bluuebunny/crossref_metadata_2025 huggingface dataset:
Diminished diabetogenic effect of streptozotocin in adrenodemedullated rats
Authors: Jean Christine , Roy Denis , Nadeau André
Published: April 2011

Although stress is suspected to play a role in the development of diabetes mellitus, no direct experimental evidence for involvement of the adrenal medullae in onset of the disease has yet been found. We recently observed that, in comparison with sham-operated rats, fewer adrenodemedullated rats become diabetic after an i.v. injection of streptozotocin (STZ); thus, the present study examined the role of the adrenal medullae in the development of experimental diabetes. Male Wistar rats were surgically adrenodemedullated (ADM) or sham-operated (SHAM). After a 3-week recovery period, they were injected with 40 mg STZ/kg freshly dissolved in citrate buffer or buffer alone. A 1-mL arterial blood sample was withdrawn 12 days later in previously cannulated animals; then the rats were killed and their pancreas was removed. The plasma glucose levels were lower in ADM rats injected with buffer alone than in their SHAM counterparts (7.7 ± 0.1 vs. 8.5 ± 0.1 mmol/L; p < 0.05). The glucose levels were higher (p < 0.001) in both groups of STZ-treated rats, with values 28% lower in ADM than in SHAM rats (14.7 ± 1.6 vs. 18.8 ± 1.2 mmol/L; p < 0.03). Whereas plasma insulin levels did not differ between ADM and SHAM rats injected with buffer alone (431 ± 38 vs. 428 ± 35 pmol/L; p > 0.05), they were diminished in SHAM animals injected with STZ (292 ± 37 vs. 428 ± 35 pmol/L; p < 0.02). However, ADM rats previously injected with STZ had insulin values higher than their SHAM counterparts (415 ± 34 vs. 292 ± 37 pmol/L; p < 0.03) and comparable with those of control animals. Pancreatic insulin content was greatly diminished (p < 0.001) by STZ in both ADM (20 ± 1 vs. 144 ± 1 μg) and SHAM (13 ± 1 vs. 166 ± 1 μg) animals. However, the pancreatic insulin content after STZ injection was greater in ADM than in SHAM rats (p < 0.05). Pancreatic glucagon content was higher in SHAM animals injected with STZ than in those injected with buffer alone (5.8 ± 0.4 vs. 4.5 ± 0.2 μg; p < 0.05). These results indicate that ADM rats appear to be more resistant to developing hyperglycemia after a single injection of STZ than SHAM animals, this being associated with a greater pancreatic insulin content. Overall, these observations suggests that the adrenal medullae may be involved in the development of experimental diabetes mellitus.Key words: diabetes, stress, rats, streptozotocin, adrenodemedullation.
The 1993 Merck Frosst Award. Acetyl-CoA carboxylase: an important regulator of fatty acid oxidation in the heart
Authors: Lopaschuk Gary D. , Gamble Jim
Published: April 2011

It has long been known that most of the energy production in the heart is derived from the oxidation of fatty acids. The other important sources of energy are the oxidation of carbohydrates and, to a lesser extent, ATP production from glycolysis. The contribution of these pathways to overall ATP production can vary dramatically, depending to a large extent on the carbon substrate profile delivered to the heart, as well as the presence or absence of underlying pathology within the myocardium. Despite extensive research devoted to the study of the individual pathways of energy substrate metabolism, relatively few studies have examined the integrated regulation between carbohydrate and fatty acid oxidation in the heart. While the mechanisms by which fatty acids inhibit carbohydrate oxidation (i.e., the Randle cycle) have been characterized, much less is known about how carbohydrates regulate fatty acid oxidation in the heart. It is clear that an increase in intramitochondrial acetyl-CoA derived from carbohydrate oxidation (via the pyruvate dehydrogenase complex) can downregulate β-oxidation of fatty acids, but it is not clear how fatty acid acyl group entry into the mitochondria is downregulated when carbohydrate oxidation increases. Recent interest in our laboratory has focused on the involvement of acetyl-CoA carboxylase (ACC) in this process. While it has been known for some time that malonyl-CoA does exist in heart tissue, and that it is a potent inhibitor of carnitine palmitoyltransferase 1 (CPT 1), it has only recently been demonstrated that an isoenzyme of ACC exists in the heart that is a potential source of malonyl-CoA. These findings led to the hypothesis that ACC may be an important regulator of myocardial fatty acid oxidation. We have recently provided evidence that heart ACC, via the production of malonyl-CoA, can regulate fatty acid oxidation. We believe that ACC represents a key enzyme in a feedback loop that decreases acyl-CoA transport into the mitochondria when carbohydrate oxidation rates are increased. It is possible that ACC may represent a novel and potentially important site for pharmacological intervention in pathological situations characterized by abnormal fatty acid metabolism. This review provides a brief overview of the regulation of myocardial metabolism followed by our recent studies that support the hypothesis that ACC has an important role in regulating the balance between carbohydrate and lipid metabolism in the heart.Key words: fatty acids, glucose, malonyl-CoA, carnitine palmitoyltransferase 1, myocardial ischemia.
Proximal tubular function in transgenic mice overexpressing atrial natriuretic factor
Authors: Sonnenberg H. , Honrath U. , Chong C. K. , Field L. J. , Veress A. T.
Published: April 2011

