bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of insulin receptor binding by prolonged enteral or parenteral nutrient infusion in the rat: role of gastric inhibitory polypeptide
Authors: Baer A. R. , Dupré J.
Published: April 2011

In the rat, prolonged enteral or parenteral alimentation with a high-carbohydrate diet results in hyperinsulinemia, which is substantially greater with the parenteral route. Supplementing the parenteral infusate with porcine gastric inhibitory polypeptide (GIP) to approximate plasma immunoreactive GIP levels achieved with enteral feeding further increases steady-state plasma insulin and glucose concentrations, suggesting insulin resistance. We examined the effects of sustained hyperinsulinemia elicited by continuous nutrient infusion on insulin binding to isolated rat adipocytes and the modification of this response by GIP. Compared with a baseline group, both enterally and parenterally alimented groups showed decreased insulin receptor binding affinity. However, despite substantially different steady-state plasma insulin levels, insulin binding was similar with either infusion route. Factors other than plasma insulin concentration alone therefore contribute to insulin receptor down-regulation during prolonged enteral alimentation. Supplementing the parenteral infusate with exogenous GIP resulted in a further reduction in insulin receptor affinity. Thus, adaptation to continuous nutrient infusion is characterized by insulin receptor down-regulation regardless of the route of nutrient delivery. An additional suppression of insulin receptor binding may in part be responsible for the insulin resistance elicited by prolonged exogenous GIP administration.Key words: gastric inhibitory polypeptide, insulin receptor binding, hyperinsulinemia.
Contribution of afferent renal nerves to the metabolic activity of central structures involved in the control of the circulation
Authors: Simon James K. , Ciriello John
Published: April 2011

Afferent renal nerves (ARN) are thought to be an important link in the pathogenesis of hypertension because of their influence on neuronal circuits involved in the control of arterial pressure and body fluid homeostasis. However, the central neural pathways involved in mediating ARN information have not been completely elucidated. In the present study, regions of the brainstem and forebrain, whose metabolic activity was altered after renal denervation, were functionally identified using hexokinase histochemistry in the rat. No differences in arterial pressure or heart rate were observed in either the 3-day or 13-day ARN-transected (tARN) animals compared with the respective sham ARN-transected (sARN) groups. Significant increases in the hexokinase reaction product were seen in the parvocellular component of the paraventricular nucleus of the hypothalamus, the supraoptic nucleus, the arcuate nucleus, the subfornical organ, the median preoptic nucleus, and the medial nucleus of the amygdala in both the 3-day and 13-day tARN animals. The bed nucleus of the stria terminalis was observed to have a significant decrease in hexokinase activity in the tARN groups, as were the caudal and medial aspects of the nucleus of the solitary tract. In the 3-day tARN group only, a significant decrease in hexokinase activity was observed in the region of the brainstem containing the A5 cell group, compared with sARN animals. The magnocellular component of the paraventricular nucleus of the hypothalamus and the lateral hypothalmus was seen to have increased hexokinase activity in the 13-day tARN animals only. These results have demonstrated that removal of ARN input alters the activity of brainstem and forebrain structures that have previously been implicated in the control of the cardiovascular system and body fluid balance. These data suggest that changes in the tonic input from renal receptors to these central structures could contribute to the development and (or) maintenance of hypertension.Key words: hypertension, renal nerves, fluid balance, paraventricular nucleus of the hypothalamus, subfornical organ, nucleus of the solitary tract, cardiovascular reflex pathways.
α-Adrenergic receptor modulation of the intrathoracic efferent sympathetic nervous system regulating the canine heart
Authors: Armour J. A.
Published: April 2011

The augmentation of ventricular inotropism induced by electrical stimulation of acutely decentralized efferent sympathetic preganglionic axons was reduced, but still present, following administraiton of hexamethonium (10 mg/kg i.v.). While hexamethonium continued to be administered, the cardiac augmentations so induced were enhanced significantly following administration of the α-adrenergic receptor blocking agent, phentolamine myselate (1 mg/kg i.v.). Stimulation of the sympathetic efferent postganglionic axons in cardiopulmonary nerves induced cardiac augmentations that were unchanged following administration of these agents singly or together. The cardiac augmentations induced by stimulation of efferent preganglionic sympathetic axons were unchanged when phentolamine was administered alone. The augmentations of cardiac inotropism induced by efferent postganglionic sympathetic axonal stimulation were decreased following local administration of the β-adrenergic antagonist timolol into the ipsilateral stellate and middle cervical ganglia. Thereafter, these augmentations were unchanged following the subsequent intravenous administration of phentolamine. It is concluded that the activation of cardiac neurons in the stellate and middle cervical ganglia by stimulation of efferent preganglionic sympathetic axons can be modified by α-adrenergic receptors and that these effects are dependent upon β-adrenergic receptors, not nicotinic ones, in intrathoracic ganglia.Key words: α-adrenergic inotropism, sympathetic ganglia, hexamethonium, phentolamine.
Involvement of different mechanisms in the stimulatory effects of cholecystokinin octapeptide on gastrointestinal and colonic motility in dogs
Authors: Fargeas M. J. , Bassotti G. , Fioramonti J. , Bueno L.
Published: April 2011

