, microsomal metabolism of tolbutamide, hepatic metabolism of tolbutamide.
The K+-evoked release of [3H]acetylcholine from slices of rat globus pallidus: modulation by δ-opioid receptors
Authors: Ruzicka Bianca B. , Jhamandas Khem
Published: April 2011

Previous investigations have shown that the activation of δ-opioid receptors depresses the release of acetylcholine (ACh) in the rat caudate putamen. This finding raised the possibility that the release of ACh is similarly modulated in the globus pallidus, a region containing a distinct population of cholinergic neurons and enriched in enkephalinergic nerve terminals. In the present study the pallidal release of ACh was characterized and the effects of δ-opioid receptor activation on this release were examined. The results show that this release is stimulated by high K+ in a concentration- and Ca2+-dependent manner. D-Pen2,L-Pen5-enkephalin (0.1 – 10 μM), a selective δ-opioid receptor agonist, produced a dose-related inhibition of the 25 mM K+-evoked tritium release. The maximal inhibitory effect, representing a 34% decrease in the K+-induced tritium release, was observed at a concentration of 1 μM. This opioid effect was attenuated by the selective δ-opioid receptor antagonist, ICI 174864 (1 μM). These findings support the role of a δ-opioid receptor in the modulation of ACh release in the rat globus pallidus.Key words: globus pallidus, acetylcholine, enkephalin, release.
Quantitative proton nuclear magnetic resonance of plasma for screening hepatic metabolism during ethanol infusion in cats
Authors: Shoemaker L. , Greenway C. V. , Peeling J. , Sutherland G. , Tomlinson G.
Published: April 2011

The effects of increasing blood ethanol levels on hepatic metabolism were studied in anesthetized cats whose prior fluid intake contained ethanol for 24 days. A hepatic venous long-circuit technique with an extracorporeal reservoir was used to allow hemodynamic measurements and repeated sampling of arterial, portal, and hepatic venous blood without depletion of blood volume. For ethanol, Vmax was 106 ± 15 μmol∙min−1∙100∙g−1 liver and Km was 164 ± 31 μM. A previous study showed that there were no changes in O2 uptake by the liver, suggesting other oxidative processes were suppressed during ethanol metabolism. In this study, proton nuclear magnetic resonance spectroscopy was used to simultaneously screen several plasma metabolites to elucidate other metabolic processes that may be perturbed in the liver during ethanol infusion. Hepatic lactate uptake remained unaltered when ethanol metabolism was less than 0.5 Vmax but was suppressed on an equimolar basis with ethanol metabolism when ethanol metabolism rose above 0.5 Vmax. Thus, lactate oxidation is one process that can be suppressed to allow ethanol oxidation without additional O2 uptake by the liver. In addition, no release of acetate from the liver occurred during ethanol metabolism in these experiments. This surprising finding suggests ethanol metabolism may, under some conditions or in some species, result in fatty acid synthesis rather than acetate release. Eight other major metabolites remained unchanged during ethanol infusion.Key words: liver circulation, hepatic ethanol metabolism, hepatic glucose metabolism, acetate metabolism, β-hydroxybutyrate metabolism.
Plasma glutathione turnover in the rat: effect of fasting and buthionine sulfoximine
Authors: Hum Susan , Robitaille Line , Hoffer L. John
Published: April 2011

Hepatic glutathione (GSH) plays an important role in the detoxification of reactive molecular intermediates. Because of evidence that the intrahepatic turnover of glutathione in the rat may be largely accounted for by efflux from hepatocytes into the general circulation, the quantitation of plasma GSH turnover in vivo could provide a noninvasive index of hepatic glutathione metabolism. We developed a method to estimate plasma glutathione turnover and clearance in the intact, anesthetized rat using a 30-min unprimed, continuous infusion of 35S-labelled GSH. A steady state of free plasma glutathione specific radioactivity was achieved within 10 min, as determined by high-pressure liquid chromatography with fluorometric detection after precolumn derivatization of the plasma samples with monobromobimane. The method was tested after two treatments known to alter hepatic GSH metabolism: 90 min after intraperitoneal injection of 4 mmol/kg buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, and after a 48-h fast. Liver glutathione concentration (mean ± SEM) was 5.00 ± 0.53 μmol/g wet weight in control rats. It decreased to 3.10 ± 0.35 μmol/g wet weight after BSO injection and to 3.36 ± 0.14 μmol/g wet weight after fasting (both p < 0.05). Plasma glutathione turnover was 63.0 ± 7.46 nmol∙min−1∙100 g−1 body weight in control rats, 35.0 ± 2.92 nmol∙min−1∙g−1 body weight in BSO-treated rats, and 41.7 ± 2.28 nmol∙min−1∙g−1 body weight after fasting (both p < 0.05), thus reflecting the hepatic alterations. This approach might prove useful in the noninvasive assessment of liver glutathione status.Key words: glutathione, nutrition, starvation.
Central mechanisms of visceral pain
Authors: Gebhart G. F. , Ness T. J.
Published: April 2011

