bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the posterior parietal cortex in coordinate transformations for visual–motor integration
Authors: Andersen Richard A. , Zipser David
Published: April 2011

Lesion to the posterior parietal cortex in monkeys and humans produces spatial deficits in movement and perception. In recording experiments from area 7a, a cortical subdivision in the posterior parietal cortex in monkeys, we have found neurons whose responses are a function of both the retinal location of visual stimuli and the position of the eyes in the orbits. By combining these signals area 7a neurons code the location of visual stimuli with respect to the head. However, these cells respond over only limited ranges of eye positions (eye-position-dependent coding). To code location in craniotopic space at all eye positions (eye-position-independent coding) an additional step in neural processing is required that uses information distributed across populations of area 7a neurons. We describe here a neural network model, based on back-propagation learning, that both demonstrates how spatial location could be derived from the population response of area 7a neurons and accurately accounts for the observed response properties of these neurons.
Determinants of biliary secretory pressure: the effects of two different bile acids
Authors: Cole Martin J. , Shaffer Eldon A.
Published: April 2011

Biliary secretory pressure represents the force generated to deliver bile through the biliary system. Bile acid-induced toxicity may decrease canalicular bile formation and (or) induce back diffusion causing cholestasis. To determine if biliary secretory pressure is a sensitive indicator of bile toxicity, taurocholate was compared with a less cytotoxic bile acid, tauroursodeoxycholate. In fasted male Sprague–Dawley rats, the common bile duct was cannulated and the endogenous bile salt pool was removed by enteroclysis. Taurocholate (n = 35) or tauroursodeoxycholate (n = 35) in saline was infused for 1 h. Maximal biliary secretory pressure was then measured by attaching the biliary cannula to a column monometer and recording the maximum height to which bile rose. With taurocholate administration, bile flow and bile salt secretion linearly rose to a maximum infusion of 0.5 μmol/(min∙g liver), above which hemolysis and death occurred. In contrast, tauroursodeoxycholate could be infused at higher rates with bile salt secretion plateauing at 1.25 μmol/(min∙g liver). Both had similar choleretic potencies. Mean biliary secretory pressure at low (< 0.15 μmol/(min∙g liver)) infusions was lower with taurocholate (22.5 cm bile) than tauroursodeoxycholate (25.2 cm). Further, increasing the taurocholate infusion decreased the biliary secretory pressure; yet for tauroursodeoxycholate, pressure remained unchanged even at higher infusions. Thus, taurocholate but not tauroursodeoxycholate decreases biliary secretory pressure at high infusion rates, likely a reflection of its toxicity to the hepatobiliary epithelium.
Effects of acute carbon tetrachloride poisoning on vitamin D3 metabolism in the rat
Authors: Theodossiou M. , Kung M. , Jones G. , Fraser D. , Kooh S. W.
Published: April 2011

To achieve biologic potency, vitamin D muct undergo two successive hydroxylations, first, in the liver and then, in the kidney. Carbon tetrachloride is known to cause extensive damage to the liver, but its effect on vitamin D metabolism has not been studied thoroughly. The effect of carbon tetrachloride on renal hydroxylation of 25-hydroxy vitamin D3 has not been studied. To evaluate the acute effect of carbon tetrachloride on vitamin D metabolism in the liver, vitamin D depleted rats received a single intraperitoneal injection of carbon tetrachloride (2.0 mL/kg body weight). After 24 h, they were given 55, 550, or 5050 pmol [3H]vitamin D3 intravenously. Twenty-four hours after injection of [3H]vitamin D3, aliquots of serum and liver were analyzed for [3H] vitamin D3 and its metabolites by high performance liquid chromatography. Sera of carbon tetrachloride treated rats had higher [3H]vitamin D3 and [3H]25-hydroxyvitamin D and lower [3H] 1,25-dihydroxyvitamin D3 concentrations than did control sera. Livers of carbon tetrachloride treated rats contained more [3H]vitamin D3, [3H]25-hydroxyvitamin D3, and more fat. Liver histology showed massive centrilobular necrosis in the treated rats. Thus, our experiment in rats given an acute dose of carbon tetrachloride provided no evidence of impairment of vitamin D metabolism by the liver, but offered a suggestion that 25-hydroxyvitamin D3 metabolism by the kidney might be impaired. To determine the acute effect of carbon tetrachloride on metabolism of vitamin D3 by the kidney, we studied hydroxylation of [3H]25-hydroxyvitamin D3 in isolated perfused kidney. Kidneys from the treated rats showed a 66% reduction in [3H]1,25-dihydroxy vitamin D3 production.
Halothane suppresses slow inward currents in hippocampal slices
Authors: Krnjević K. , Puil E.
Published: April 2011

Single-electrode voltage-clamp experiments were made on CA1 neurons in the presence of tetrodotoxin and K channel blockers. Applications of halothane (1–3% v/v) for 3–10 min caused a similar marked and reversible depression of slow inward currents (probably Ca currents) evoked by depolarizing pulses from a holding potential near−80 or near−40 mV. The peak amplitudes of the inward currents were much reduced, in a concentration-dependent manner, and they decayed more rapidly (half-decay time was shortened by a quarter). In most cases, leak conductances were diminished by halothane, making it unlikely that the suppression of inward currents was primarily caused by enhancement of outward currents. A similar inactivation of Ca currents in presynaptic terminals would explain why halothane depresses synaptic transmission.
Placental barrier to atrial natriuretic peptide in rats
Authors: Mulay S. , Varma D. R.
Published: April 2011