A transgenic mouse model in which atrial natriuretic factor (ANF) expression is targeted to the liver was used to study intrarenal adjustments to the chronically elevated hormone level. Such animals, designated TTR-ANF, are characterized by reduced arterial blood pressure but similar sodium excretion compared with nontransgenic siblings. Proximal tubular micro-puncture gave the following results: single-nephron filtration rate = 12.7 ± 1.1 vs. 15.6 ± 1.9 nL/min (TTR-ANF versus nontransgenic, ns); end-proximal tubular fluid/plasma concentration ratio of inulin = 1.93 ± 0.09 vs. 1.97 ± 0.15 (ns); fractional reabsorption of sodium = 45.5 ± 2.8 vs. 46.0 ± 3.8% (ns); fractional reabsorption of chloride = 33.6 ± 3.3 vs. 32.4 ± 4.1% (ns). These data indicate that life-long elevation of plasma ANF concentration was not associated with significant alteration in single-nephron filtration rate and proximal tubular function. We conclude that compensatory anti-natriuretic mechanisms, localized downstream from the proximal tubule, can prevent ANF natriuresis.Key words: micropuncture, single-nephron filtration rate, sodium chloride reabsorption.
Reduced oxygen consumption of brown adipocytes isolated from progesterone-treated rats
Authors: Abelenda M. , Castro C. , Venero C. , Puerta M.
Published: April 2011

It has been previously shown that responsiveness to noradrenaline is reduced in brown adipocytes isolated from estradiol-treated rats. The possibility that high plasma levels of progesterone could also alter adrenergic response was checked. The oxygen consumption of brown adipocytes isolated from control and progesterone-treated rats was monitored in basal conditions and in the presence of increasing concentrations of noradrenaline. In both situations, cells isolated from treated animals showed a lower respiratory rate than those from control animals. These results suggest that not only estradiol but also progesterone could modulate the adrenergic response of brown adipocytes. The study of α1- and β-adrenergic responses indicates that the β-response parallels the general reduction in oxygen consumption, although the α 1-response seems to be more deeply depressed. Estimation of cell number in brown fat depots indicates some hyperplasia induced by progesterone; this increase in cell number could counterbalance partially but not totally the decreased cellular oxygen consumption at the organ level.Key words: brown adipocytes, progesterone, noradrenaline, oxygen consumption, sympathetic nervous system.
Relaxation of smooth muscle
Authors: Stephens N. L. , Jiang H.
Published: April 2011

We have demonstrated that in dogs antigen sensitization results in alterations of contractile properties. These changes could account for the hyperresponsiveness reported in asthma. The failure of the muscle to relax could be another important factor responsible for maintaining high airway resistance. We therefore developed an index of isotonic relaxation, t1/2,CE (half time for relaxation that is independent of muscle load and initial contractile element length), for evaluation of the relaxation process. Because the maximum shortening velocity at 2 s but not at 10 s was greater in sensitized bronchial smooth muscle than that in controls, studies of relaxation were also undertaken at these two times. The mean half-relaxation time indicated by t1/2,CE showed no difference between sensitized and control muscles after 10 s of stimulation (8.38 ± 0.92 vs. 7.78 ± 0.93 s, means ± SE); however, it was prolonged significantly in the sensitized muscle only stimulated for 1 s (12.74 ± 2.5 s, mean ± SE) compared with the control (6.98 ± 1.01 s). During the late phase of isotonic relaxation, both groups showed an unexpected spontaneous increase in zero-load shortening velocity, which is an index of cross-bridge cycling rate. We conclude that (i) both contraction and relaxation properties of early normally cycling cross bridges are altered after sensitization and these changes may account for the hyperresponsiveness observed in asthmatics and (ii) the cross-bridge cycling rate increases spontaneously during isotonic relaxation, probably as a result of reactivation of the contractile mechanism.Key words: smooth muscle relaxation, isotonic relaxation, spontaneous activation in late relaxation, mechanisms for airway hyperresponsiveness, new index of muscle relaxation.
A model for the coregulation of smooth muscle actomyosin by caldesmon, calponin, tropomyosin, and the myosin regulatory light chain
Authors: Haeberle Joe R. , Hemric Mark E.
Published: April 2011

