bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial variability in release at the frog neuromuscular junction measured with FM1-43
Authors: Wu L -G , Betz W J
Published: April 2011

We quantified the spatial variability in release properties at different synaptic vesicle clusters in frog motor nerve terminals, using a combination of fluorescence and electron microscopy. Individual synaptic vesicle clusters labeled with FM1-43 varied more than 10-fold in initial intensity (integrated FM1-43 fluorescence) and in absolute rate of dye loss during tetanic electrical nerve stimulation. Most of this variability arose because large vesicle clusters spanned more than one presynaptic active zone (inferred from postsynaptic acetylcholine receptor stripes labeled with rhodamine-conjugated alpha-bungarotoxin); when the rate of dye loss was normalized to the length of receptor stripe covered, variability from spot to spot was greatly reduced. In addition, electron microscopic measurements showed that large vesicle clusters (i.e., those spanning multiple active zones) were also thicker, and the increased depth of vesicles led to increased total spot fluorescence without a corresponding increase in the rate of dye loss during stimulation. These results did not reveal the presence of "hot zones" of secretory activity.Key words: synaptic transmission, exocytosis, synaptic vesicles, neuromuscular junction.
Calcium signals in long-term potentiation and long-term depression
Authors: Connor John A , Petrozzino Jeffrey , Pozzo-Miller Lucas D , Otani Satoru
Published: April 2011

We describe postsynaptic Ca2+signals that subserve induction of two forms of neuronal plasticity, long-term potentiation (LTP) and long-term depression (LTD), in rat hippocampal neurons. The common induction protocol for LTP, a 1-s, 50-Hz tetanus, generates Ca2+increases of about 50 µM in dendritic spines of CA1 neurons. These very large increases, measured using a low affinity indicator (Mg fura 5), were found only in the spines and tertiary dendrites, and were dependent upon influx through N-methyl-D-aspartate (NMDA) gated channels. High affinity Ca2+indicators (e.g., fura 2) are unable to demonstrate these events. In acute slices, neighboring dendritic branches often showed very different responses to a tetanus, and in some instances, neighboring spines on the same dendrite responded differently. LTD in mature CA1 neurons was induced by a low frequency stimulus protocol (2 Hz, 900 pulses), in the presence of GABA- and NMDA-receptor blockers. This LTD protocol produced dendritic Ca2+increases of <1 µM. Duration of the Ca2+increase was ~30 s and was due to voltage-gated Ca2+influx. Finally, the ability of synaptically addressed Ca2+stores to release Ca2+was studied in CA3 neurons and was found to require immediate preloading and high intensity presynaptic stimulation, conditions unlike normal LTP-LTD protocols.Key words: long-term potentiation, long-term depression, Ca2+, neuronal plasticity, fluorescence imaging, N-methyl-D-aspartate (NMDA) receptor, metabotropic receptor.
Enhanced reactivity of the adrenal medulla in response to pituitary adenylate cyclase activating polypeptide1-27 (PACAP) during insulin-induced hypoglycemia in anesthetized dogs
Authors: Yamaguchi Nobuharu , Lamouche Stéphane
Published: April 2011

The present study was to test the hypothesis that the reactivity of the adrenal medulla to pituitary adenylate cyclase activating polypeptide1-27 (PACAP27) is enhanced during insulin-induced hypoglycemia (IIH) in anesthetized dogs. Plasma catecholamine (CA) concentrations in adrenal venous and aortic blood were determined by an HPLC method coupled with electrochemical detection, and the plasma glucose concentration in aortic blood was measured using a glucometer. PACAP27 (25 ng) was administered locally via the adrenolumbar artery to the left adrenal gland. The resulting CA responses were compared before and during IIH following an intravenous bolus injection of insulin (0.15 IU/kg, iv). In the first group with normal adrenal innervation, the basal adrenal CA secretion gradually increased, reaching a maximum level 45 min after the insulin injection. The net increase in PACAP27-induced CA secretion was significantly greater 30, 45, and 60 min after the induction of hypoglycemia, compared with the initial net response to PACAP27 observed before insulin injection. In the second group receiving local adrenal denervation, neither the basal CA secretion nor the net CA response to PACAP27 significantly increased despite the presence of IIH, which developed to an extent similar to that found in the first group. In the third group, which was the normoglycemic control group, both the basal CA secretion and the net CA response to PACAP27 remained unchanged during the experimental period. The results indicate that the adrenomedullary reactivity to PACAP27 was significantly enhanced during IIH only when the sympathoadrenal system was activated. The present study suggests that PACAP27 may play a beneficial role in glucose counterregulatory mechanisms in the adrenal medulla during hypoglycemia.Key words: catecholamine, counterregulation, denervation, secretion, splanchnic, sympathoadrenal.
Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+-K+ATPase
Authors: Almotrefi Abdulrahman A , Basco Chona , Moorji Azadali , Dzimiri Nduna
Published: April 2011