The effects of an intravenous infusion of cholecystokinin octapeptide (CCK-8, 1 μg∙kg−1∙h−1) were investigated in conscious fasted dogs chronically fitted with strain-gauge transducers on the antrum, the jejunum, and the colon. Attempts to antagonize the increase of motility appearing at the three levels during CCK infusion were made using different blockers to elucidate the mechanisms involved. Asperlicin (a specific CCK antagonist) blocked the effects of CCK-8 at the three levels, while atropine and somatostatin were only effective in the jejunum and colon. Methyl-levallorphan (a μ-opiate antagonist that poorly crosses the blood-brain barrier) antagonized the CCK-induced colonic stimulation when intracerebroventricularly administered. Serotonin, histamine, substance P, and κ-antagonists as well as a benzodiazepine did not modify the CCK-8 induced stimulation. It was concluded that the stimulatory effect of CCK-8 resulted from (a) a direct stimulation of the smooth muscle cells at gastric level, (b) a cholinergic activation of the jejunum and the colon, and (c) the involvement of a μ-opioid central component in the colonic response only.Key words: cholecystokinin octapeptide, gastrointestinal motility, dog, cholecystokinin antagonists, opiates, cholinergic system.
Effect of ganglionic stimulating and blocking agents on the fast components of colonic myoelectrical activity in the rat
Authors: Chandran A. P. , Marya R. K. , Sharma L. K.
Published: April 2011

The presence of two types of fast myoelectrical activities, medium fast activity and fast activity, has been demonstrated previously in the electromyogram of colon in normal children and in the rat by the authors. An absence of medium fast activity in Hirschsprung's disease and in experimental aganglionosis of colon in the rat has also been described. In the present study the fast components of colonic myoelectrical activity were analysed during the procedures affecting ganglionic transmission. It was observed that ganglionic stimulants, such as balloon inflation, and intra-arterial injections of acetylcholine and small amounts of nicotine, increased the spike activity and the frequency of medium fast activity without affecting fast activity. The intra-arterial injections of ganglionic blocking agents, such as nicotine in large amounts and pentolinium tartrate, completely abolished the medium fast activity. These observations suggest that the ganglionic activity is responsible for the genesis of medium fast activity and that the absence of cholinergic ganglionic transmission is the most important single factor for the reported altered electromyogram pattern in aganglionosis.Key words: colon, myoelectrical activity, cholinergic ganglionic transmission, aganglionosis.
Calcium current in embryonic Xenopus muscle cells in culture
Authors: Moody-Corbett F. , Gilbert R. , Akbarali H. , Hall J.
Published: April 2011

We have investigated the appearance of calcium current in Xenopus muscle cells in 1- to 6-day-old cultures. Whole cell currents were recorded using a patch-clamp amplifier with sodium and potassium replaced with tetraethylammonium and cesium, respectively, and BaCl2 used in place of CaCl2. When the muscle membrane was depolarized above −30 mV, a slow inward current was activated, the current reached a peak amplitude near 0 mV, and an outward current became apparent above + 10 mV. This slow current was enhanced by adding barium or Bay K 8644 to the extracellular recording solution and was blocked by the addition of cobalt, cadmium, or the dihydropyridines nifedipine or (+)PN 200-110. Taken together these results indicate the presence of an inward calcium current mediated through L-type channels. Thirty-one percent of the cells examined on the first day in culture showed no discernible slow inward current; however, as the age of the culture increased, all cells showed slow inward current and there was an increase in the amplitude of the current. A small proportion of the muscle cells (5 out of 34) also showed a fast activating and inactivating inward current. This current, which activated at more hyperpolarized potentials (−40 mV) was only present when 5 mM ATP was included in the internal recording solution. It also appeared to be mediated through a calcium channel but not a dihydropyridine, sensitive channel.Key words: embryonic skeletal muscle, calcium current.
Lack of protective effect of oral enprostil, a synthetic prostaglandin E2, on intestinal transport and morphology following abdominal irradiation in the rat
Authors: Thomson A. B. R. , Keelan M. , Clandinin M. T. , Tavernini M. , Lam T. , Walker K. , Cheeseman C. I.
Published: April 2011