The purpose of these studies was to evaluate the effects of the actin-binding proteins tropomyosin, caldesmon, and calponin on the activation of smooth muscle actomyosin by phosphorylation of the regulatory light chain of myosin (LC20), and to interpret these findings in the context of a two-state kinetic model for the cross-bridge cycle. An in vitro motility assay was used to broadly classify each regulatory protein according to whether it modulates the apparent on-rate for cross bridges (fapp) or the apparent off-rate (gapp). In addition to measuring actin-filament velocity, a method was developed to measure relative changes in the force exerted on actin filaments under isometric conditions. Based primarily on the results of these motility studies, a qualitative model is proposed in which LC20 phosphorylation, tropomyosin, and caldesmon all regulate fapp and calponin regulates gapp. The model predicts that the sensitivity of activation by LC20 phosphorylation is determined by tropomyosin, caldesmon, and calponin, whereas unloaded shortening velocity is regulated primarily by calponin.Key words: smooth muscle, caldesmon, calponin, tropomyosin, motility assay.
Studies of acute effect of prolactin on distribution of absorbed calcium and long-term effect on calcium balance in weaned, young, and sexually mature rats
Authors: Krishnamra N. , Cheeveewattana V.
Published: April 2011

An acute effect of a single dose of 0.02 mg prolactin/100 g body weight administered intraperitoneally on distribution of absorbed calcium and the effect of daily subcutaneous injections of 0.25 mg prolactin/100 g body weight for 13 days on calcium balance were assessed in weaned, young, and mature female rats. The acute administration of prolactin failed to affect distribution of absorbed calcium at 2 h after instillation of test solution. In contrast, the daily injection of a lower dose of prolactin over 13 days significantly decreased fecal and urinary excretion of 45Ca, an index of absorbed calcium, in mature rats, while having no effect on muscle and tibial 45Ca contents. In young rats, in addition to a reduction in the urinary 45Ca excretion, prolactin decreased the gastrocnemius muscle total calcium content from 7.28 ± 0.37 to 5.58 ± 0.37 μmol/g dry weight (p < 0.01) while increasing tibial calcium content from 6.65 ± 0.18 to 7.35 ± 0.15 mmol/g dry weight (p < 0.01). Bone formation (represented by serum alkaline phosphatase) in weaned rats was significantly elevated by prolactin, but bone resorption (represented by urinary hydroxyproline) was not altered. It could be concluded that prolonged administration of prolactin decreased calcium excretion in mature rats and increased bone formation and tibial calcium content in growing rats.Key words: bone formation, bone resorption, calcium, calcium balance, prolactin.
Aromatic hydrocarbon receptor in cultured fetal cells from C57BL/6J and DBA/2J mice: similarity in molecular mass to receptors in adult livers
Authors: Huang Ying , Okey Allan B. , Harper Patricia A.
Published: April 2011