The notion that the inhibition of the Mg2+-dependent ATP-hydrolytic function of the myocardial Na+-K+ATPase by class I antiarrhythmic agents occurs as a result of their binding to the same receptor sites as the digitalis glycosides was tested by performing competitive binding assays of [3H]ouabain (OUA) with eight drugs: disopyramide, encainide, lidocaine, lorcainide, phenytoin, procainamide, quinidine, and tocainide in guinea pig heart microsomal preparations. In the first set of experiments, 10-200 µM concentrations of the drugs were preincubated with the enzyme and displacement assays performed with 250 nM OUA. The drugs showed receptor occupancy of 19-32% at 50 µM, 25-44% at 100 µM, and 37-56% at 200 µM. Then, 10-500 nM concentrations of OUA were preincubated with the enzyme, and competitive assays were performed using 200 µM concentrations of the drugs. OUA occupied 39-51% of the receptor sites at 100 nM, 44-67% at 250 nM, and 62-82% at 500 nM, displacing the drugs in a concentration-dependent fashion. The results show that antiarrhythmic drugs interact with the same or similar receptor sites as ouabain on the Na+-K+ATPase, pointing to a possible contribution of these interactions to the mechanism for their inhibitory actions on the enzyme, and perhaps their arrhythmogenic effects.Key words: class I antiarrhythmic agents, proarrhythmias, Na+-K+ATPase, ouabain binding.
Effects of pregnancy and chronic exercise on maternal cardiac structure and function
Authors: Wolfe L A , Preston R J , Burggraf G W , McGrath M J
Published: April 2011

This study examined the interactive effects of pregnancy and aerobic conditioning on maternal cardiac structure and function. Effects of closely monitored cycle ergometer conditioning were studied during the second (TM2) and third trimesters (TM3) in 22 previously sedentary pregnant women (exercised group, EG) and a nonexercising pregnant control group with similar characteristics (CG, n = 19). Subjects were studied in the resting state by two-dimensional echocardiography and during cycle ergometer exercise at three steady-state power outputs at the start of TM2 (ENTRY), at the end of TM2 and TM3 (postconditioning), and 3-4 months postpartum (NPR, nonpregnant reference, CG only). Aerobic conditioning did not increase left ventricular dimensions beyond those attributable to pregnancy itself. In addition, in contrast with previous studies of nonpregnant women, physical conditioning during pregnancy did not reduce heart rate (HR) in the resting state. During exercise, the slope of the HR versus oxygen uptake (Vo2) regression decreased significantly between preconditioning and the end of TM3 in the EG, suggesting that training-induced reductions in HR become more evident with increasing exercise intensity. Also, significant reductions in oxygen pulse (Vo2/HR) were observed at all three work rates in the CG, but not in the EG. These findings support the hypothesis that the cardiovascular effects of aerobic conditioning are obscured by more powerful effects of pregnancy in the resting state but become "unmasked" during strenuous exercise.Key words: human gestation, cycle ergometer exercise, echocardiography, heart rate, stroke volume.
Effects of diabetes and hypertension on myocardial Na+-Ca2+ exchange
Authors: Kashihara Haruyo , Shi Zhong Q , Yu Jen Z , McNeill John H , Tibbits Glen F
Published: April 2011

Abnormalities in cardiac function have been extensively documented in experimental and clinical diabetes. These aberrations are well known to be exaggerated when hypertension and diabetes co-exist. The objective of the present study was to examine whether alterations in the activity of the myocardial Na+-Ca2+ exchanger (NCX) can account for the deleterious effects of diabetes and (or) hypertension on the heart. To this aim, the following experimental groups were studied: (i) control; (ii) diabetic; (iii) hypertensive; and (iv) hypertensive-diabetic. Wistar rats served as the control group (C) while Wistar rats injected with streptozotocin (STZ, 55 mg/kg) served as the diabetic (D) group. Spontaneously hypertensive (SH) rats were used as the hypertensive group (H) while SH rats injected with STZ served as the hypertensive-diabetic (HD) group. Sarcolemma was isolated from the ventricles of the C, D, H, and HD groups and NCX activity was examined using rapid quenching techniques to study initial rates over a [Ca2+]o range of 10-160 µM. The Vmax of NCX was lower in the D group when compared with the C group (D, 2.96 ± 0.26 vs. C, 4.0 ± 0.46 nmol·mgprot-1·s-1, P < 0.05), however combined diabetes and hypertension (HD) did not affect the Vmax of NCX activity (HD, 3.84 ± 0.88 vs. H, 3.59 ± 0.24 nmol·mgprot-1·s-1, P > 0.05). However, analysis of the Km values for Ca2+ indicated that both the D and HD groups exhibited a significantly lower Km when compared with their respective control groups (D, 42 ± 4 vs. C, 56 ± 4 µM,P < 0.05; HD, 33 ± 7 vs. H, 51 ± 8 µM, P < 0.05). Immunoblotting using polyclonal antibodies (against canine cardiac NCX) exhibited the typical banding of 160, 120, and 70 kDa. The 120 kDa band is believed to represent the native exchanger with its post-translational modifications. Examination of the blots revealed a lower intensity of the 120 kDa band in the D group when compared with the C group, however, no significant difference in the HD group was observed. We speculate that the lower Vmax in the D group may be due to a reduced concentration of exchanger protein in the membrane. The absence of this defect in the HD group may be a result of compensatory mechanisms to the overall hemodynamic overload, however, this remains to be determined. The increased affinity for Ca2+ in both the D and HD groups (determined by the lower Km values) is an interesting finding and may be due to changes in sarcolemmal lipid bilayer composition secondary to diabetes-induced hyperlipidemia.Key words: diabetes, hypertension, cardiac, Na+-Ca2+ exchange, contractility.
Homocyst(e)ine impairs endocardial endothelial function
Authors: Tyagi Suresh C , Smiley Lane M , Mujumdar Vibhas S
Published: April 2011