Previous studies have demonstrated that abdominal irradiation alters intestinal uptake of nutrients. The purpose of this study was to determine the effect of an orally administered synthetic prostaglandin E2, enprostil, given on three occasions shortly prior to a single exposure to 600 cGy external abdominal irradiation, on intestinal active and passive transport processes and villus morphology measured 7 days later. Animals were sham-irradiated (CONT) or were exposed to a single dose of 600 cGy external abdominal irradiation (RAD); two and one mornings before the day of irradiation or sham irradiation, and 1 h before irradiation or sham irradiation enprostil was administered. One half of CONT and RAD groups were dosed orally with enprostil, 5 μg/kg body weight, and the other half of the CONT and RAD groups were dosed with placebo. Seven days later the in vitro uptake of glucose, galactose, long-chain fatty acids, and cholesterol was determined in the four groups (CONT with and without enprostil, and RAD with and without enprostil). In CONT, enprostil was associated with increased jejunal uptake of glucose and ileal uptake of galactose. In RAD given enprostil, there was increased jejunal uptake of galactose but reduced ileal uptake of glucose and galactose. The expected radiation-associated decline in jejunal galactose uptake was prevented with enprostil. In CONT given enprostil, there was increased jejunal uptake of fatty acid (FA) 14:0 and 16:0 but reduced uptake of FA 18:0, 18:1, and 18:2; enprostil had no effect on lipid uptake in the ileum in CONT. Enprostil had a different effect in RAD, with reduced jejunal uptake of FA 14:0; 16:0, 18:0, 18:3, and cholesterol and reduced ileal uptake of FA 16:0, 18:1, 18:2, 18:3, and cholesterol. Enprostil was associated with a reduced jejunal mucosal surface area in CONT and a reduced ileal mucosal surface area in RAD. The irradiation-associated decline in body weight was not observed in animals given enprostil despite the lack of change in food intake. The alterations in nutrient uptake were not due to differences in food intake, weight change, or mucosal surface area. Thus, enprostil given on three occasions just before a single dose of abdominal irradiation was associated with increased intestinal uptake of galactose, but failed to prevent most of the other irradiation-associated changes in active and passive intestinal transport, and accentuated rather than prevented the irradiation-associated diminution in mucosal surface area.Key words: adaptation, cholesterol, fatty acids, galactose, glucose, ileum, jejunum.
Hemodynamic effects of a combination of clonidine and propranolol in conscious cirrhotic rats
Authors: Roulot Dominique , Gaudin Christophe , Braillon Alain , Sekiyama Tatsuya , Bacq Yannick , Lebrec Didier
Published: April 2011

The hemodynamic effects of the combination of clonidine and propranolol were studied in conscious rats with portal hypertension owing to secondary biliary cirrhosis. Pressure and blood flow measurements (radioactive microsphere method) were performed in three groups of eight rats before and after drug administration. The combined effects of clonidine (2 μg/100 g body wt., i.v.) and propranolol (0.2 mg/min for 10 min) were compared with those observed after administration of either clonidine alone or propranolol alone. The association of clonidine and propranolol induced significant decreases in portal pressure (30%) and portal tributary blood flow (43%), the magnitude of these changes being significantly more marked than that after administration of either clonidine alone (12 and 20%, respectively) or propranolol alone (16 and 17%, respectively). After the combination, no significant change in arterial pressure was observed, but cardiac output significantly decreased and systemic vascular resistance significantly increased. Renal blood flow decreased to a similar extent (40%) in the three groups. These findings indicate that the combination of clonidine and propranolol is more effective for reversing splanchnic hemodynamic changes than clonidine alone or propranolol alone. The additive effects of this association are in agreement with the action of clonidine and propranolol at different levels (central and peripheral) and on different receptors (α and β). It suggests that an increase in sympathetic activity may play a major role in hemodynamic changes observed in experimental cirrhosis.Key words: portal hypertension, cirrhosis, splanchnic blood flow, α2-adrenergic agonist, β-blocker.
Altered electrical response to caffeine exposure in hypertrophied rat myocardium
Authors: Thollon C. , Kreher P.
Published: April 2011

We investigated the electrophysiological effects of cardiac hypertrophy induced by different experimental models. Comparison of the action potentials of hypertrophied and control rat hearts reveals a pronounced prolongation of the action potential for all types of hypertrophy. This prolongation affects the entire repolarization phase of the action potential 8 days after severe aortic constriction, after 8 days of isoproterenol treatment (5 mg/kg per day), and 3 months after an aortocaval fistula. The electrical changes associated with myocardial hypertrophy induced by pressure overload (aortic constriction) were compared with those resulting from volume overload (aortocaval fistula). Our results show that action potential alterations depend on the nature, duration, and severity of the work load. Thus, pressure overload is more potent to induce these modifications. In the hearts subjected to pressure overload, action potential alterations appear more rapidly and are more marked for the same degree of hypertrophy than those of the volume-hypertrophied myocardium. Furthermore, such data also demonstrate that the early alteration of the action potential during the development of compensatory hypertrophy is a prolongation of the later phase of repolarization (phase 3), without prolongation of the other repolarization phases (1 and 2). This change appears 3 days after aortic constriction, 1 month after coronary artery ligation (in the healthy part of the left ventricle), and 1 month after an aortocaval fistula. In the rat heart, the ionic currents underlying this later phase of repolarization are known to be dependent on the increase of intracellular free calcium during activity. Since this elevation of myoplasmic calcium results from calcium release from the sarcoplasmic reticulum, we compared the effects of caffeine (a substance known to act on the sarcoplasmic reticulum) on the electrical events of hypertrophied and control hearts. Caffeine has a different qualitative effect in hypertrophied and control hearts. The results suggest that hypertrophy should be due to increased calcium release from the sarcoplasmic reticulum related to increased phosphoinositide hydrolysis and therefore that the prolongation of the action potential duration (phase 3) may be the result of an increase of the Na–Ca exchange current or of a specific suppression of the outward K+ current.Key words: aortic stenosis, isoproterenol treatment, coronary artery ligation, aortocaval fistula, action potential, caffeine.
Action of histamine on the rapidly adapting airway receptors in the dog
Authors: Ravi K. , Teo K. K. , Kappagoda C. T.
Published: April 2011