In liver of adult responsive C57BL/6J (B6) mice the aromatic hydrocarbon receptor (AHR) has high affinity for specific halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as well as nonhalogenated aromatic hydrocarbons (PAHs), such as benz[a]anthracene (BA) or 3-methylcholanthrene (MC). In livers of adult nonresponsive DBA/2J (D2) mice TCDD binds to a low-affinity variant form of AHR. Both TCDD and MC induce aryl hydrocarbon hydroxylase (AHH) in adult B6 mice, whereas adult D2 mouse liver is nonresponsive to MC. In fetal cell cultures derived from D2 mice AHH is induced by PAHs such as MC or BA, and these PAHs bind to cytosolic AHR (P.A. Harper, C.L. Golas, and A.B. Okey. Mol. Pharmacol. 40: 818–826, 1991). We compared AHR from fetal cell cultures with AHR from adult livers to determine whether there was some structural difference in receptors expressed in fetal cell culture that might permit cells from "nonresponsive" mice to respond to PAHs. The apparent molecular mass of AHR from cells cultured from 18-day fetuses is identical with that from adult liver within each strain of inbred mice tested (Mr~ 95 kDa in B6 and ~ 105 kDa in D2 mice). The AHR in D2 fetal cells was able to activate a transfected chloramphenicol acetyltransferase linked to a dioxin-responsive element nucleotide sequence (DRE–CAT) when the cells were treated with TCDD or MC. The potency of CAT expression in D2 fetal cells was similar to that in B6 fetal cells. Our data suggest that the responsiveness of fetal cells from "nonresponsive" mice is likely mediated by AHR in these cells but is not due to expression of a different allelic form of AHR ligand-binding subunit in fetal cells versus adult liver.Key words: aromatic hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, cultured fetal cells, C57BL/6J mice, DBA/2J mice.
Intraluminal pH modulates gastric prostaglandin synthesis
Authors: Curtis Glenn H. , Gall D. Grant , Wallace John L. , MacNaughton Wallace K.
Published: April 2011

Prostaglandins play an important role in modulating gastric mucosal integrity and in regulating gastric acid secretion, but little is known regarding regulation of prostaglandin synthesis by the stomach. We have therefore examined the effects of changes in gastric intraluminal pH on the capacity of gastric tissue to synthesize prostaglandin E2. Oral administration of solutions with a pH of 8.3 or 10 markedly reduced the capacity of the gastric tissue to synthesize prostaglandin E2, but did not affect synthesis of leukotriene B4. This phenomenon was observed in three strains of rats. Administration of the same solutions subcutaneously did not affect gastric prostaglandin synthesis. On the other hand, oral administration of a solution of pH 1 significantly increased prostaglandin synthetic capacity, while a solution with a pH of 3 had no effect. The effects observed were not attributable to differences in the osmolarity of the test solutions. These studies suggest that changes in gastric intraluminal pH result in changes in gastric prostaglandin synthesis. It is possible that this represents a physiological response aimed at maintaining gastric mucosal integrity when intraluminal pH is low, while also providing a feedback inhibition of gastric acid secretion.Key words: prostaglandin, stomach, acid, gastrin, cytoprotection.
Liver transplantation induces cytochrome P450 1A1 dependent monooxygenase activity in rat lung and kidney
Authors: Sinal Christopher J. , Bend John R. , Zhu Lin-Fu , Zhong Robert , Cherian M. George
Published: April 2011

Although liver transplantation has been the subject of intensive investigation, comparatively little is known regarding the effects of this procedure on the metabolism of xenobiotics. The objective of the present study was to examine the effect of orthotopic liver transplantation on rat hepatic, pulmonary, and renal microsomal cytochrome P450 (P450) monooxygenase activity through the use of isozyme-selective substrates. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufm O-deethylation (ERFD) activity increased over time in recipient rats, with maximal induction (750% of donor) observed after 21 days. Similarly, ERFD activity in renal microsomes was increased (200% of donor) after 21 days. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyresorufin O-depentylation (PRFD) activity was decreased (50 and 75% of donor) 1 day after transplantation but was essentially unchanged 3, 7, and 21 days after transplantation. Pulmonary and renal microsomal heme oxygenase activities were not significantly affected by liver transplantation. In contrast, total hepatic microsomal P450 concentrations were decreased maximally (to 45% of donor concentration) 7 days after transplantation and remained low (55% of donor) up to 21 days. Similarly, hepatic P450 1A dependent ERFD and P450 2B dependent PRFD activities were maximally depressed (20 and 25% of donor activities) after 7 days and remained low (75 and 30% of donor) up to 21 days after transplantation. The decreases in rates of hepatic P450 monooxygenation were accompanied by significant increases in microsomal heme oxygenase activity. The data presented in this study suggest the existence of generalized stress responses to inflammation that result in tissue- and isozyme-selective modulation of P450 monooxygenase activity. These responses most likely reflect complex interactions among multiple inflammatory mediators as well as perturbations in the levels of endogenous P450 substrates.Key words: cytochrome P450, orthotopic liver transplant, inflammation, heme oxygenase, lung, kidney, rat.
Circadian variations of adenosine and of its metabolism. Could adenosine be a molecular oscillator for circadian rhythms?
Authors: Sánchez Victoria Chagoya de
Published: April 2011