Homocyst(e)ine injured vascular endothelium and modulated endothelial-dependent vascular function. Endothelium plays an analogous role in both the vessel and the endocardium. Therefore, we hypothesized that homocyst(e)ine modulated endocardial endothelium (EE) dependent cardiac function. The ex vivo cardiac rings from normal male Wistar-Kyoto rats were prepared. The contractile responses of left and right ventricular rings were measured in an isometric myobath, using different concentrations of CaCl2. The response was higher in the left ventricle than right ventricle and was elevated in endocardium without endothelium. The half effective concentration (EC50) and maximum tension generated by homocyst(e)ine were 106 and 5-fold lower than endothelin (ET) and angiotensin II (AII), respectively. However, in endothelial-denuded endocardium, homocyst(e)ine response was significantly increased (p < 0.005, compared with intact endothelium) and equal to the response to ET and AII. To determine the physiological significance of ET, AII, homocyst(e)ine, and endothelial nitric oxide in EE function, cardiac rings were pretreated with AII (10-10 M) or ET (10-13 M) and then treated with homocyst(e)ine (10-8 M). Results suggested that at these concentrations AII, ET, or homocyst(e)ine alone had no effect on cardiac contraction. However, in the presence of 10-10 M AII or 10-13 M ET, the cardiac contraction to homocyst(e)ine (10-8 M) was significantly enhanced (p < 0.01, compared with without pretreatment) and further increased in the endocardium without endothelium. The pretreatment of cardiac ring with the inhibitor of nitric oxide, Nω-nitro-L-arginine methyl ester (L-NAME), increased contractile response to homocyst(e)ine. These results suggested that homocyst(e)ine impaired EE-dependent cardiac function and acted synergistically with AII and ET in enhancing the cardiac contraction.Key words: endocardial remodeling, homocyst(e)ine, contraction, endothelin, angiotensin, endothelial-derived relaxing factor (EDRF), Nω-nitro-L-arginine methyl ester (L-NAME), endothelial dysfunction, ex vivo cardiac function, heart failure.
Results of simulated mastication suggest existence of a periodontogastric motility reflex
Authors: Lorber Mortimer
Published: April 2011

Various reflexes inhibit gastric motor activity. Might a contrary one permit the oral region to increase gastric motility? Ten fasted rats were allowed to feed for 15 min. Following anesthesia and cannula insertion, antral pressure was recorded during three consecutive 5-min intervals: the baseline, procedure, and postprocedure periods. The procedure involved manually lowering and raising the mandible about once per second, causing repetitive molar occlusion. Doing this when food is in the stomach resembles conditions as the latter part of a meal is consumed. Gastric motor events increased from 1.10 ± 1.67 (mean ± SD) to 5.50 ± 4.12 per 5 min during the procedure (p < 0.05) and 5.80 ± 3.97 in the ensuing period (p < 0.05). The findings suggest an excitatory reflex following stimulation of mechanoreceptors in one or more sites related to mastication: the periodontium, temporomandibular joints, or masticatory muscles. Because rubbing the maxillary molars while the mouth remained constantly open also increased motor events, the periodontium is the most likely location of the receptors. They and associated trigeminal neurons would comprise the reflex's afferent arm. The vagi, perhaps with intermediaries, are its likely efferent arm. In these recently fed rats this reflex acts despite receptive relaxation and enterogastric reflexes to increase distal gastric motor activity.Key words: gastrointestinal motility, mastication, periodontal ligament.
Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis
Authors: Mertineit Carmen , Samlalsingh-Parker Jacqueline , Glibetic Maria , Ricard Ginette , Noya Francisco JD , Aranda Jacob V
Published: April 2011

Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nω-nitro-L-arginine, a NO inhibitor. Sterile saline or 109colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nω-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF.Key words: cerebrovascular autoregulation, group B Streptococcus, neonatal meningitis, anti-inflammatory agents, prostanoids, nitric oxide synthase, gene expression, nitric oxide.
Potent and selective tools to investigate neuropeptide Y receptors in the central and peripheral nervous systems: BIBO3304 (Y1) and CGP71683A (Y5)
Authors: Dumont Yvan , Cadieux Alain , Doods Henri , Fournier Alain , Quirion Rémi
Published: April 2011