Deep pain arising from muscle, joints, connective tissue, and the viscera is different in character and quality from pain arising from cutaneous structures. Deep pains, particularly visceral pain, are poorly localized, typically referred or transferred to a cutaneous site, and generally produce strong emotional and autonomic responses and tonic muscle contractions. Despite the prevalence and clinical importance of deep pains, it is only relatively recently that investigative efforts have begun to focus on the mechanisms of deep pain. The present report briefly reviews the development and use of a model of visceral pain that employs constant pressure distension of the colon and rectum as a noxious stimulus. Converging behavioral, pharmacological, and physiological evidence that colorectal distension is a valid, reliable, noxious, visceral stimulus is presented.Key words: visceral pain, colorectal distension, pain modulation, pain model, adequate visceral stimuli.
Muscle pain, dyskinesia, and sleep
Authors: Lavigne G. J. , Velly-Miguel A. M. , Montplaisir J.
Published: April 2011

not available
IV. Comment: Sensory and pharmacological modulation of pain
Authors: Melzack Ronald
Published: April 2011

Traditional neurosurgical methods to control pain have been replaced by a variety of modulation techniques. The major types of modulation are pharmacological, physical, and psychological. Important advances are occurring in the development of all three modulation approaches.
Restoration of lipoprotein lipase activity in insulin-deficient rats by insulin infusion is tissue-specific
Authors: Deshaies Yves , Géloën Alain , Paulin Anne , Bukowiecki Ludwik J.
Published: April 2011

The activity of lipoprotein lipase was measured in white and brown adipose tissues, red vastus lateralis muscle, and heart of rats that have been insulin deficient (streptozotocin, 75 mg∙kg−1) for 2 weeks, and that have then received implants of insulin-delivering minipumps (17 U∙kg−1∙day−1) for 1 or 4 days. Normal glycemia was restored in insulin-deficient animals after 4 days of insulin treatment. Hypertriglyceridemia, but not hypercholesterolemia, was reversed after 4 days of insulin infusion. After 2 weeks of insulin deficiency, fasting lipoprotein lipase activity was lowered in all tissues studied. In white adipose tissue, lipoprotein lipase decreased to 50% of control values. After a single day of insulin infusion, even if tissue weight has not yet been greatly affected, total activity was completely restored to control levels. Enzyme activity in brown adipose tissue was also depressed in deficient animals, and insulin infusion was followed by a slow recovery of activity, to a level intermediate between those of control and insulin-deficient groups. Insulin status had milder effects on lipoprotein lipase activity in vastus lateralis muscle than in the adipose tissues. Deficient rats displayed 60% less activity than controls, and 4 days of hormone infusion only partially restored enzyme activity. There was a large loss of lipoprotein lipase in the heart following 2 weeks of insulin depletion, which was not counteracted by hormone infusion. Thus the speed and extent of recovery of lipoprotein lipase activity following hormone replacement in insulin-deficient animals varied widely among tissues. These findings suggest that insulin is part of the factors that determine the tissue specificity of lipoprotein lipase regulation.Key words: insulin, lipoprotein lipase, white adipose tissue, brown adipose tissue, skeletal muscle, heart.
Impairment of iodothyronine 5′-deiodinase activity in brown adipose tissue and its acute stimulation by cold in selenium deficiency
Authors: Arthur John R. , Nicol Fergus , Beckett Geoffrey J. , Trayhurn Paul
Published: April 2011