The present review describes the biological implications of the periodic changes of adenosine concentrations in different tissues of the rat. Adenosine is a purine molecule that could have been formed in the prebiotic chemical evolution and has been preserved. The rhythmicity of this molecule, as well as its metabolism and even the presence of specific receptors, suggests a regulatory role in eukaryotic cells and in multicellular organisms. Adenosine may be considered a chemical messenger and its action could take place at the level of the same cell (autocrine), the same tissue (paracrine), or on separate organs (endocrine). Exploration of the circadian variations of adenosine was planned considering the liver as an important tissue for purine formation, the blood as a vehicle among tissues, and the brain as the possible acceptor for hepatic adenosine or its metabolites. The rats used in these studies were adapted to a dark–light cycle of 12 h with an unrestrained feeding and drinking schedule. The metabolic control of adenosine concentration in the different tissues studied through the 24-h cycle is related to the activity of adenosine-metabolizing enzymes: 5′-nucleotidase adenosine deaminase, adenosine kinase, and S-adenosylhomocysteine hydrolase. Some possibilities of the factors modulating the activity of these enzymes are commented upon. The multiphysiological action of adenosine could be mediated by several actions: (i) by interaction with extracellular and intracellular receptors and (ii) through its metabolism modulating the methylation pathway, possibly inducing physiological lipoperoxidation, or participating in the energetic homeostasis of the cell. The physiological meaning of the circadian variations of adenosine and its metabolism was focused on: maintenance of the energetic homeostasis of the tissues, modulation of membrane structure and function, regulation of fasting and feeding metabolic pattern, and its participation in the sleep–wake cycle. From these considerations, we suggest that adenosine could be a molecular oscillator involved in the circadian pattern of biological activity in the rat.Key words: adenosine, circadian rhythm energy, membrane structure, sleep–wake cycle.
Phasic contractions of the muscular components of human esophagus and gastroesophageal junction in vitro
Authors: Preiksaitis Harold G. , Diamant Nicholas E.
Published: April 2011

This study was performed to assess the repetitive phasic mechanical and (or) electrical activity of the muscle from different regions of the human gastroesophageal junction (GEJ). Muscle strips from the circular and longitudinal layers of the gastric fundus and esophagus and of the clasp and sling components of the GEJ were obtained from surgical specimens and prepared for in vitro recording of contractile or electrical activity. Phasic contractions occurred in all regions except the longitudinal muscle of the gastric fundus and that overlying the sling. Robust phasic activity (2.6 ± 0.6 min−1) was most frequent (92% of specimens) in longitudinal muscle overlying the clasp, arising spontaneously in 67%. Stretch or carbachol stimulation increased the frequency of these contractions. Transmural electrical stimulation produced a transient cessation of phasic activity. Electrical recording showed slow waves with superimposed spiking coinciding with phasic contractions. These activities were unaltered by 1 μM atropine or 1 μM tetrodotoxin, but inhibited by 2 μM verapamil. In conclusion, several muscles of the human esophagus and GEJ manifest repetitive contractions in vitro, particularly the longitudinal muscle overlying the clasp muscle fibers. These oscillations are due to electrical slow waves, can potentially be modulated by intrinsic nerves, and may play a role in the intermittent phasic contractions of lower esophageal sphincter pressure in vivo.Key words: oscillators, myolgenic, cardia, pacemaker, lower esophageal sphincter.
Peripheral vascular smooth muscle responsiveness to tumour-promoting phorbol esters in pacing-induced heart failure
Authors: Forster Christine
Published: April 2011

Contractions of the dorsal pedal artery and saphenous vein to phorbol 12,13-dibutyrate (PDBu), 12-O-tetradecanoylphorbol 13-acetate (TPA), and 4α-phorbol 12,13-didecanoate (4α-phorbol) were measured from dogs with and without pacing-induced heart failure. The effects of polymyxin B (a relatively selective protein kinase C inhibitor), nifedipine (calcium channel blocker), and prazosin (α-adrenoceptor antagonist) were examined on the contractions developed to PDBu before heart failure, after 1 week of pacing, and at end-stage heart failure. PDBu and TPA, but not 4α-phorbol, produced concentration-dependent increases in contractile force in both the artery and the vein. In the dorsal pedal artery, efficacy of and sensitivity to PDBu and TPA were enhanced after 1 week of pacing, but returned to control level at end-stage heart failure. In the saphenous vein, the concentration–effect curve to PDBu was displaced to the left after 1 week of pacing; EC50 values for PDBu were 3.2 × 10−9 and 3.2 × 10−8 M for 1 week paced and control, respectively. Polymyxin B significantly decreased the efficacy of PDBu in the dorsal pedal artery at all time points, but was less effective with advancing heart failure. In contrast, in the vein, there was a significant increase in inhibitory potential at end-stage heart failure. In all cases, nifedipine inhibited PDBu in a concentration-dependent manner. With the progression of heart failure, the contractions of the saphenous vein, developed to PDBu, became more sensitive to inhibition by nifedipine. Prazosin failed to inhibit vascular effects of PDBu. These results are discussed in terms of protein kinase C involvement in vascular contractions and its role in the pathogenesis of heart failure.Key words: tumour-promoting phorbol esters, protein kinase C, polymyxin B, nifedipine, peripheral vascular contraction, experimental heart failure.
Exposure to ionizing radiation alters vasoreactivity in rat jejunum ex vivo
Authors: MacNaughton Wallace K. , Prud'homme-Lalonde Louise
Published: April 2011