Transplacental passage of 125I-labelled synthetic rat atrial natriuretic peptide (ANP) was investigated in 20-day pregnant rats under pentobarbitone anesthesia. Although significant quantities of radioactivity were detected in the fetal plasma after maternal injections and in the maternal plasma after fetal injections of 125I-labelled synthetic ANP, no fraction of the placentally transferred radioactivity was due to intact ANP. Despite a rapid maternal and fetal metabolism of ANP, both maternal and fetal plasma radioactivity remained relatively stable for at least 3 h and less than 10% of the injected radioactivity was excreted in the maternal urine during a 90-min period. It is concluded that ANP is not transported in either direction across the placenta in rats.Key words: atrial natriuretic peptide, placental barrier, urinary excretion, maternal metabolism, fetal metabolism.
Effects of intrahypothalamic injections of GABA, muscimol, pentobarbital, and L-glutamic acid on feed intake of satiated sheep
Authors: Wandji S. A. , Seoane J. R. , Roberge A. G. , Bédard L. , Thibault L.
Published: April 2011

Five wethers were surgically prepared with cranial implants to study the role of gabaminergic neural pathways on the hypothalamic control of feeding behaviour in ruminants. In the first experiment, the animals were injected (1 μL) with a physiological Tyrode (0.95%) solution, muscimol (0.5 and 1.0 nmol), GABA (0.5 and 1.0 nmol), and L-glutamic acid (0.5 and 1.0 nmol). Feed intake following injections of muscimol (1.0 nmol) and L-glutamic acid (0.5 and 1.0 nmol) was twice as large as that following the Tyrode solution, at 60-min postinjections. These results, however, were not statistically significant (p = 0.12–0.15). In the second experiment, the animals were injected (1 μL) with saline, muscimol (0.8 nmol), L-glutamic acid (0.8 nmol), and pentobarbital (0.26 μmol). Fifteen minutes after the injections, pentobarbital had induced a significant feeding response when compared with control values (p < 0.01), whereas the effect of L-glutamic acid was not significant. However, 30 min after the injections, feed intake of sheep having received L-glutamic acid was higher than that obtained with the control injections (p < 0.01). The response to pentobarbital was stronger than that to either muscimol or L-glutamic acid. Histological analyses of brain tissue indicated that injections were performed in the ventromedial hypothalamus of four sheep and in the dorsomedial hypothalamus of the other. The data indicate that L-glutamic acid stimulates feed intake by acting either as a precursor of GABA or by a direct stimulation of glutaminergic neural pathways involved in the control of feed intake.Key words: Feeding behaviour, glutamic acid, GABA, sheep.
The canine tail artery as a model for cerebral aneurysm studies
Authors: Boyce Teresa Terpin , Roach Margot R.
Published: April 2011

The occluded canine tail artery, which comes off in the same plane as the aortoiliac junction, has been used as a flow model for cerebral aneurysms. These experiments were designed to determine if it is a realistic distensible model of human intracranial aneurysms. Distensibility studies were done on the aorta, and the iliac and tail arteries of four dogs. From these pressure–volume studies, tension–strain curves, elastances, and collagen slack were obtained. The tail artery is stiffer longitudinally and more distensible circumferentially than the other vessels. The iliac arteries and the aorta are not significantly different. The elastance of elastin and collagen is lower in the tail artery, and the collagen is more wavy circumferentially. Longitudinally, the collagen slack is least for the tail artery, and the elastance of elastin is not different in all three vessels. The number of elastin layers in the iliac and tail arteries seen in cross section is not significantly different, but the aorta is different from both these vessels. In another four dogs the aorta proximal to the trifurcation was cannulated and infused with saline to increase pressure. India ink marks were put on the surface to measure changes in length. Photographs were taken at intervals of 10 mmHg(1 mmHg = 133.3 Pa). This was done with the vessels tethered and untethered in the body and then taken out and studied with the same method in vitro. Arteries tethered in the body expanded circumferentially more than longitudinally. The tail artery becomes less distensible if untethered in the body and therefore acts more like an aneurysm. This makes it a good distensible flow model for aneurysm study. Even though the walls of the tail artery are thick and the geometry is not spherical, it is a reasonable model to study flow in aneurysms.Key words: elasticity, aorta, aneurysm, tethering, canine.
Propranolol antagonizes hypotension induced by α-blockers but not by sodium nitroprusside or methacholine
Authors: Tabrizchi Reza , Pang Catherine Cheuk Ying
Published: April 2011

A pressor response has been observed with propranolol, a nonselective β-adrenoceptor antagonist, in animals given a nonselective α-adrenoceptor antagonist. This study investigates whether a pressor response to propranolol occurs in conscious unrestrained rats following a hypotensive response induced by phentolamine (nonselective α-antagonist), prazosin (selective α1-antagonist) and (or) rauwolscine (selective α2-antagonist), sodium nitroprusside (smooth muscle relaxant), or methacholine (muscarinic agonist). The rats were subjected to a continuous infusion of a hypotensive agent or normal saline followed by i.v. injection of propranolol. The infusion of phentolamine significantly decreased mean arterial pressure (MAP). Subsequent injection of propranolol restored MAP to the control level. Prazosin and rauwolscine each caused a small but not significant decrease in MAP which was reversed by propranolol. Concurrent infusions of prazosin and rauwolscine caused a significant decrease in MAP. Subsequent injection of propranolol caused a large pressor response which increased MAP to 20% above control MAP prior to the administration of drugs. Nitroprusside or methacholine each caused a significant decrease in MAP, but the hypotension was not antagonized by propranolol. The concurrent infusions of a low dose of nitroprusside and prazosin caused a significant decrease in MAP which was reversed by propranolol. The infusion of saline did not alter MAP, and propranolol did not cause a pressor response. It is concluded that propranolol antagonizes the hypotensive effect of an α-blocker but not that of sodium nitroprusside or methacholine. Our results suggest the presence of a specific interaction between α- and β-antagonists.Key words: vasodilators, β-blockers, α-blockers, hypertension, adrenoceptors.
Opposite effects of lidocaine and diltiazem on electrophysiologic alterations in acutely ischemic porcine myocardium
Authors: Cardinal René , Carson D. Leigh , Lambert Chantal , Shenasa Jafar , Parent Robert , Vermeulen Michel , Nadeau Réginald
Published: April 2011