We have evaluated 3 newly developed neuropeptide Y receptor antagonists in various in vitro binding and bioassays: BIBO3304 (Y1), T4[NPY33-36]4(Y2), and CGP71683A (Y5). In rat brain homogenates, BIBO3304 competes for the same population of [125I][Leu31,Pro34] peptide YY (PYY) binding sites (75%) as BIBP3226, but with a 10 fold greater affinity (IC50of 0.2 ± 0.04 nM for BIBO3304 vs. 2.4 ± 0.07 nM for BIBP3226),while CGP71683A has high affinity for 25% of specific [125I][Leu31,Pro34]PYY binding sites. Both BIBO3304 and CGP71683A (at 1.0 µM) were unable to compete for a significant proportion of specific [125I]PYY3-36/Y2sites. The purported Y2antagonist T4[NPY33-36]4competed against [125I]PYY3-36binding sites with an affinity of 750 nM. These results were confirmed in HEK 293 cells transfected with either the rat Y1, Y2, Y4, or Y5receptor cDNA. BIBO3304, but not CGP71683A, competed with high affinity for [125I][Leu31,Pro34]PYY binding sites in HEK 293 cells transfected with the rat Y1receptor cDNA, whereas the reverse profile was observed upon transfection with the rat Y5receptor cDNA. Additionally, both molecules were inactive at Y2and Y4receptor subtypes expressed in HEK 293 cells. Receptor autoradiographic studies revealed the presence of [125I][Leu31,Pro34]PYY/BIBO3304-insensitive sites in the rat brain as reported previously for BIBP3226. Finally, the selective antagonistic properties of BIBO3304 were demonstrated in a Y1bioassay (rabbit saphenous vein; pA2value of 9.04) while being inactive in Y2(rat vas deferens) and Y4(rat colon) bioassays. These results confirm the high affinity and selectivity of BIBO3304 and CGP71683A for the Y1and Y5receptor subtypes, respectively, while the purported Y2antagonist, T4[NPY33-36]4possesses rather low affinity for this receptor.Key words: NPY receptor antagonist, receptor subtypes, bioassays, receptor binding assays, autoradiographic studies, receptor distribution.
PYY preference is a common characteristic of neuropeptide Y receptors expressed in human, rat, and mouse gastrointestinal epithelia
Authors: Holliday Nicholas D , Pollock Emma L , Tough Iain R , Cox Helen M
Published: April 2011

This investigation describes the relative potencies of four peptide agonists, namely, peptide YY (PYY), [Leu31,Pro34]PYY (Pro34PYY), neuropeptide Y (NPY), and [Leu31,Pro34]NPY (Pro34NPY), as antisecretory agents in human, rat, and mouse gastrointestinal preparations. The inhibition of agonist responses by the Y1-receptor antagonist BIBP 3226 was also tested in each preparation. An unexpectedly pronounced preference for PYY and Pro34PYY was observed in functional studies of two human epithelial lines stably transfected with the rat Y1receptor (Y1-7 and C1Y1-6). NPY and Pro34NPY were at least an order of magnitude less effective than PYY in these functional studies but were only marginally less potent in displacement binding studies using membrane preparations of the same clonal lines. The orders of agonist potency obtained in Y1-7 and C1Y1-6 epithelia were compared with those obtained from a single human colonic adenocarcinoma cell line (Colony-6, which constitutively expresses Y1receptors) and also from mucosal preparations of rat and mouse descending colon. Similar peptide orders of potency were obtained in rat and mouse colonic mucosae and Colony-6 epithelia, all of which exhibited PYY preference (although less pronounced than with Y1-7 and C1Y1-6 epithelia) and significant sensitivity to the Y1receptor antagonist, BIBP 3226. We have compared the pharmacology of these five mammalian epithelial preparations and provide cautionary evidence against the reliance upon agonist concentration-response relationships alone, in the characterization of NPY receptor types.Key words: Y receptors, neuropeptide Y, gastrointestinal epithelia, ion transport.
Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1 receptor selective antagonists
Authors: Kask Ants , Schiöth Helgi B , Harro Jaanus , Wikberg Jarl ES , Rägo Lembit
Published: April 2011

Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects on food intake: NPY-like peptides and MC receptor antagonists stimulate feeding and increase body weight, whereas melanocortins and NPY antagonists inhibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]- D-argininamide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304), and decapeptide [D-Tyr27,36D-Thr32]NPY27-36, after icv administration in freely feeding male rats. All three NPY receptor antagonists inhibited the orexigenic effects of HS014 partially and with markedly different potency. [D-Tyr27,36D-Thr32]NPY27-36 was active only in subconvulsive dose. The NPY Y1 selective antagonist BIBP3226 was more effective in inhibiting the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding, indicating that the effects of BIBO3304 were stereoselective. These results suggest that stimulation of food intake caused by weakening of melanocortinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y1 receptor activation.Key words: neuropeptide Y, NPY Y1 receptor antagonist, BIBO3304, BIBP3226, [D-Tyr27,36D-Thr32]NPY(27-36), 1229U91, food intake, MC4 receptor antagonist, HS014.
Proteinase-activated receptors (PARs): activation of PAR1 and PAR2 by a proteolytic fragment of the neuronal growth associated protein B-50/GAP-43
Authors: Hollenberg Morley D , Saifeddine Mahmoud , Zwiers Henk
Published: April 2011