The effects of histamine on the activity of rapidly adapting receptors (RAR) of the airways were investigated in anesthetized dogs. With bolus injections given into the right atrium, the threshold dose of histamine required for the excitation of RAR (n = 7) was 0.82 μg/kg (+1.33/−0.51, geometric mean). With increasing doses of histamine, a dose–response relationship was seen in the activity of RAR. Obstruction of the lymphatic drainage from the lungs reduced the threshold dose to histamine (i.e., shifted the dose–response curve to the left significantly). This change in the dose–response relationship was not accompanied by a corresponding change in the relationship of histamine dose to airway pressures recorded before and after lymphatic obstruction. Against a background of pulmonary venous congestion produced by partial obstruction of the mitral valve, subthreshold doses of histamine stimulated the RAR (n = 4). The excitatory effect of histamine on RAR was found to be abolished by the administration of the H1 receptor antagonist diphenhydramine but not by the H2 receptor antagonist cimetidine. Intravenous infusion of histamine (0.4 μg∙kg−1∙min−1) for a period of 10 min increased the RAR activity (n = 6) significantly without producing detectable changes in airway mechanics. The results indicate that contraction of the smooth muscle of the airways may not be a prerequisite for the excitation of RAR, especially at low doses. It is suggested that some of the effects of histamine on RAR are mediated by a local expansion of the extravascular fluid caused by an increase in the permeability of the bronchial vasculature.Key words: histamine, pulmonary congestion, vagal sensory receptors.
Inhibition of bombesin-stimulated gastrin release from isolated canine G cells by bombesin antagonists
Authors: Campos Robert V. , Buchan Alison M. J. , Pederson Raymond A. , McIntosh Christopher H. S. , Coy David H.
Published: April 2011

This study investigated the effects of two putative bombesin antagonists, [D-Arg1,D-Pro2,D-Trp7,9,Leu11]substance P and [Leu13-Ψ-CH2NH-Leu14]bombesin, on bombesin-stimulated gastrin release from isolated canine G cells following short-term culture. Canine antral tissue was dispersed by sequential collagenase and EDTA treatment, and counterflow elutriation was used to enrich for G cells. Plates were seeded with 2 × 106 cells/mL in each well and cultured for 2 days prior to testing. Gastrin-containing and somatostatin-containing cells were identified by immunocytochemistry using the biotin–avidin–peroxidase method and accounted for 8.5 and 1%, respectively, of adhered cells. Basal gastrin secretion was 1.91 ± 0.48% of total cell content. After a 2-h incubation period, bombesin (0.01–100 pM) stimulated gastrin release in a concentration-dependent fashion. The substance P analog, at a concentration of 1 μM, modestly inhibited bombesin-stimulated gastrin release from canine G cells. This analog also produced weak stimulation of basal gastrin release. In contrast, the bombesin analog, at a concentration of 1 μM, did not affect basal gastrin secretion. The bombesin analog completely blocked bombesin-stimulated gastrin release from 0.01 to 1 pM and produced greater than 50% inhibition at higher doses. The ability of the bombesin analog to directly inhibit bombesin-stimulated gastrin release from cultured canine G cells underscores its usefulness in studies involving the role of bombesin and its mammalian counterpart, gastrin-releasing peptide, in the control of gastrin cell function.Key words: gastrin, bombesin, antagonists, cultured cells.
Possible role of Na+–Ca2+ exchange in the regulation of contractility in isolated adult ventricular myocytes from rat and guinea pig
Authors: Horackova M.
Published: April 2011

Action potentials and developed contractions of externally unloaded single ventricular myocytes isolated from adult rat and guinea pig hearts were recorded by means of an optical system for recording contractile activity during regular stimulation by microelectrodes. Under control conditions, the shortenings (twitches) in the rat myocytes were fully inhibited by 0.1 μM ryanodine, but they were rather insensitive to the Ca2+ blocker 0.2–0.5 μM nifedipine. In contrast, the contractions of the isolated guinea pig ventricular myocytes were greatly suppressed by 0.2–0.5 μM nifedipine (to <30%), while they were only slightly reduced by 1 μM ryanodine. When the Na+ gradient was decreased by reducing [Na]o or by elevating [Na]i in the presence of veratridine, the twitch contractions were increased in both species. The effect of reduced [Na]o on twitch contractions was not affected by ryanodine in either type of myocytes, while nifedipine still fully abolished the twitches in the guinea pig cells, indicating a strong dependence of guinea pig contractions on Ca2+ influx. On the other hand, the effect of a reduced Na gradient by veratridine was more complex; the usual twitch (phasic component) was increased and it was followed by a second (tonic) component which relaxed only after the repolarization of the action potential. While the phasic component was decreased by nifedipine and ryanodine in the usual way (as in the controls), the sustained contractions (lasting up to several seconds) were ryanodine and nifedipine insensitive. Furthermore, the cardiomyocytes of both species exposed to strontium in place of external calcium still exhibited all the effects observed when reducing the Na+ gradient. These data indicated that Sr2+ transport may occur via various routes similar to those of Ca2+ transport, including the Na+–Sr2+ exchange. In addition, in the presence of SrCl2 the rat myocytes exhibited longer durations of action potentials and their contractions became insensitive to ryanodine (like the guinea pig cells). It is concluded that Na+–Ca2+ exchange probably does not directly contribute in a quantitative fashion to the activation of contractile activity under normal conditions, but when the Na+ gradient is decreased, especially by increasing [Na]i, the contractions could be increased severalfold via this mechanism in both the rat and guinea pig cardiomyocytes.Key words: excitation–contraction coupling, isolated cardiac myocytes, nifedipine, ryanodine, veratridine, reduced [Na]o, epinephrine, SrCl2.
Time course of structure, function, and metabolic changes due to an exogenous source of oxygen metabolites in rat heart
Authors: Gupta Madhu , Singal Pawan K.
Published: April 2011