To investigate the actions of lidocaine and diltiazem on the ischemic alterations associated with the onset of acute ischemic arrhythmias, the left anterior descending coronary artery was occluded for 6-min periods separated by 30 min of reperfusion, under control conditions and after injection of lidocaine (2.4–3.8 μg/mL of plasma) or diltiazem (390–510 ng/mL) in open–chest anesthetized pigs. Sixty-one unipolar electrograms were continuously recorded in the ischemic zone. Isochronal maps and isopotential maps were determined by computer analysis. The magnitude of beat-to-beat alternation of unipolar waveforms was described by the difference between the time integrals subtended by electrograms of consecutive beats. Activation times were prolonged by ischemia and the ST segment became elevated. Delay and ST elevation developed at a faster rate in the presence of lidocaine than under control conditions, but were reduced by diltiazem. ST-T alternation was not significantly different between control and lidocaine occlusions, but the incidence of negative T waves and that of ventricular tachycardia degenerating to fibrillation were higher in lidocaine occlusions than in control occlusions. In contrast, unipolar waveform alternation and negative T waves were virtually abolished by diltiazem, even at fast pacing rates (180–210 beats/min) at which diltiazem did not reduce ST elevation. Ventricular arrhythmias also were abolished by diltiazem. Thus, lidocaine and diltiazem produce opposite effects on the ischemic alterations most closely associated with the initiating mechanism of tachycardia. This could be related to differences between these drugs with regard to their actions on transmembrane currents during repolarization.Key words: acute myocardial ischemia, lidocaine, diltiazem, ventricular arrhythmias, electrical alternans.
Acetate-induced depression of electrical and contractile activity in normoxic and hypoxic guinea pig papillary muscle
Authors: Hayashi Hideharu , Terada Hajime , Kholopov Alexander , McDonald Terence F.
Published: April 2011

The action potential configuration, developed tension, and resting tension were monitored in normoxic and hypoxic guinea pig papillary muscles superfused with solutions containing no substrate, glucose, or acetate (1–10 mM). In normoxic muscle, acetate provoked a concentration-dependent transient depression of the action potential duration and force of contraction, depression was maximal after 10–30 min, and recovery was complete after 90–120 min. In hypoxic muscle, acetate accelerated functional rundown (action potential shortening, decline of developed tension, increase in resting tension). Because rundown in hypoxic muscle was sensitive to factors affecting glycolysis (moderated by external glucose; accentuated by 2-deoxyglucose), the accentuated rundown with acetate may be accounted for by a partial block of glycolysis. However, block of glycolysis cannot explain the acetate-induced transient depression in normoxic muscle, since the depression was enhanced in normoxic muscle with 2-deoxyglucose-blocked glycolysis. We suggest that the transient depression is due to a transient depression of high energy nucleotides with consequent effects on ionic currents.Key words: acetate, action potential duration, 2-deoxyglucose, hypoxia, ATP.
Electrical, contractile, and ultrastructural properties of adult rat and guinea-pig ventricular myocytes in long-term primary cultures
Authors: Horackova M. , Mapplebeck C.
Published: April 2011

The electrical, contractile, and morphological characteristics of ventricular myocytes isolated from adult rat and guinea-pig hearts and maintained in cultures for 7–24 days are described. These cultured cells form different networks, depending on the species, when plated at certain density and maintained under specific conditions; the cells within the networks appear to be electrically coupled. Their resting and action potentials, their contractile activity (shortenings), and their pharmacological responses qualitatively resemble those of freshly isolated myocytes. Cultured cells from both species exhibit near-normal ultrastructural organization of sarcomeres, myofilaments, and mitochondria, as well as formation of intercellular contacts, or gap junctions. These data indicate that cultured adult rat and guinea-pig myocardial cells that make intercellular contacts possess electrical, contractile, and ultrastructural properties and responses to pharmacological agents similar to those of the respective adult myocardial tissues and the functionally intact freshly isolated cells from which these cultures are prepared. Thus, this study indicates that long-term cultures (7–24 days) of networked cardiac myocytes could be used as a valuable experimental model in various investigations of excitation–contraction coupling in cardiac muscle.Key words: cultured adult cardiomyocytes, contractility, electrical activity, ultrastructure, long-term primary cultures.
Analysis of the effects of (−) and (+) isomers of the 1,4-dihydropyridine calcium channel agonist BAY k 8644 on postrest potentiation in the canine ventricular muscle
Authors: Saha J. K. , Hryshko L. V. , Bouchard R. A. , Chau T. , Bose D.
Published: April 2011