The neuronal growth associated protein B-50/GAP-43 has been localized in synaptosomes both as an intact protein and as a partial proteolysis product (termed B-60) that has an N-terminal sequence SFRGHITR.... Because of the relationship of this amino acid sequence to those of the tethered ligand for the human proteinase activated receptors PAR1 (SFLLRN...) and PAR2 (SLIGKV...), we wished to determine whether the B-50/GAP-43-derived proteolytic fragment SFRGHITR (SFRB60) might function as a PAR-activating peptide (PAR-AP) to stimulate either PAR1 or PAR2. With the use of a newly developed PAR1/PAR2 receptor activation-desensitization assay, employing PAR1/PAR2-bearing cultured human embryonic kidney (HEK293) cells, we found that SFRB60 could activate both PAR1 and PAR2 so as to elevate intracellular calcium with EC50 values of approximately 200 and 50 µM, respectively. We also showed that trypsin can rapidly degrade B-50 to smaller fragments that would include the sequence SFRB60. Because PAR1 and PAR2 are present on neurones, our data raise the possibility that in certain circumstances in vivo, B-50/GAP-43 may play a signalling role by serving as a precursor for proteolytically generated PAR-activating peptides.Key words: proteinase-activated receptors, neurones, B-50/GAP-43, calcium signalling.
Doxorubicin-induced late cardiotoxicity: delayed impairment of Ca2+-handling mechanisms in the sarcoplasmic reticulum in the rat
Authors: Chugun Akihito , Temma Kyosuke , Oyamada Toshifumi , Suzuki Natsuyo , Kamiya Yoshinori , Hara Yukio , Sasaki Takushi , Kondo Hiroshi , Akera Tai
Published: April 2011

Doxorubicin treatment causes delayed development of cardiotoxicity. Whether the doxorubicin-induced impairment of cardiac functions reverses or progresses with time after the cessation of the treatment was examined. The rats were injected with doxorubicin (2.5 mg/kg, i.v., once a week for 3 weeks) and sacrificed at 1 (1W), 13 (13W), or 18 (18W) weeks after the final doxorubicin administration. The time to peak of twitch contraction observed at 2-Hz stimulation was not altered in left atrial or ventricular muscle preparations isolated from 1W rats, but it was prolonged in those from 13W and 18W rats. The reduction of the magnitude of postrest contraction and the alteration of force-frequency relationships in left atrial muscle preparations in 1W rats were not significant, but were intensified in the 13W and 18W groups. Alterations in the postrest contraction and the force-frequency relationships in ventricular muscle preparations isolated from doxorubicin-treated rat hearts were weaker, but the pattern of alteration was similar to that observed in left atrial muscle preparations. Caffeine-induced contraction observed in skinned fibers that were isolated from the 1W rats was not altered, but it was reduced in the 18W rats. The Ca2+ sensitivity of contractile proteins was not altered in doxorubicin-treated rat hearts in any of the groups. The Kd values estimated from a [3H]ryanodine binding study were not altered, but the Bmax values were significantly lower in the 13W and 18W groups than those observed in control rats. These results suggest that the dysfunction of the sarcoplasmic reticulum progresses after the completion of doxorubicin treatment and contributes to the doxorubicin-induced late cardiotoxicity.Key words: doxorubicin, late cardiotoxicity, rat heart, sarcoplasmic reticulum.
Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?
Authors: Castañeda-Hernández Gilberto , Granados-Soto Vinicio
Published: April 2011

It is frequently assumed that pharmacological responses depend solely on the extent of drug binding to its receptor according to the occupational theory. It is therefore presumed that the intensity of the effect is determined by drug concentration at its receptor site, yielding a unique concentration-effect relationship. However, when dependence, abstinence, and tolerance phenomena occur, as well as for pharmacological responses in vivo that are modulated by homeostatic mechanisms, the rate of drug input shifts the concentration-effect relationship. Hence, such responses cannot be explained on the sole basis of the extent of drug binding to its receptor. Information on the cellular and molecular processes involved in the generation of abstinence, dependence, and tolerance will undoubtedly result in the development of pharmacodynamic models allowing a satisfactory explanation of drug effects modulated by these phenomena. Notwithstanding, integrative physiology concepts are required to develop pharmacokinetic-pharmacodynamic models allowing the description of drug effects in an intact organism. It is therefore important to emphasize that integrative physiology cannot be neglected in pharmacology teaching and research, but should be considered as an equally valuable tool as molecular biology and other biomedical disciplines for the understanding of pharmacological effects.Key words: pharmacodynamics, pharmacokinetics, drug-receptor binding, occupational theory.
Levels of specifically bound [3H]ketanserin compared with levels of serotonin (5HT) in the brain regions of juvenile and sexually recrudescing female rainbow trout, Oncorhynchus mykiss
Authors: Agrawal Smriti M , Omeljaniuk Robert J
Published: April 2011

This study compared the distribution of specifically bound [3H]ketanserin (Bsp) with serotonin (5HT) in brain regions of juvenile and sexually recrudescing female trout. Amounts of Bsp varied widely among brain regions and consistently differed between juvenile and sexually recrudescing females. Levels of Bsp were significantly greater in the hypothalamus than the olfactory lobe, which were at least threefold greater than in all other tissues examined (Kruskal-Wallis test, p < 0.05). Bsp densities in the hypothalamus, preoptic area, and optic lobe were significantly greater in juveniles compared with corresponding tissues from sexually recrudescing females (Mann-Whitney U test, p < 0.05); in contrast, Bsp in olfactory lobe and spinal cord did not differ significantly between the two classes of fish. 5HT concentration was determined by high performance liquid chromatography - electrochemical detection (HPLC-EC) analysis. Biogenic amine standards eluted in a stereotypic pattern, with peaks consistently separable in time. 5HT concentration was significantly greater in hypothalamus than in olfactory lobe and undetectable in the pituitary (Kruskal-Wallis test, p < 0.05). Trends in distribution of Bsp and 5HT were comparable in the hypothalamus and preoptic area in juvenile and sexually recrudescing females. In general, density of specific [3H]ketanserin binding sites was directly related to 5HT content of brain regions in juvenile and sexually recrudescing females. 5HT concentrations (pmol/g tissue) were approximately 900-fold greater than Bsp (fmol/g tissue) in all brain regions, and approximately 300-fold greater than Bsp in the olfactory lobe. These results suggest important regulatory role(s) for 5HT in the trout preoptic-hypothalamo-hypophysial axis, which may differ from 5HT role(s) in trout olfactory lobe.Key words: high performance liquid chromatography - electrochemical detection, [3H]ketanserin, sexually recrudescing female trout.
Distribution of α1-adrenoceptor subtype proteins in different tissues of neonatal and adult rats
Authors: Shen Hao , Peri Krishna G , Deng Xing-Fei , Chemtob Sylvain , Varma Daya R
Published: April 2011