The activity of the type II iodothyronine 5′-deiodinase enzyme in brown adipose tissue has been examined in rats fed a selenium-deficient diet. Iodothyronine 5′-deiodinase activity was threefold lower in brown adipose tissue of deficient rats than in control animals. The activity of glutathione peroxidase, a biochemical index of selenium deficiency, was also greatly decreased in deficient animals. Cytochrome oxidase activity in brown fat was, however, unaltered by selenium deficiency. Acute exposure to cold (4 °C for 18 h) resulted in a substantial increase in iodothyronine 5′-deiodinase activity in brown adipose tissue of control rats, but the stimulatory effect of cold was attenuated in selenium-deficient animals. These results support the concept that the iodothyronine 5′-deiodinases are selenium-dependent enzymes, and indicate that the thermogenic response to cold may be impaired in selenium deficiency.Key words: iodothyronine 5′-deiodinase, glutathione peroxidase, selenium deficiency, brown adipose tissue, cold exposure.
Relationship between myocardial amiodarone concentration and antiarrhythmic effect in dogs with myocardial infarction and electrically induced ventricular arrhythmias
Authors: Abdollah Hoshiar , Brennan F. James , Jimmo Sandra , Brien James F.
Published: April 2011

The relationship between the antiarrhythmic effect of amiodarone and its myocardial concentration was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia or ventricular fibrillation. Three groups of animals (n = 10/group) received amiodarone, 40 mg∙kg−1∙day−1 (low-dose amiodarone), amiodarone 60 mg∙kg−1∙day−1 (high-dose amiodarone), or no amiodarone (control group). After 1 week of treatment, programmed electrical stimulation was repeated, and plasma and myocardial amiodarone and desethylamiodarone concentrations were measured. In the control group, sustained ventricular tachycardia or ventricular fibrillation was induced in six dogs (p = NS) when compared with baseline data. In the low-dose amiodarone group, sustained ventricular tachycardia or ventricular fibrillation was induced only in two dogs after 1 week of treatment (p < 0.01 vs. baseline data). Sustained ventricular tachycardia or ventricular fibrillation was induced in seven dogs after treatment with high-dose amiodarone (p = NS vs. baseline data). Plasma amiodarone concentration in the low-dose amiodarone group (2.54 ± 1.9 μg/mL) was significantly less (p < 0.01) than that in the high-dose amiodarone group (4.64 ± 1.66 μg/mL). Similarly, the plasma desethylamiodarone in the low-dose amiodarone group (0.32 ± 0.16 μg/mL) was significantly less (p < 0.001) than that in the high-amiodarone dose group (0.56 ± 0.23 μg/mL). The myocardial amiodarone concentration in the low-dose amiodarone group (49.7 ± 23.1 μg/g) was significantly lower (p < 0.001) than that in the high-dose group (98.4 ± 32.1 μg/g). There was no significant difference in the myocardial desethylamiodarone concentrations between the two treatment groups (25.1 ± 12.2 μg/g in the low-dose amiodarione group vs. 37.4 ± 16.4 μg/g in the high-dose amiodarone group). These data show that the high-dose amiodarone regimen, which produced high myocardial amiodarone concentration, didn't suppress sustained ventricular arrhythmias.Key words: amiodarone, ventricular arrhythmias, plasma and myocardial drug concentrations.
Resistance of hepatic glycogen to depletion in obese Zucker rats
Authors: Koubi Harry , Duchamp Claude , Géloën Alain , Fréminet Alain , Minaire Yves
Published: April 2011