Contraction of canine ventricular trabeculae were recorded at a stimulation frequency of 0.5 Hz and after rest periods of 2 and 8 min to analyze the effect of the Ca channel agonist BAY k 8644, on sarcoplasmic reticular function. Short periods of rest interposed between steady trains of stimuli caused a potentiation of the postrest beat. This is believed to be due to the mobilization of activator Ca from the sarcoplasmic reticulum (SR). Racemic BAY k 8644 and its Ca channel agonist enantiomer, (−) BAY k 8644, both produced an increase in contraction in response to a steady train of stimuli but converted rest potentiation into rest depression. This has been interpreted as increased loss of Ca from the SR during diastole. Addition of Ca channel antagonists, (+) BAY k 8644, nitrendipine, or nifedipine, to reverse the agonistic effect of (−) and racemic BAY k 8644 on the Ca channel did not convert the rest depression into rest potentiation. In the presence of any of the Ca channel antagonist alone, rest potentiation was not reversed but enhanced. The rank order of rest potentiation after these drugs was nifedipine > nitrendipine > (+) BAY k 8644. It is concluded that (−) BAY k 8644 enhances the ongoing loss of Ca from the SR during diastole in a manner similar to that of racemic BAY k 8644. However, its depressant effect on the postrest tension cannot be attributed to an increase in Ca current because (+) BAY k 8644 and other Ca channel antagonists did not reverse rest depression due to (−) or racemic BAY k 8644 even though they normalized steady-state tension. The difference between the effects of the three Ca channel antagonists on the postrest contraction suggests that they may have variable effects on the release of Ca from the SR in addition to causing inhibition of transsarcolemmal Ca influx. This difference may be related to different degrees of intracellular penetration of these compounds.Key words: cardiac, contractility, excitation – contraction coupling, heart.
Persistent impairment of endothelium-dependent relaxation to acetylcholine and progression of atherosclerosis following 6 weeks of cholesterol feeding in the rabbit
Authors: Jayakody Laal , Senaratne Manohara P. J. , Thomson Alan B. R. , Sreeharan Nadarajan , Kappagoda C. Tissa
Published: April 2011

The synthesis and (or) release of endothelium-dependent relaxant factor released by acetylcholine is impaired in New Zealand white rabbits fed an atherogenic diet. Experiments were designed to investigate whether the synthesis and (or) release of the endothelium-dependent relaxant factor from rabbit aortas are restored after reversal from an atherogenic diet to a non-atherogenic diet. Atherosclerosis was induced by feeding a diet containing lipids and 2% cholesterol for 6 weeks. Rabbits were sacrificed after 6 weeks on the atherogenic diet and 36 weeks after return to a standard laboratory diet. Synthesis and (or) release of the factor from the thoracic aorta was assayed using a bioassay system. The relaxant responses produced in the assay tissue were impaired both in the acute stage and after 36 weeks on non-atherogenic food. This impaired relaxation is probably due to a persistent functional abnormality in the aortic endothelium resulting in the failure to synthesize and (or) release endothelium-dependent relaxation factor 36 weeks after induction of atherosclerosis.Key words: endothelium dependent relaxation, rabbit aorta, atherosclerosis, regression, cholesterol feeding.
Urinary excretion of mandelic, phenylglyoxylic, and specific mercapturic acids in rats exposed repeatedly by inhalation to various concentrations of styrene vapors
Authors: Truchon Ginette , Gérin Michel , Brodeur Jules
Published: April 2011

Adult male Sprague–Dawley rats were exposed by inhalation to various concentrations of styrene vapors (25, 50, 100, or 200 ppm) 6 h/day, 5 days/week, for 4 consecutive weeks. The concentrations were varied from day to day according to a random pattern allowing treated animals to be exposed five times to each concentration of styrene. Each day, the following urinary metabolites were analysed from samples collected during exposure (0–6 h) and after exposure (6–24 h): mandelic acid; phenylglyoxylic acid; and two mercapturic acids, N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (M2). Various parameters of renal toxicity and hepatic microsomal and cytosolic enzyme activities were also measured. The results show that there is a very good relationship between the excretion of all four styrene metabolites and the degree of daily exposure to styrene over the entire period of urine collection, with correlation coefficients ranging from 0.82 to 0.98. The correlation was poor for mandelic acid during the 0–6 h period. There was no evidence that repeated exposure to styrene caused renal toxicity, nor induced hepatic microsomal enzyme activities; cytosolic glutathione S-transferase activity was increased moderately by 1.5 times. Thus, under conditions of exposure to styrene likely to be found in the workplace, all four metabolites measured were good indicators of styrene exposure throughout the length of the experiment. Since mercapturic acids result from the conjugation of styrene oxide with glutathione, the data suggest that measurement of these metabolites offers the possibility to monitor internal exposure to a toxic electrophilic compound more directly.Key words: styrene, mercapturic acids in urine, mandelic acid in urine, phenylglyoxylic acid in urine, inhalation of styrene.
Extracellular calcium-dependent and -independent effects of adenosine in bovine coronary artery
Authors: Ramagopal Mudumbi V. , Mustafa S. Jamal
Published: April 2011