Distribution of α1-adrenoceptor (α1AR) subtype (α1A, α1B, α1D) proteins in brain, heart, kidney, and liver of 1-week-old rats and in brain, heart, aorta, kidney, liver, vas deferens, prostate, and adrenal glands of adult rats was investigated by Western analysis, using receptor subtype specific polyclonal antibodies. High levels of immunoreactive α1AAR and α1DAR in brain and heart and of α1BAR in liver and heart of neonatal rats were detected. In adult rat tissues, the abundance of α1AAR protein was most marked in the brain, intermediate in heart, aorta, liver, vas deferens, and adrenals, and minimal in the kidney and prostate; relative to other tissues, the expression of α1BAR was higher in brain and heart and that of α1DAR in brain. All the three receptor subtypes increased with age in the brain cortex, whereas the abundance of α1BAR increased in the heart but decreased in the liver; α1AAR and α1DAR in liver, kidney, and heart were not affected by age. It is concluded that α1AR subtypes are widely expressed in different neonatal and adult rat tissues.Key words: α1A-adrenoceptors, α1B-adrenoceptors, α1D-adrenoceptors, α1-adrenoceptor proteins.
Acute cord occlusion increases blood ionized magnesium concentration in preterm fetal sheep during maternal magnesium sulfate exposure
Authors: Reynolds James D , Grubbs Elizabeth G , Dexter Franklin , Punnahitananda Santi , Dense Tracy A , Penning Donald H
Published: April 2011

This study tested the hypothesis that a pathophysiologic insult to the fetus that decreases pH (umbilical cord occlusion) produces an increase in physiologically active (i.e., ionized) magnesium concentration. Preterm pregnant sheep (n = 7) were instrumented with maternal and fetal catheters and an inflatable vascular occluder was placed around the umbilical cord. After a 2-day recovery period, each ewe received a 4-g loading dose, followed by continuous intravenous infusion of 1 g magnesium sulfate/h. After 48 h, an episode of acute fetal distress was produced by inflation of the umbilical occluder for 10 min. Maternal and fetal arterial blood samples were collected at regular intervals to quantitate ionized magnesium concentration and monitor physiologic status. Magnesium sulfate infusion increased maternal and fetal blood ionized magnesium concentration. In vitro blood analysis demonstrated that there was a linear inverse correlation (r2= 0.99) between fetal sheep blood pH and ionized magnesium concentration. In vivo, 10 min of umbilical cord occlusion produced an increase in fetal blood ionized magnesium concentration in all animals (P = 0.02) that was temporally related to the decrease in fetal blood pH. Whether this increase in physiologically active magnesium concentration is beneficial (via neuroprotection) or deleterious (via suppression of stress response) to the distressed fetus remains to be determined.Key words: fetal, hypoxia, ionized magnesium, magnesium sulfate, sheep.
Age-dependent metabolic effects of repeated hypoxemia in piglets
Authors: Côté Aurore , Barter Jill , Meehan Brian
Published: April 2011

The aim of this study was to determine whether repeated exposure to hypoxemia would modify the response to hypoxemia during maturation. We exposed piglets to three 1-h cycles of hypoxemia (PaO2= 30 to 35 mmHg; 1 mmHg = 133.3 Pa) at 1 week (n = 9), 2-3 weeks (n = 10), and 4-5 weeks of age (n = 10). O2consumption (VO2) and CO2production (VCO2) were measured, and alveolar ventilation (VA) was derived from VCO2and PaCO2. Levels of lactic acid (lactate) and serum catecholamines were also measured. With hypoxemia, time had a significant effect on VO2and body temperature in an age-dependent fashion: that is, whereas the 1 week group and the 4-5 week group showed both variables decreasing over time, the 2-3 week group showed no drop in VO2and a small increase in body temperature over time. Lactate levels increased with hypoxemia in all animals during the first exposure. However, with repeated exposures to hypoxemia, only the 2-3 week group continued to increase its lactate levels. Furthermore, the changes in lactate levels paralleled the changes in epinephrine levels with hypoxemia. We found, too, that although VA increased significantly with hypoxemia in all animals, this change was not modified by age or repeated exposures. No significant effects of age or repeated exposures were found in the cardiovascular response to hypoxemia. We concluded that, from a metabolic viewpoint, after repeated exposures to hypoxemia the 2-3 week animals responded differently.Key words: metabolic rate, lactic acid, maturation, catecholamines.
Effects of serotonin on the physiology of the rabbit small intestine
Authors: Salvador M T , Murillo M D , Rodríguez-Yoldi M C , Alcalde A I , Mesonero J E , Rodríguez-Yoldi MJ
Published: April 2011