Effects of xanthine (2 mM) and xanthine oxidase (10 U/L) perfusion on myocardial function, lipid peroxide content, high-energy phosphates and their metabolites, and ultrastructure were examined in isolated perfused rat hearts to define the time course of myocardial injury due to exogenous supply of active oxygen species. Peak-developed force and dF/dt showed a decline within 5 min and complete contractile failure was seen at 20 min. Resting tension was higher at 10 min and reached a maximum value of 400% at 40 min. These changes in contractile parameters were reduced by superoxide dismutase (1.2 × 105 U/L), catalase (2 and 4 × 104 U/L), and mannitol (10 and 20 mM). Lipid peroxide content was significantly higher at 5 min and rose continuously with xanthine – xanthine oxidase (X–XO) perfusion. A close correlation was noted (r = 0.935) between increased lipid peroxide content and a decrease in peak-developed force. Creatine phosphate and adensoine triphosphate (ATP) showed a time-dependent decrease due to X–XO perfusion. Loss of ATP also correlated (r = 0.819) with the contractile failure. Adenosine diphosphate showed an increase at 5 min followed by a decrease at 20 and 40 min. Adenosine monophosphate, adenosine, and creatine content increased with X–XO perfusion. In a semiquantitative morphometric study, significant myocardial and vascular changes became apparent only after 10 min of X–XO perfusion. When a 5-min perfusion with X–XO was followed by a control perfusion, a recovery of developed force and normal structure was noted at 40 min. These data show that X–XO induced contractile failure involves partially reduced forms of oxygen such as superoxide, hydroxyl radicals, and hydrogen peroxide. The negative inotropic effect of a vascular supply of these active oxygen species may be related to increased lipid peroxidation as well as the loss of high-energy phosphates. Structural damage to myocytes and blood vessels and a rise in resting tension were delayed events requiring a continuous and longer exposure to radical species.Key words: myocardial failure, oxygen radicals, lipid peroxidation, myocardial high-energy phosphates, myocardial cell damage, antioxidant protection.
Extracellular calcium and the inotropic effect of epinephrine on frog skeletal muscle
Authors: Williams Jay H. , Barnes William S.
Published: April 2011

The purpose of these experiments was to determine if extracellular calcium plays an important role in mediating the inotropic effect of epinephrine in isolated frog sartorius muscle. Initial experiments indicated that epinephrine potentiated the muscle twitch in a concentration-dependent manner with concentrations of 10 μM to 1 mM, increasing peak tension by approximately 33%. To inhibit the influx of extracellular calcium, muscles were incubated for 20 min in media containing epinephine in which calcium had been removed and replaced by magnesium or EDTA, or in experimental media containing epinephrine and the calcium channel blockers D-600 or diltiazem (5 μM). Each experimental condition was found to antagonize the effects of epinephrine such that peak twitch tensions were not significantly different from the control. When muscles were returned to normal Ringer's solution containing epinephrine, twitches exhibited progressive potentiation. Muscles were also incubated for 20 min in epinephrine without stimulation. Once stimulation was resumed, twitches were not immediately potentiated but rather gradually increased over time. These results suggest that the inotropic effects of epinephrine are influenced by the influx of extracellular calcium, an event that is dependent on muscle activation.Key words: epinephrine, skeletal muscle contraction, extracellular calcium, calcium antagonists, twitch potentiation.
Dantrolene suppresses the hyperpolarization or outward current observed during anoxia in hippocampal neurons
Authors: Krnjević K. , Xu Y. Z.
Published: April 2011

Hyperpolarizations, or outward currents, recorded in CA1 pyramidal cells during brief anoxia (2–3 min) (but not postanoxic hyperpolarizations) are markedly reduced (92 ± 4.8%) by dantrolene sodium, applied by superfusion (10–20 μM). This effect, which is at least partly reversible by prolonged washing, is in keeping with the idea that anoxia activates a Ca2+-sensitive K conductance by releasing Ca2+ from internal stores.Key words: anoxia, dantrolene, hippocampal slices, Ca-mediated K conductances.
Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies
Authors: O'Brien Peter James , Ianuzzo C. David , Moe Gordon W. , Stopps Terry P. , Armstrong Paul W.
Published: April 2011