Adenosine relaxes the coronary arteries of various species through A2 receptors. The aim of the present investigation was to evaluate the relaxing effects of adenosine in relation to the role of calcium in bovine coronary arteries by studying the vasodilatory effect of adenosine in normal and calcium-free medium and on calcium-45 efflux into calcium-free medium. Acetylcholine (ACh) and norepinephrine (NE) were used to induce tone in coronary artery rings. Adenosine, 5′-(N-ethylcarboxamido)adenosine (NECA), and N6-(L-phenylisopropyl)adenosine (L-PIA) produced concentration-dependent relaxations of the coronary artery rings. Both in normal and calcium-free medium, the order of potency for adenosine analogs (NECA > L-PIA > adenosine) was similar and 8-phenyltheophylline antagonized the relaxation responses to adenosine and its analogs. Removal of extracellular calcium shifted the concentration–response curves to the right in a parallel fashion, slowed the rate of relaxation, and in NE contracted rings reduced the maximum responses for adenosine and its analogs. In calcium-free medium, adenosine was without an effect on calcium-45 efflux in the presence of ACh. However, adenosine inhibited the stimulated calcium-45 efflux induced by NE. The data suggest that the vasodilatory action of adenosine in bovine coronary smooth muscle has both extracellular calcium-dependent and -independent components.Key words: adenosine receptors, calcium, coronary circulation, vascular smooth muscle, acetylcholine, norepinephrine.
Adaptation of small intestinal membrane transport processes during diabetes mellitus in rats
Authors: Fedorak Richard N.
Published: April 2011

Intestinal amino acid and glucose transport is increased in various disease states and physiological circumstances. This enhancement is generally due to an increase in transport capacity (Vmax) without a change in carrier affinity (KD). Furthermore, the increase in transport capacity is too large to be attributed, in most cases, to simple intestinal hypertrophy. In the streptozotocin-treated chronically diabetic rat model, specific binding indicated an enhanced total number of glucose carriers in the small intestine compared with controls. Furthermore, autoradiography reveals that specific phlorizin (i.e., glucose) binding extends into the intervillous region of the intestine, while in age-matched controls binding is confined to the villous tip. These studies suggest that during experimental diabetes mellitus in rats, enhanced intestinal nutrient absorption may occur as a consequence of recruitment of carriers into previously nontransporting enterocytes. This review looks at ways in which this alteration may be influenced, and examines the expression of various isoforms of Na–K ATPase during streptozocin-induced diabetes mellitus.Key words: intestinal transport, glucose, sodium–potassium ATPase, adaptation.
Species differences in the binding kinetics of 25-hydroxyvitamin D3 to vitamin D binding protein
Authors: Vieth Reinhold , Kessler Matt J. , Pritzker Kenneth P. H.
Published: April 2011

The specific binding of 25-hydroxyvitamin D3 to its binding protein was studied in serum of the human, rhesus monkey, cow, horse, and rat. The free fraction of 25-hydroxyvitamin D3 in the rat was 0.34 ± 0.15 pmol free/nmol total (±SD) and this was lower than in any of the other species (p < 0.01). In the human, the free fraction was 1.5 ± 0.32 pmol free/nmol total, which was higher than in any of the other species (p < 0.001). The differences in the free fraction were mainly due to differences in dissociation constant. The relative levels of free 25-hydroxyvitamin D should be taken into account when extrapolating findings about vitamin D metabolism in animals to the human. A technical outcome of this study is that of the species tested, vitamin D binding protein from rat serum is the most suitable as a reagent component for methods used to measure total 25-hydroxyvitamin D by competitive protein binding assay.Key words: vitamin D binding protein, 25-hydroxyvitamin D, free metabolite, species comparison.
Effect of RU486 on different stages of mouse preimplantation embryos in vitro
Authors: Juneja Subhash C. , Dodson Melvin G.
Published: April 2011

17β-Hydroxy-11β-(4-dimethylaminophenyl)-17α-(1-propynyl)estra-4,9-dien-3-one (RU486) inhibited the in vitro development of different stages of mouse preimplantation embryos under study. Two-celled embryos, morulae, and early blastocysts were obtained from B6D2F1 mice. The embryos were grown in Ham F-10 nutrient mixture (with glutamine) supplemented with sodium bicarbonate (2.1 g/L), calcium lactate (282 mg/L), and bovine serum albumin (fraction V, 3 mg/mL) at 37 °C in a humidified incubator supplied with 5% CO2 in air. RU486 was added to the culture medium at concentrations of 1, 5, 10, and 20 μg/mL. Culture medium with 0.05% ethanol served as the control. In vitro growth of embryos was assessed by the following criteria: (i) two-celled stage embryo development to blastocyst stage after 72 h, (ii) morula stage grown to blastocyst stage after 24 h, and (iii) early blastocyst stage development to hatching blastocyst after 12 h, in culture. RU486 inhibited the in vitro development of two-celled embryos, morulae, and early blastocysts at concentrations of 5, 10, and 20 μg/mL culture medium (p < 0.001). The inhibitory effect of RU486 at these concentrations on the development of all the stages of embryos under study was irreversible. However, RU486 did not affect embryo development at 1 μg/mL culture medium. The study indicates the direct adverse effect of RU486 at 5 μg/mL and higher concentrations in culture medium on the development of mouse preimplantation embryos in vitro, and it encourages its further investigation as a postcoital contraceptive in animal models and humans.Key words: RU486, mouse, preimplantation embryos, embryo culture, postcoital contraceptive.
The effects of peripubertal testosterone on ethylmorphine demethylase activity in adult rats testectomized neonatally
Authors: Virgo Bruce B.
Published: April 2011