Serotonin has been shown to alter the intestinal transport of ions and intestinal motility. These effects may interfere with each other, modulating the whole physiology of the intestine. We have previously shown that serotonin also alters the transport of nutrients. Thus, the aims of the present work were to determine the possible interference between the secretagogue effect of serotonin and the mechanism by which serotonin inhibits the absorption of nutrients, and to study the effect of serotonin on the digestive activity of nutrients of the brush border membrane jejunum enterocyte in the rabbit. The results show that the secretagogue effect of serotonin neither affects the inhibitory effect of serotonin on the intestinal absorption of the nutrients, nor affects the activity of Na+/K+-ATPase. The activity of sucrase and aminopeptidase N was also not affected by serotonin in the rabbit jejunum. Finally, we also studied different parameters of the motility in the rabbit small intestine. Serotonin seemed to stimulate the motility of the rabbit small intestine by increasing integrated mechanical activity and tone of muscle fibers in duodenum, jejunum, and ileum. In conclusion, serotonin might alter or modulate the whole intestinal physiology.

Key words: serotonin, small intestine, motility, absorption, rabbit.
Neuropeptide Y stimulates DNA synthesis in human vascular smooth muscle cells through neuropeptide Y Y1 receptors
Authors: Nilsson T , Edvinsson L
Published: April 2011

We investigated the mitogenic effect, measured as [3H]thymidine incorporation, of neuropeptide Y (NPY) on smooth muscle cells (SMCs) from human subcutaneous arteries (diameter: 0.4 mm). NPY stimulated DNA synthesis in a concentration-dependent manner, Emax 32 ± 5% relative to control. The effect was potently antagonised by the NPY Y1 receptor antagonist BIBP3226 ((R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine-amide), indicating the effect to be mediated via the NPY Y1 receptor. Noradrenaline (NA) also induced mitogenesis, Emax 35 ± 10% relative to control. When added together, NPY and NA potentiated the [3H]thymidine incorporation, Emax 109 ± 38% relative to control. Also, this effect seems to be mediated by the NPY Y1 receptor, since BIBP3226 blocked the effect (44 ± 9% relative to control). The mitogenic effect of NPY and NA, two important transmitters of the sympathetic nervous system, might have clinical consequences on conditions with elevated sympathetic nerve activity.Key words: BIBP3226, mitogenesis, neuropeptide Y, vascular smooth muscle cells.
Changes in coyote activity patterns due to reduced exposure to human persecution
Authors: Kitchen Ann M , Gese Eric M , Schauster Edward R
Published: April 2011

Activity patterns in animals are influenced by a number of factors, including the animal's physiological adaptations, prey availability and distribution, and disturbances caused by predators and humans. We compared coyote (Canis latrans) activity patterns estimated using radio-tracking locations between 1983 and 1988 with those documented between 1996 and 1997 on the Pinon Canyon Maneuver Site, in southeastern Colorado. We tested the hypothesis that changes in the type of disturbance experienced by coyotes would result in changes in their activity patterns. Disturbance experienced by the coyote population studied during 1983-1988, included >50 years of intense exploitation (shooting and trapping by ranchers) and intensive removal efforts using aerial gunning. In contrast, coyotes tracked during 1996-1997 experienced some periodic disturbance from army maneuvers occurring in the area, but were not exposed to any direct form of persecution (e.g., shooting). From August 1983 to July 1988, 49 coyotes (26 males and 23 females) were tracked for >2400 h using radiotelemetry. From April 1996 to August 1997, 22 coyotes (12 males and 10 females) were tracked for >950 h. The average rate of diurnal movement of the coyotes in the 1996-1997 field study (mean = 0.97 km/h) was significantly higher than that of the coyotes in the 1983-1988 field study (mean = 0.68 km/h). This occurred despite no significant increase in the overall (24 h) rate of movement between the two field studies. Estimates of prey use by the coyotes in both field studies were obtained, to test an alternate hypothesis that prey switching might explain the changes in coyote movement patterns. However, there was no significant difference between the frequency of occurrence of diurnally versus nocturnally active mammalian prey species in the diets of coyotes in any season or overall between the 1983-1988 and 1996-1997 field studies. This study demonstrated that coyote activity patterns can be influenced by the type of disturbance experienced by the animal. A coyote population that had historically been exposed to human persecution shifted to higher levels of diurnal activity when exploitation ceased.
The reproductive cycle of male Atlantic cod (Gadus morhua L.) from Placentia Bay, Newfoundland
Authors: Rideout Rick M , Burton Margaret PM
Published: April 2011

The timing of the reproductive cycle of male Atlantic cod (Gadus morhua L.) from Placentia Bay, Newfoundland, was determined from histological gonad samples collected throughout the year. Cycles in gonad mass, whole mass, and somatic mass indices were also determined. Results were consistent with a spring spawning population, with males having testes filled with spermatozoa as early as January. There was a short resting period following spermiation, during which residual sperm was resorbed, followed by rapid development so that some sperm was again evident in the testes as early as November. At first, the presence of spermatozoa was accompanied by cells in all other stages of development, but by spermiation the testes were filled mostly with spermatozoa. Gonad size was largest in April, smallest in October, and increased steeply again in November. Energy for gonad growth came from food intake, as well as liver lipid stores. Gonad development was, for the most part, finished prior to the winter reduction in feeding intensity.
A new phylogeny and phylogenetic classification for the Canthyloscelidae (Diptera: Psychodomorpha)
Authors: Amorim Dalton de Souza
Published: April 2011