Glycogen stores (liver and carcass) have been studied in lean and obese Zucker rats. The animals were submitted to one of three feeding conditions: ad libitum, a 48-h fast, or a 48-h fast and food ad libitum for 24 h, and to two environmental conditions, either thermoneutrality or an acute cold exposure (2 days at 4–7 °C). After a 2-day fast at 25 °C, the liver glycogen store was reduced by 45 times in the lean rats, while it was decreased by only 3 times in the obese rats. Under these conditions, the liver glycogen store was 45 times higher in the obese than in the lean rats. After 2 days in the cold, liver glycogen store was 4.4 times higher in obese rats than in lean rats. After a 2-day fast in the cold, the liver glycogen store in the obese rats was 30 times higher than in the lean rats. In comparison to fasting at thermoneutrality, fasting in the cold did not lead to a further reduction in hepatic glycogen in obese Zucker rats. The differences observed in the mobilization of the hepatic glycogen store between obese and lean rats have not been found in the mobilization of the carcass glycogen store. Drastic conditions, such as a 2-day fast in the cold, did not exhaust the glycogen store in obese Zucker rats. The present observations point out that obese Zucker rats cannot mobilize the entire hepatic glycogen store, as seen in lean control rats. The role of this abnormality in the high hyperlipogenesis that maintains the obese state is still to be evaluated.Key words: glycogen, fasting and refeeding, cold exposure, obesity, liver.
Vascular effects of some opioid receptor agonists
Authors: El-Sharkawy T. Y. , Al-Shireida M. F. , Pilcher C. W. T.
Published: April 2011

Opioid peptides have been implicated in shock-associated hypotension. Our aim was to find out whether opioid agonists have direct vasodilator actions on vascular smooth muscle. The study was conducted on rat abdominal aortic rings. In rings precontracted with either norepinephrine, prostaglandin F2α, or high potassium Krebs (HPK), the effects of the opioid agonists tested (morphine, U50488H, ethylketocyclazocine (EKC), and bremazocine) depended on the precontracting agent used. HPK-precontracted rings were relaxed by all agonists tested. In norepinephrine-precontracted rings, all caused contraction at low concentrations and relaxation at high concentrations except bremazocine, which caused only relaxation. In prostaglandin F2α-precontracted rings, U50488H produced contraction at low concentrations and relaxation at high concentrations while EKC caused only relaxation and morphine or bremazocine caused only contraction. All relaxant responses were endothelium-independent and were antagonized by verapamil but not by a number of antagonists including naloxone, MR2266, propranolol, diphenhydramine, cimetidine, and indomethacin. They may reflect calcium channel blockade. Morphine-induced vasoconstriction was antagonized by high concentrations of naloxone or mepyramine and may be due to release of histamine by a naloxone-sensitive mechanism. We conclude that (a) the opioid agonists tested exert direct actions on vascular smooth muscle; (b) the nature of the response depended not only on the agonist used and its concentration but also on the agent used to precontract the tissue; and (c) it is unlikely that direct actions of endogenous opioids contribute to the shock-associated hypotension because high doses were needed to elicit them.Key words: vascular smooth muscle, opioids, neurohormonal peptides, circulatory shock.
Potentiation of bradykinin effects and inhibition of kininase activity in isolated smooth muscle
Authors: Schaffel Rony , Rodrigues Mozart S. , Assreuy Jamil
Published: April 2011

Prolongation of bradykinin half-life following kininase inhibition has been proposed as the reason for the potentiation of kinin effects. We have reassessed this assumption by using three different isolated smooth muscle preparations and simultaneously studying the inhibition of kininase activity and the potentiation of bradykinin effects by enalaprilat and BPP9a. Rat duodenum displayed higher total kininase activity, metabolizing half of the added bradykinin in 6.5 min, while this time for rat uterus was greater than 60 min. Guinea-pig ileum showed the intermediate value of 14.6 min. Enalaprilat and BPP9a slowed the metabolism of bradykinin by 50–100% in rat duodenum and by 50–180% in guinea-pig ileum, showing that a significant fraction of total kininase activity appears to be due to kininase II. In rat duodenum, an almost complete blockade of kininase activity was achieved when bacitracin and mergetpa were used together with enalaprilat. Enalaprilat and BPP9a potentiated bradykinin effects in guinea-pig ileum and rat uterus. In contrast, bradykinin-induced relaxations and contractions in rat duodenum were not potentiated by enalaprilat, BPP9a, or by the enzyme inhibitor mixture (enalaprilat – bacitracin – mergetpa). The results suggest that inhibition of bradykinin enzymatic metabolism by kininases does not necessarily lead to the potentiation of bradykinin effects.Key words: bradykinin, kininase II, potentiation, smooth muscle.