The physiologic activity of ethylmorphine demethylase (EMDM) is 2.5 times greater in adult male rats than in females. Defeminization, effected neonatally by testicular androgens, causes 65% of the increase while masculinization causes the rest. Castration of the intact adult does not alter the defeminized activity of the enzyme but abolishes its masculinized activity. Testosterone restores the latter. Adults that are not defeminized, because of neonatal castration, have enzymes unresponsive to testosterone. Thus, defeminization seems necessary for the expression of masculine activity. This was studied by castrating males at birth (day 1) and implanting capsules of testosterone propionate on day 35. On day 71, the activity had increased 4.4-fold to physiologic levels, compared with rats receiving no steroid (1.9 nmol∙min−1∙mg−1). Removal of the implant on day 71 decreased the activity on day 84 to that of the no-steroid rats. Thus, defeminization is neither caused by androgen in peripubertal rats nor needed to effect full physiologic activity of the enzyme. The activation of EMDM by peripubertal testosterone may reflect its regulation of growth hormone: first, testosterone (days 35–71) failed to increase enzyme activity in males hypophysectomized on day 35; second, growth hormone infused (5 μg∙h−1) over days 71–76 blocked the activation, actually decreasing activity 3.7-fold; third, the activity induced by testosterone was further increased (26%) by growth hormone release-inhibiting hormone (5 μg∙h−1, days 71–76).Key words: cytochrome P450, drug metabolism, imprinting, sex differences, testosterone, defeminization, masculinization.
The effect of isoproterenol on right and left atrial dynamics and plasma atrial natriuretic factor in anesthetized rabbits
Authors: King K. A. , Wong A. , Ledsome J. R.
Published: April 2011

The effect of isoproterenol on mean right and left atrial pressures (RAP, LAP) and dimensions (RAD, LAD), and plasma immunoreactive atrial natriuretic factor (IR-ANF) was investigated in anesthetized rabbits. Infusion of isoproterenol (10 μg∙kg−1∙min−1 for 10 min) significantly increased plasma IR-ANF and heart rate. There were no significant changes in mean RAP or LAP following isoproterenol. Neither mean RAD, systolic RAD and diastolic RAD nor mean LAD, systolic LAD or diastolic LAD changed significantly. Systolic right and left atrial wall stress and diastolic right and left atrial wall stress did not change significantly during the infusion of isoproterenol. Since atrial dimensions did not increase, it is unlikely that the release of IR-ANF in response to isoproterenol is mediated by atrial stretch. These results suggest that the release of IR-ANF in response to this dose of isoproterenol is mediated by factors other than stretch or changes in atrial dynamics.Key words: atrial natriuretic factor, atrial pressure, atrial dimensions, atrial wall stress, isoproterenol.
Fish oil-enriched diet is mucosal protective against acetic acid-induced colitis in rats
Authors: Empey Lonnie R. , Jewell Laurence D. , Garg Manohar L. , Thomson Alan B. R. , Clandinin M. Thomas , Fedorak Richard N.
Published: April 2011

Products of arachidonic acid metabolism are elevated in patients with inflammatory bowel disease and this elevation is correlated with disease activity. Eicosapentaenoic acid competes with arachidonic acid and alters eicosanoid biosynthesis. In this experiment, the possibility that eicosapentaenoic acid could be used in the treatment of inflammatory bowel disease was investigated by determining the effect of 6 weeks of a fish oil-supplemented diet, enriched in eicosapentaenoic acid, on colonic and ileal morphology, histology, and in vivo fluid absorption in rats with 4% acetic acid-induced colitis. The results of an eicosapentaenoic acid-enriched diet were compared with results of saturated and polyunsaturated fatty acid-enriched diets. In rats with misoprostol pretreated acetic acid-induced colitis, an eicosapentaenoic acid-enriched diet reversed net colonic fluid secretion to absorption and prevented macroscopic and histologic injury, compared with saturated and polyunsaturated fatty acid-enriched diets, which did not. The fish oil mucosal protective effect occurred in the presence of a 30-fold enhancement of PGE2 synthesis. In rats with non-misoprostol pretreated acetic acid-induced colitis, an eicosapentaenoic acid-enriched diet returned ileal fluid absorption to control levels, as compared with saturated and polyunsaturated fatty acid-enriched diets, which did not. In conclusion, a fish oil (eicosapentaenoic acid)-enriched diet, but not a saturated-or a polyunsaturated-enriched diet, protected colonic and ileal net fluid absorption in an experimental model of inflammatory bowel disease.Key words: eicosapentaenoic acid, fish oil, colitis, inflammatory bowel disease, leukotrienes, prostaglandins, misoprostol.
The 1991 Merck Frosst Award. Multidrug resistance in small cell lung cancer
Authors: Cole Susan P. C.
Published: April 2011