A new phylogeny and phylogenetic classification for the Canthyloscelidae (Diptera: Psychodomorpha) is presented. A phylogenetic analysis of the Scatopsoidea is performed. A sister-group relationship between the Canthyloscelidae and Scatopsidae is accepted and the monophyly of the Canthyloscelidae is corroborated, including the genera Exiliscelis, Synneuron, Hyperoscelis, and Canthyloscelis. An earlier phylogenetic analysis of the group is considered, in which Synneuron was accepted as the sister-group of the Scatopsidae and Exiliscelis was considered the sister-group of Synneuron + Scatopsidae. Some apomorphic similarities between the larvae of all genera of Canthyloscelidae, especially the reduction of the head capsule, are considered true synapomorphies. Exiliscelis is considered the sister-group of the rest of the family and is placed in a new subfamily, Exiliscelinae. In the Canthyloscelinae, Synneuron is the sister-group of Hyperoscelis + Canthyloscelis. A phylogenetic classification of the group is proposed. Prohyperoscelis rohdendorfi Kovalev, 1985, from the Middle Jurassic in Russia, is accepted as the sister-group of Canthyloscelis.
Cyclic dynamics of eastern Canadian ermine populations
Authors: Johnson Donald R , Swanson Bradley J , Eger Judith L
Published: April 2011

Based on partial autocorrelation analysis, 20 ermine (Mustela erminea) populations in Manitoba, Ontario, and Quebec demonstrated cyclic dynamics characterized by a latitudinal gradient of decreasing first-order feedback and increasing negativity of second-order feedback. Most of these populations exhibited three cyclic peaks and a 10-year interval of noncyclic dynamics during the sampling period (1915-1940). Changes in ermine density probably reflected those in the density of microtine rodents, their primary prey. Analysis of the limited number of long-term lemming and vole series from boreal North America indicated a latitudinal gradient in cyclic dynamics similar to that of microtine rodent populations in northern Europe. Complex geographic and temporal variation in ermine population dynamics, including cyclic, noncyclic, and shifting patterns of density change, supports the specialist-generalist hypothesis of predator-prey interaction at temperate latitudes.
Movements and distribution of polar bears in the Beaufort Sea
Authors: Amstrup S C , Durner G M , Stirling I , Lunn N J , Messier F
Published: April 2011

We fitted 173 satellite radio collars (platform transmitter terminals) to 121 adult female polar bears in the Beaufort Sea and relocated the bears 44 736 times between 1985 and 1995. We regularly resighted many instrumented bears so that we could ascertain whether changes in movements or distribution were related to reproductive status. Mean short-term movement rates were less than 2 km/h for all classes of bears. Maximum movement rates occurred in winter and early summer. In the southern Beaufort Sea (SBS), net geographic movements from the beginning to the end of each month were smaller for females with cubs of the year than for solitary females, and larger in November than in April, May, or July. In May, June, July, and August, radio-collared bears in the SBS moved north. They moved south in October. In the northern Beaufort Sea (NBS), bears moved north in June and south in March and September. Total annual movements ranged from 1406 to 6203 km. Mean total distances moved each month ranged from 79 to 420 km. Total monthly movements by SBS bears were largest in early winter and smallest in early spring. In the NBS, movements were largest in summer and smallest in winter. In the SBS, females with cubs moved less each month than other females. Annual activity areas ranged from 7264 to 596 800 km2. Monthly activity areas ranged from 88 to 9760 km2. Seasonal fidelity to activity areas of bears captured in all parts of the Beaufort Sea was strongest in summer and weakest in spring.
Age- and sex-specific responses of the gray-tailed vole, Microtus canicaudus, to connected and unconnected habitat patches
Authors: Davis-Born Renee , Wolff Jerry O
Published: April 2011

We monitored demography, movement, and reproductive behavior of gray-tailed voles, Microtus canicaudus, in experimental habitat patches with and without corridors to test the hypotheses that more individuals would move among patches in corridor than in control unconnected habitats, and that individuals would distribute themselves more evenly among patches if corridors were present than if they were not. We predicted that more males than females would move among patches in both treatments and that juveniles in control habitats would exhibit delayed sexual maturation if their dispersal was delayed and opposite-sex relatives remained in proximity to each other. All experiments were conducted in eight 0.2-ha enclosures planted with alfalfa that was fragmented into four patches (each 156 m2) separated by 12.5 m of bare ground. In four of the enclosures, patches were connected by 1 m wide habitat corridors. Corridors facilitated movements, with males moving more than females. However, corridors did not result in an even distribution of animals in the four patches. Unconnected habitat patches resulted in female-biased juvenile dispersal, and females dispersed at a lower body mass than males in both connected and unconnected habitats. Males that did not disperse from their natal patch grew at a slower rate than those that did disperse. We conclude that movement was deterred in patchy environments, enhanced by corridors, and differentially affects males and females. Behavioral factors that affect an individual's dispersal or reproductive pattern should be considered in landscape design.