The effect of ionizing radiation on jejunal blood flow was investigated in rats receiving whole-body exposure to 10 Gy γ-radiation. Irradiation resulted in increased myeloperoxidase activity, indicative of neutrophil infiltration, and prostaglandin E2 synthesis by 2 h post-irradiation, but had no effect on leukotriene B4 synthesis. In ex vivo intestinal chamber studies, exposure to radiation reversed the mucosal–submucosal blood flow changes elicited by intravenous administration of leukotriene C4 (1 μg∙kg−1∙min−1 for 10 min) or endothelin 1 (1 μg∙kg−1∙min−1 for 5 min), but not that elicited by topical capsaicin (100 or 640 μM), as measured by laser Doppler flowmetry. The effect of radiation on vascular responses to leukotriene C4, but not those to endothelin 1, was reversed by pretreatment of the rats with the cyclooxygenase inhibitor, indomethacin (5 mg/kg). There was no significant effect of irradiation on mean arterial pressure or on ion or protein effluxes into the chamber bathing solution, nor did irradiation alter transmural potential difference. These studies point to altered responsiveness of the jejunal mucosal–submucosal vasculature shortly after exposure to ionizing radiation. Changes in function could reflect the onset of an acute inflammatory response, and appear to have cyclooxygenase-dependent and -independent components.Key words: intestine, blood flow, inflammation, leukotriene, endothelin.
Baclofen-induced block of the Hering–Breuer expiratory-promoting reflex in rats
Authors: Trippenbach Teresa
Published: April 2011

Baclofen, a γ-aminobutyric acid (GABA) agonist acting on GABAB receptors, has profound effects on respiratory function. We tested a hypothesis that GABAB receptors are involved in modulation of the respiratory reflexes mediated by pulmonary slowly adapting stretch receptors. Urethane-anesthetized (1.2–1.6 g/kg; i.p.) Wistar rats with body weight 230–320 g were breathing room air supplemented with oxygen. The gas mixture was applied to the T-shaped tracheal cannula at a flow rate of 1.5 L/min. The head of the animals was mounted in a stereotaxic apparatus, and the medulla was exposed. We recorded integrated diaphragmatic EMG (Di) and tracheal and arterial blood pressures. Injections of 100 nL of saline into the nucleus tractus solitarii (NTS) preceded injections of 60 or 110 pmol baclofen in group 1 (n = 14), and 2.8 nmol CGP 35348, a GABAB receptor antagonist, in group 2 (n = 5). Saline had no effects on baseline Di. Occlusion of the tracheal cannula caused an increase in tracheal pressure to 8 cmH2O (1 cmH2O = 98.1 Pa) and provoked a prolongation of expiration (the Hering–Breuer expiratory-promoting reflex) in all drug-free rats. Baclofen abolished the Hering–Breuer reflex in all rats. CGP 35348 reversed the block of the reflex. In group 2, CGP 35348 prevented the effects of baclofen, and alone did not affect respiration. These results support our hypothesis and suggest that GABAB receptors are present on the medullary pathway of slowly adapting mechanoreceptor input. However, GABAB receptors in the rat NTS may not be involved in modulation of the fundamental respiratory function.Key words: nucleus tractus solitarii, vagal reflexes, baclofen, CGP 35348, rat.
Interaction between calcium and zinc on L-threonine absorption in rabbit jejunum
Authors: Rodríguez-Yoldi María-Carmen , Mesonero J. E. , Rodríguez-Yoldi María-Jesús
Published: April 2011