The two-year survival rate of patients with small cell lung cancer is less than 10%. The major reason for this poor outcome is the development of drug resistance. Panels of small cell lung cancer cell lines have been established, providing models for the study of drug resistance in this tumour. One such model is the doxorubicin-selected H69AR cell line. H69AR displays the typical multidrug resistance phenotype in that it is cross-resistant to anthracyclines, Vinca alkaloids (e.g., vinblastine) and epipodophyllotoxins (e.g., VP-16). However, H69AR cells do not overexpress P-glycoprotein, the membrane drug efflux pump frequently found on multidrug resistant cells. Some alterations in glutathione levels and associated enzyme activities were found but the data do not support the notion that enhanced drug detoxication is involved in H69AR cell resistance. Fewer drug-induced DNA strand breaks, reduced levels of topoisomerase II, and reduced formation of drug-stabilized DNA/topoisomerase II complexes were observed in H69AR cells. These data implicate topoisomerase II in the resistance phenotype of H69AR cells, but cannot explain H69AR cell resistance to the Vinca alkaloids, which do not have topoisomerase II as a target. Monoclonal antibodies against antigens overexpressed on H69AR cells have been derived and four have been characterized. Immunoscreening of an H69AR cDNA expression library has allowed the identification of one of these antigens as p36 (annexin II), a Ca2+/phospholipid binding protein. Chemosensitizers and novel xenobiotics have been examined for their ability to circumvent the drug resistance of H69AR cells. The limited success of these investigations suggests that innovative approaches may be required. In conclusion, the data obtained with H69AR and other models of small cell lung cancer indicate that multiple mechanisms contribute to drag resistance in this disease.Key words: small cell lung cancer, multidrug resistance, topoisomerase II, annexin II (p36, lipocortin II, calpactin I), monoclonal antibody.
Modulatory effect of steroid hormones on GnRH-induced LH secretion by cultured rat pituitary cells
Authors: Pérez Gabriela T. , Apfelbaum Marta E.
Published: April 2011

The purpose of the present experiments was to examine the short- and long-term effects of estradiol-17β (E2), progesterone (P), and 5α-dihydrotestosterone (DHT), alone and in combination, on the gonadotrophin-releasing hormone (GnRH)-induced luteinizing hormone (LH) secretion, using an ovariectomized rat pituitary cells culture model. After 72 h in steroid-free medium, pituitary cells were further cultured for 24 h in medium with or without E2 (1 nM), P (100 nM), or DHT (10 nM). Cultures were then incubated for 5 h in the absence or presence of 1 nM GnRH with or without steroids. LH was measured in the medium and cell extract by radioimmunoassay. The results show that the steroid hormones exert opposite effects on the release of LH induced by GnRH, which seems to be dependent upon the length of time the pituitary cells have been exposed to the steroids. In fact, short-term (5 h) action of E2 resulted in a partial inhibition (64% of control) of LH release in response to GnRH, while long-term (24 h) exposure enhanced (158%) GnRH-induced LH release. Similar results were obtained with DHT, although the magnitude of the effect was lower than with E2. Conversely, P caused an acute stimulatory action (118%) on the LH released in response to GnRH and a slightly inhibitory effect (90%) after chronic treatment. GnRH-stimulated LH biosynthesis was also influenced by steroid treatment. Significant increases in total (cells plus medium) LH were observed in pituitary cells treated with E2 or DHT. While the stimulatory effect of E2 was evident after both acute (133%) and chronic (119%) treatment, that of DHT appears to be exerted mainly after long-term priming (118%). These results suggest that the steroids modulate GnRH-induced LH secretion by acting on both synthesis and release of LH. On the other hand, total hormone content was not affected by P. The acute (5 h) effects of E2, P, and DHT on the GnRH response in E2-primed (24 h) cells during a short-term incubation, were also tested. Addition of P to the pituitary cells primed with E2 led to an acute potentiation of the stimulatory effect of E2 on GnRH-induced LH release and total content. Conversely, the augmentative E2 effect on pituitary responsiveness to GnRH was abolished by DHT. Taken together, these findings suggest that the physiological significance of the stimulatory action of progesterone could be to define the final magnitude of the LH preovulatory surge, while the inhibition by DHT could be required to limit the LH surge to that day of proestrus.Key words: luteinizing hormone, gonadotrophin-releasing hormone, steroid hormones, cultured pituitary cells.
Evidence for an effector role of endothelin in closure of the ductus arteriosus at birth
Authors: Coceani Flavio , Kelsey Lois , Seidlitz Eric
Published: April 2011

The ductus arteriosus is a special muscular shunt that in the fetus allows blood to bypass the unexpanded lungs. It closes rapidly after birth and this event is initiated by the physiologic rise in blood oxygen tension. Endothelin-1 has been proposed by us as a local mediator for oxygen after demonstrating that it is formed within the ductus and is a potent ductus constrictor. To confirm this possibility, we have now measured the release of endothelin-1 from the isolated ductus of near-term fetal lambs at different oxygen concentrations of the medium. In addition, using the same preparation, we have examined the effect on contractile tone of compounds interfering with the synthesis (phosphoramidon, 50 μM) and action (BQ123, 1 μM) of endothelin-1. We report that release of endothelin-1 from the ductus tends to increase with the oxygen concentration up to a value mimicking the neonatal condition. Phosphoramidon and, to a greater degree, BQ123 inhibit the contraction of the vessel to oxygen. These results implicate endothelin-1 as the effector agent for oxygen in the ductus and, by extension, assign to this peptide a critical role in the closure of the vessel at birth.Key words: ductus arteriosus closure, oxygen, endothelin.
Extracellular ATP stimulates elastase secretion from human neutrophils and increases lung resistance and secretion from normal rat airways after intratracheal instillation
Authors: Flezar M. , Olivenstein R. , Cantin A. , Heisler S.
Published: April 2011

The effect of ATP on intracellular Ca2+ levels and elastase secretion in isolated normal human peripheral blood neutrophils was investigated as was its in vivo effect on lung resistance and mucous secretion. ATP (10−5 M) increased [Ca2+]i from 61 ± 3 to 165 ± 15 nM in nonactivated neutrophils; elastase secretion was increased by 40% from nonactivated neutrophils but was unaffected in fMLP (10−5 M) activated cells. Instillation of ATP (10−5 and 10−3 M) into the airways of brown Norway rats increased both lung resistance and secretion. These findings suggest that aerosolization of ATP into the cystic fibrosis-affected bronchial tree might be hazardous in terms of enhancement of parenchymal damage, which would result from neutrophil elastase release, and in terms of impaired respiratory lung function.Key words: extracellular ATP, respiratory airway, elastase secretion, resistance, pulmonary secretion.
Regulation of intestinal glucose transport
Authors: Philpott D. J. , Butzner J. D. , Meddings J. B.
Published: April 2011