Chronic, rapid ventricular pacing produces congestive heart failure in dogs. The objectives of this study were to determine whether or not (i) in vitro myocardial biochemical alterations reported for heart failure by volume or pressure overload also occurred with heart failure due to rate overload, and (ii) these biochemical alterations were related to relevant in vivo cardiac physiologic alterations. We compared 27 dogs that were paced to advanced heart failure with 21 sham-operated dogs. Dogs with heart failure had 55% lower left ventricular ejection fraction (22.5 ± 7.6 vs. 50.5 ± 5.1%) and cardiac index (81 ± 22 vs. 178 ± 48 mL∙min−1∙kg−1), 287% higher pulmonary capillary wedge pressure (27.5 ± 6.8 vs. 7.1 ± 3.4 mmHg; 1 mmHg = 133.3 Pa), and 64% greater left ventricular diastolic area (18.4 ± 3.7 vs. 11.2 ± 1.3 cm2) (all p < 0.05). Dogs with heart failure also had (i) 69% lower norepinephrine (232 ± 139 vs. 747 ± 220 ng/g protein), (ii) 25–50% lower activities of myofibrillar Ca ATPase (0.188 ± 0.026 vs. 0.253 ± 0.051 U/mg myofibrils), sarcoplasmic reticulum Ca-transport ATPase (0.155 ± 0.074 vs. 0.288 ± 0.043 U/mg membrane), and the glycolytic enzyme phosphofructokinase (33.4 ± 10.0 and 47.7 ± 15.8 U/g), (iii) 32% higher activity of the β-oxidation enzyme hydroxyacyl-CoA dehydrogenase (11.43 ± 1.48 vs. 8.67 ± 1.70 U/g), and (iv) 60% higher activity of Krebs cycle oxoglutarate dehydrogenase (2.89 ± 0.77 vs. 1.81 ± 0.95 U/g) (all p < 0.05). No differences between groups were observed for isozyme patterns and ATPase activity of myosin. The pacing-induced alterations in left ventricular norepinephrine and sarcoplasmic reticular and myofibrillar Ca ATPase best correlated with in vivo physiological alterations. Biochemical alterations produced by rate overload were similar to those reported for volume or pressure overload.Key words: heart disease, chronic tachycardia, biochemical changes.
Smooth muscle contractility and calcium channel density in hibernating and nonhibernating animals
Authors: Wolowyk M. W. , Howlett S. , Gordon T. , Wang L. C. H.
Published: April 2011

Hibernating animals consistently survive prolonged periods of cold with body temperatures near the freezing point. Previous studies have suggested that regulation of calcium influx may be a fundamental cellular mechanism for cold tolerance in hibernating species. The present study was undertaken to compare (i) the calcium dependence of contractility and (ii) [3H]nitrendipine binding in homogenates of ileal longitudinal smooth muscle from the nonhibernating guinea pig (Cavia porcellus) and a hibernator, the ground squirrel (Spermophilus richardsonii). The contractility studies indicate that both the activation threshold for calcium and the concentration–response curve were shifted to the right in ground squirrel when compared with guinea pig. The binding site density in ground squirrel muscle was about an order of magnitude less than in guinea pig (Bmax = 10 ± 2 (n = 12) and 86 ± 6 fmol/mg protein (n = 5), respectively). These results indicate that ground squirrel tissues are less sensitive to external calcium and clearly have fewer calcium channels than the smooth muscle of the non-hibernator. The results continue to support the hypothesis that cold tolerance in hibernating species involves calcium homeostatic control mechanisms.Key words: smooth muscle, calcium, [3H]nitrendipine binding.
Attenuation of febrile seizures in epileptic chicks by N-methyl-D-aspartate receptor antagonists
Authors: Pedder Simon C. J. , Wilcox Robert I. , Tuchek John M. , Johnson Dennis D. , Crawford R. D.
Published: April 2011

Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(±)2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-α-aminoadipic acid (AAA), and DL-α,ε-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH > APV [Formula: see text] AAA > DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.Key words: seizures, NMDA antagonists, epileptic chickens, anticonvulsant activity, receptors.
Dose-dependent inhibition of cyclosporine metabolism in mice by fluconazole
Authors: Delfa Ignazio La , Xia Yifan , Blaschke Terrence F.
Published: April 2011

Fluconazole, a potent bis-triazole antimycotic drug, has been demonstrated to inhibit antipyrine metabolism, a cytochrome P-450 dependent process, in vivo in mice. Cyclosporine is metabolized by the cytochrome P-450 enzyme system in both mice and man. We investigated whether fluconazole had any effects on the metabolism of cyclosporine in vivo in mice. The effects of three different doses of fluconazole (1, 5, and 20 mg/kg) on the metabolism of cyclosporine in CD-1 mice were studied in single-dose experiments. Fluconazole produced significant dose-dependent decreases in the elimination rate constant and increases in the terminal half-life of cyclosporine. The 1 mg/kg dose caused a 26% prolongation of the terminal half-life and the 5 and 20 mg/kg dose prolonged the half-life by 72 and 187%, respectively. Fluconazole doses in the 1–5 mg/kg range are effective in mouse models of fungal infections. These results provide further in vivo evidence that fluconazole is a potent inhibitor of the cytochrome P-450 dependent enzyme system in mice. Future experimental studies in animals and humans are needed to evaluate possible metabolic drug–drug interactions involving fluconazole.Key words: cyclosporine, drug metabolism, drug–drug interaction, fluconazole, cytochrome P-450, animal, antifungal.
Effects of chronic nicotine treatment on nicotinic receptors in the rabbit urinary bladder
Authors: Kizawa Yasuo , Shinkai Michiko , Takayanagi Issei
Published: April 2011