The essential minerals calcium and zinc serve unique functions in higher organisms, and it is well recognized that homeostatic mechanisms are involved in regulating their metabolism. However, it has been reported that zinc, at higher concentrations (1 mM), inhibits intestinal absorption of sugars and amino acids. The aim of the present work was to determine whether the inhibitory effect on L-threonine absorption across the rabbit jejunum could be modified by calcium. In media with Ca2+, zinc significantly reduced L-threonine absorption. In Ca2+-free media, where calcium chloride was omitted and replaced isotonically with choline chloride, the amino acid transport was not modified by zinc, but when calcium chloride was replaced isotonically with magnesium chloride, the inhibition was observed. Verapamil (blocking mainly Ca2+ transport) did not modify the inhibitory effect of zinc on L-threonine transport. When A23187 (Ca2+-specific ionophore) was added in media with and without Ca2+, zinc produced no change in L-threonine transport. These results suggest that calcium and zinc could have an affinity with the same chemical groups of the enterocyte membrane, which would be related to the intestinal absorption of amino acids.Key words: zinc, calcium, L-threonine transport, rabbit jejunum, verapamil, A23187.
Characterization of the vasorelaxant activity of tyramine and other phenylethylamines in rat aorta
Authors: Varma Daya R. , Deng Xing-Fei , Chemtob Sylvain , Nantel Francois , Bouvier Michel
Published: April 2011

We recently reported that tyramine caused concentration-dependent relaxation of rat aorta, which was endothelium independent and was not exerted via α1-adrenoceptors (AR), α2AR, β1AR, β2AR, or receptors for 5-hydroxytryptamine, histamine, and adenosine. The present studies were done on endothelium-denuded strips to determine structure – vasorelaxant activity after blockade of βAR by propranolol plus irreversible blockade of α1AR with benextramine. Vasorelaxation under these conditions was limited to noncatecholamines, and their vasorelaxant potencies were methoxyphenamine > tyramine > p-hydroxyephedrine > L-amphetamine > L-ephedrine > phenylethylamine > synephrine > methoxamine > octopamine. β3AR agonists (BRL 37344 and CGP 12177A) did not produce vasorelaxation, although tyramine could compete for cyanopindolol binding to murine L cells expressing human β2AR or β3AR. There was no significant specific binding of [3H]tyramine to aortic membrane preparations after the inhibition of monamine oxidase. Yohimbine, which has a high affinity for Drosophila tyramine receptors, also caused dose-dependent vasorelaxation like tyramine. It is concluded that tyramine and several other phenylethylamines produce relaxation of rat aorta, which does not involve any of the known adrenoceptors but may be exerted via novel tyramine receptors.Key words: tyramine, phenylethylamines, yohimbine, β3-adrenoceptors, vasorelaxation.
Inhibition of the response to nasal provocation with bradykinin by HOE- 140: efficacy and duration of action
Authors: Proud David , Bathon Joan M. , Togias Alkis G. , Naclerio Robert M.
Published: April 2011

The present studies were undertaken as a first step to evaluate the potential usefulness of the bradykinin antagonist HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis. Intranasal single-dose administration of HOE-140, at doses up to 500 μg, was safe and well tolerated. Bradykinin-induced symptoms and increased vascular permeability could be inhibited, in a dose-dependent manner, by preadministration of HOE-140 5 min prior to kinin challenge. The results of dose-ranging experiments suggested that bradykinin and HOE-140 were approximately equipotent at bradykinin receptors. Preadministration of HOE-140 2 h before kinin challenge caused a significant but much weaker level of inhibition than that seen with 5-min preadministration. Comparison of data with those obtained during dose-ranging studies suggested that more than 90% of the administered HOE-140 was lost during this 2-h period. We conclude that topical HOE-140 is an effective inhibitor of the effects of bradykinin on the nasal mucosa but that the short duration of action of this drug may severely limit the utility of HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis.Key words: rhinitis, airways, kinins, antagonists.
Receptors for calcitonin, calcitonin gene related peptide, amylin, and adrenomedullin
Authors: Muff Roman , Born Walter , Fischer Jan A.
Published: April 2011