The small intestine is capable of adapting nutrient transport in response to numerous stimuli. This review examines several possible mechanisms involved in intestinal adaptation. In some cases, the enhancement of transport is nonspecific, that is, the absorption of many nutrients is affected. Usually, increased transport capacity in these instances can be attributed to an increase in intestinal surface area. Alternatively, some conditions induce specific regulation at the level of the enterocyte that affects the transport of a particular nutrient. Since the absorption of glucose from the intestine is so well characterized, it serves as a useful model for this type of intestinal adaptation. Four potential sites for the specific regulation of glucose transport have been described, and each is implicated in different situations. First, mechanisms at the brush-border membrane of the enterocyte are believed to be involved in the upregulation of glucose transport that occurs in streptozotocin-induced diabetes mellitus and alterations in dietary carbohydrate levels. Also, factors that increase the sodium gradient across the enterocyte may increase the rate of glucose transport. It has been suggested that an increase in activity of the basolaterally located Na+–K+ ATPase could be responsible for this phenomena. The rapid increase in glucose uptake seen in hyperglycemia seems to be mediated by an increase in both the number and activity of glucose carriers located at the basolateral membrane. More recently, it was demonstrated that mechanisms at the basolateral membrane also play a role in the chronic increase in glucose transport observed when dietary carbohydrate levels are increased. Finally, alterations in tight-junction permeability enhance glucose absorption from the small intestine. The possible signals that prompt these adaptive responses in the small intestine include glucose itself and humoral as well as enteric nervous interactions.Key words: intestinal transport, glucose transport, intestinal adaptation.
Evidence for endothelium-dependent and endothelium-independent vasodilation in human skin flaps
Authors: Kreidstein Michael L. , Pang Cho Y. , Carlsen Lloyd N. , Xu Ning
Published: April 2011

Acetylcholine (ACh) and nitroglycerin (NTG) were used as probes to study endothelium-dependent and endothelium-independent vascular relaxation in isolated perfused transverse paraumbilical human skin flaps. It was observed that ACh (10−6 M) significantly (p < 0.05) decreased the vascular resistance and increased dermal capillary perfusion (assessed by surface fluorometry) in norepinephrine (NE, 10−6 M) preconstricted skin flaps, despite the presence of a cyclooxygenase inhibitor (indomethacin, 3 × 10−5 M) and a β-adrenergic receptor antagonist (propranolol, 10−6 M). The ability of ACh to induce vascular relaxation in NE-preconstricted skin flaps was lost after damaging the vascular endothelial lining with saponin perfusion (100 mg∙L−1, 5 min). In contrast, NTG (10−6 M) induced vascular relaxation to a similar extent before and after saponin treatment. In a separate study, ACh was seen to induce vascular relaxation in a concentration-dependent manner in skin flaps preconstricted with NE (10−6 M). This vascular relaxation effect of ACh over the dose range of 10−9–10−5 M was significantly (p < 0.01) inhibited in the presence of Nω-nitro-L-arginine (10−5 M), a nitric oxide (NO) synthesis inhibitor. These observations were taken to indicate the presence of endothelium-dependent and endothelium-independent vascular relaxation in human skin flaps and that the ACh-induced endothelium-dependent relaxation is probably mediated by NO. The importance of impairment of endothelium-dependent relaxation in the pathogenesis of skin flap ischemia, and the potential use of topical nitrovasodilators or NO donors for prevention and (or) treatment of skin flap ischemia were also discussed.Key words: acetylcholine, nitroglycerin, Nω-nitro-L-arginine, vascular relaxation, human skin.
Effects of fructose loading in streptozotocin-diabetic and nondiabetic rats
Authors: Dai Soter , McNeill John H.
Published: April 2011

The present study compares the cardiovascular consequences of a 6-week fructose feeding in nondiabetic and streptozotocin-diabetic rats. Myocardial performance of these animals was determined using the isolated perfused working heart preparation. Systolic blood pressure, pulse rate, ventricular weight/body weight ratio, and plasma levels of glucose, insulin, triglycerides, and cholesterol were measured. In nondiabetic rats, fructose drinking caused significant increases in blood pressure, pulse rate, and plasma concentrations of insulin and triglycerides. Streptozotocin-diabetic animals exhibited significantly less body weight growth, slower pulse rate, higher plasma levels of cholesterol and triglycerides, ventricular enlargement, and functional impairment of the myocardium. The fructose-loaded diabetic rats had larger increases in plasma cholesterol and triglycerides than did control fructose-fed rats, but the fructose-induced increases in blood pressure and pulse rate were attenuated significantly. However, plasma levels of glucose and insulin and the degree of ventricular enlargement and myocardial dysfunction were not significantly different from those of control diabetic rats. These results show that fructose loading for 6 weeks can cause increases in blood pressure, pulse rate, and plasma lipids in both nondiabetic and diabetic rats. However, fructose ingestion does not significantly alter glycemic control or affect the development of myocardial dysfunction in streptozotocin-diabetic rats.Key words: fructose, diabetes, hypertension, hyperlipidemia, myocardial dysfunction.