Nicotine induced a phasic contraction in the rabbit urinary bladder. The response was abolished by hexamethonium and partially reduced by atropine and capsaicin. Simultaneous atropine and capsaicin treatment did not abolish the contraction. These findings suggest that the response to nicotine is due to acetylcholine, tachykinins, and unknown mediator release. In contrast, nicotine-induced contraction diminished following the chronic nicotine treatment without a change of its pharmacological properties. These results suggest the possibility that chronic nicotine treatment causes a decrease in nicotinic receptor numbers. Therefore, the binding properties of (−)-[3H]nicotine on rabbit urinary detrusor muscle membrane fractions were studied to evaluate the effects of chronic nicotine treatment on nicotinic receptors. Specific (−)-[3H]nicotine binding reached saturation and Scatchard plots were curvilinear, suggesting the existence of two different affinity sites for (−)-[3H]nicotine. Dissociation constants (KD) and maximum binding sites (Bmax) were KD1 = 4.91 ± 1.88 nM, Bmax1 = 2.42 ± 0.22 fmol/mg protein and KD2 = 263 ± 56 nM, Bmax2 = 25.0 ± 4.3 fmol/mg protein. In urinary bladder membrane fractions from chronic nicotine-treated rabbits, KD and Bmax values were KD1 = 3.96 ± 0.38 nM, Bmax1 = 1.07 ± 0.25 fmol/mg protein and KD2 = 249 ± 12 nM, Bmax2 = 10.8 ± 1.5 fmol/mg protein. Dissociation constants for both sites following chronic nicotine treatment did not change but maximum binding site numbers for both sites significantly decreased (p < 0.05). These results suggest that the decrease in contractile response evoked by nicotine after chronic nicotine treatment in rabbit urinary bladder is due to a decrease in numbers of nicotinic receptors.Key words: nicotine, rabbit urinary bladder, nicotinic receptors.
The effect of cyclosporine A on bile secretion in dogs
Authors: Sutherland Francis R. , Preshaw Roy M. , Shaffer Eldon A.
Published: April 2011

Cyclosporine A is reported to cause cholestasis, but the evidence is confounded by anesthesia and surgery used in acute experiments. To better investigate the effect of cyclosporine on the liver, bile output was directly measured in three cholecystectomized dogs by cannulating the common duct through a chronic duodenal fistula. Control studies were done 1 month after surgery. Cyclosporine in oral doses of 5, 15, and 50 mg∙kg−1∙d−1 was then given for consecutive 1-week periods. Twice during each study period, bile output was measured for 5 h in fasted, awake animals: 3 h to establish basal conditions, followed by 2 h of taurocholate infusions at 1 and then 2 μmol∙kg−1∙min−1. Under basal conditions, bile flow rose with each dose of cyclosporine, increasing 63, 127, and 179% above control with cyclosporine 5, 15, and 50 mg∙kg−1∙d−1 respectively. Bile flow increased similarly during taurocholic acid stimulation. Cyclosporine had no effect on bile salt or bilirubin secretion. In this chronic dog model isolated from other causes of cholestasis, cyclosporine did not induce cholestasis but rather caused a dose-related choleresis without any change in bile salt secretion.Key words: cyclosporine A, bile, cholestasis, hepatotoxicity.
Increased nonshivering thermogenesis, brown fat cytochrome-c oxidase activity, GDP binding, and uncoupling protein mRNA levels after short daily cold exposure of Phodopus sungorus
Authors: Wiesinger Herbert , Klaus Susanne , Heldmaier Gerhard , Champigny Odette , Ricquier Daniel
Published: April 2011

In their natural environment, burrowing rodents experience rather fluctuating ambient temperatures and are acutely cold exposed only for short periods outside their burrows. The effect of short daily cold exposure on basal metabolic rate, nonshivering thermogenesis, brown fat thermogenesis, and uncoupling protein mRNA was studied in the Djungarian hamster, Phodopus sungorus. They were kept at 23 °C and exposed to 5 °C daily either for one 4-h period or twice for 2 h (in 12-h intervals). At the same time control hamsters were kept continuously either at thermoneutrality (23 °C) or at 5 °C. Two 2-h cold exposures daily were sufficient to increase basal metabolic rate and nonshivering thermogenesis to the same level as continuous cold exposure, whereas one 4-h cold period per day did not result in a significant increase of both parameters. Brown fat thermogenesis (as measured by cytochrome-c oxidase activity and GDP binding to the mitochondrial uncoupling protein) increased to the same extent by both treatments with short daily cold exposure. However, this increase was less than in the chronically cold-exposed hamsters. A similar result was found for uncoupling protein mRNA: both short-term cold-exposed hamsters increased uncoupling protein mRNA levels to a similar extent, but less than after chronic cold treatment. It is concluded that short daily cold exposures are sufficient to cause adaptive increases of the capacity of metabolic heat production as well as brown fat thermogenic properties.Key words: nonshivering thermogenesis, brown fat, GDP binding, uncoupling protein mRNA, Phodopus sungorus.
Effect of sialoadenectomy on ethanol-induced gastric mucosal damage in the rat: role of neutrophils
Authors: Tepperman B. L. , Soper B. D.
Published: April 2011

We have observed that removal of the salivary glands is associated with an increase in the susceptibility to gastric mucosal damage in the rat. In the present study, we have examined the effect of sialoadenectomy on ethanol-induced mucosal hemorrhagic damage and myeloperoxidase (MPO) activity. Hemorrhagic damage and MPO activity in response to intragastric 50% w/v ethanol were greater in sialoadenectomized rats when compared with sham-operated animals. Pretreatment with 16,16-dimethylprostaglandin E2 (0.3 μg/kg s.c.) reduced damage and MPO activity in both sialoadenectomized and sham control rats receiving 50% ethanol. The reduction in these parameters was greater in control than in sialoadenectomized rats. Pretreatment with epidermal growth factor (5 μg/kg s.c.) significantly reduced MPO activity but did not significantly affect the extent of damage. These data suggest that sialoadenectomy is associated with an increase in mucosal inflammation in animals given ethanol. However, in some situations tissue inflammation (as indicated by MPO activity) was reduced, while the proportion of gastric mucosa exhibiting hemorrhagic damage was not changed.Key words: salivary glands, gastric mucosa, neutrophils, prostaglandin E2, epidermal growth factor.
Cancer therapy, vomiting, and antiemetics
Authors: Stewart David J.
Published: April 2011

Both radiotherapy and chemotherapy for cancer are capable of causing nausea and vomiting. With both treatment modalities, the nausea and vomiting is thought to be a second-order process rather than being due to direct stimulation of neuromechanisms that control vomiting. Both a peripheral (gastrointestinal tract) and central (chemoreceptor trigger zone) effect may be operating with both radiotherapy- and chemotherapy-induced vomiting. With radiotherapy, gastrointestinal toxicity is affected by the type of radiation, radiation dose and field size, fractionation schedule, individual patient factors, and the part of the patient that is radiated. Many different factors also influence the frequency and severity of nausea and vomiting following chemotherapy. With both radiotherapy and chemotherapy, the frequency and severity of nausea and vomiting is probably mediated by a reduction in breakdown of various neurotransmitters. It is presumed that as the levels of neurotransmitters increase, nausea and vomiting develop. Antagonists of these neurotransmitters may afford some antiemetic protection. Nausea and vomiting may be so severe in patients with cancer that they may refuse potentially curative therapy because of it. Anticipatory nausea and vomiting may develop in patients who have become quite sick after receiving treatment. Exposure to stimuli associated with the emetogenic agent is then sufficient to trigger nausea and vomiting. Standard antiemetics do not help anticipatory nausea and vomiting, although behavioural training may. A variety of different drugs have proven useful as antiemetics, including dopamine antagonists such as phenothiazines, metoclopramide, corticosteroids (dexamethasone and methylprednisolone), cannabinoids, and benzodiazapines. Antihistamines and anticholinergics are of value in some situations. New serotonin antagonists appear to be very promising and are currently undergoing clinical studies. Multiagent antiemetic regimens appear to be more effective than single agent regimens in some situations.Key words: nausea/vomiting, cancer, chemotherapy, radiotherapy, antiemetics.
The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity
Authors: Andrews P. L. R. , Davis C. J. , Bingham S. , Davidson H. I. M. , Hawthorn J. , Maskell L.
Published: April 2011

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.Key words: emesis, visceral nerves, vagus nerve, ferret, plasticity, serotonin antagonists.
Role of neural input in photoperiod-induced changes in hamster brown adipose tissue
Authors: Desautels M. , Dulos R. A.
Published: April 2011

Repeated injections of 6-hydroxydopamine in Syrian hamster neonates maintained under long-day (16L:8D) photoperiod for 30 days retarded body growth and cellular proliferation in brown adipose tissue but did not affect the cellular content of mitochondrial proteins. Sympathectomy reduced GDP binding to isolated mitochondria without affecting the organelle uncoupling protein (UCP) content. Unilateral surgical denervation of the brown fat pad of 30-day-old hamsters caused loss of tissue protein and succinate dehydrogenase as well as reductions in GDP binding and UCP content of isolated mitochondria but did not prevent an increase in GDP binding observed after 1 month exposure to a short-day photoperiod. The increased GDP binding was not due to increased UCP content. These results indicate that an adrenergic neural input may not be essential for UCP expression in Syrian hamsters and that changes in GDP binding observed in a short-day photoperiod environment can be observed in denervated tissue in the absence of changes in mitochondrial UCP content.Key words: mitochondria, nonshivering thermogenesis, uncoupling protein, energy balance.