Calcitonin, calcitonin gene related peptide, amylin, and adrenomedullin are structurally related polypeptides characterized by a six or seven amino acid ring structure linked by a disulfide bridge and an amidated C-terminus. They exhibit overlapping biological actions as a result of cross-reactivity between the different receptors. In this article, the respective receptors and G-protein-coupled postreceptor events are reviewed in relation to some of the biological actions of the peptides.Key words: adrenomedullin, amylin, calcitonin gene related peptide, cyclic AMP, receptors.
Calcitonin gene related peptide released from dural nerve fibers mediates increase of meningeal blood flow in the rat
Authors: Meßlinger K. , Hanesch U. , Kurosawa M. , Pawlak M. , Schmidt R. F.
Published: April 2011

The parietal dura mater encephali of the rat was shown by immunohistochemistry to be densely innervated by calcitonin gene related peptide (CGRP) immunoreactive nerve fibers spreading around the medial meningeal artery and its branches. Electrical stimulation of the dural surface (10–20 V, 5–10 Hz, 10–30 min) caused a depletion of CGRP-immunopositive fibers, suggesting a release of CGRP. The dural blood flow around branches of the medial meningeal artery was also monitored with a laser Doppler flowmeter. Short periods (30 s) of electrical stimulation with parameters that presumably released CGRP from nerve fibers caused a repeatable and constant increase of the blood flow for 1–2 min. This evoked increase could dose dependently be inhibited by topical application of the CGRP antagonist hCGRP8–37. Accordingly, administration of hCGRP increased the basal blood flow. We conclude that stimulation of trigeminal afferents innervating the dura mater releases CGRP from peptidergic afferent terminals, thereby causing vasodilatation and increasing the meningeal blood flow, an important element of neurogenic inflammation.Key words: dura mater encephali, afferent nerve fibers, calcitonin gene related peptide, immunohistochemistry, laser Doppler flowmetry.
Responses of human motoneurons to la inputs: effects of background firing rate
Authors: Jones Kelvin E. , Bawa Parveen
Published: April 2011

The effects of synchronous Ia volleys on the firing probability of repetitively firing human motoneurons were examined at fast and slow firing rates. Ia afferents of either the median or the posterior tibial nerve were stimulated, while single motor unit activity was recorded from the homonymous muscles. Motoneuron responses to the Ia inputs were quantified by measurement of the magnitude of the short latency excitatory peak in peristimulus time histograms (PSTHs). When the stimuli were given at random with respect to the times of motor unit spikes, the magnitude of the PSTH peak (response probability) was significantly lower at a faster firing rate. In the "triggered" mode of stimulation, stimuli were given at various known times during the interspike interval. In this mode the response probability to the input increased monotonically as the stimuli were delivered progressively later during the interspike interval. The response probability at a fixed delay with respect to the triggering spike was higher at the faster firing rate. The results obtained with the two modes of stimulation are not in contradiction and both may be explained by the nature of membrane voltage trajectories and ionic conductances during the interspike interval described for repetitively firing cat motoneurons.Key words: motor unit, H-reflex, flexor carpi radialis, soleus, afterhyperpolarization, excitatory postsynaptic potential.
Development and plasticity of the neural circuitry underlying visual recognition memory
Authors: Webster Maree J. , Ungerleider Leslie G. , Bachevalier Jocelyne
Published: April 2011

In adult monkeys, visual recognition memory, as measured by the delayed nonmatching to sample (DNMS) task, requires the interaction between inferior temporal cortical area TE and medial temporal lobe structures (mainly the entorhinal and perirhinal cortical areas). Ontogenetically, monkeys do not perform at adult levels of proficiency on the DNMS task until 2 years of age. Recent studies have demonstrated that this protracted development of visual recognition memory is due to an immaturity of the association areas of the neocortex rather than the medial temporal lobe. For example, lesions of the medial temporal lobe structures in infancy or in adulthood yield profound and permanent visual recognition loss, indicating that the medial temporal lobe structures operate early in life to sustain visual memory. In contrast, early lesions of area TE, unlike late lesions, result in a significant and long-lasting sparing of visual memory ability. Further evidence for neocortical immaturity is provided by studies of the development of opiatergic and cholinergic receptors, of the maturation of metabolic activity, and of the connectivity between inferior temporal areas TE and TEO and cortical and subcortical structures. Together these results indicate greater compensatory potential after neonatal cortical than after neonatal medial temporal removals. In support of this view, early damage to area TE leads to the maintenance of normally transient projections as well as to reorganization in cortical areas outside the temporal lobe. In addition, lesion studies indicate that, during infancy, visual recognition functions are widely distributed throughout many visual association areas but, with maturation, these functions become localized to area TE. Thus, the maintenance of exuberant projections together with reorganization in other cortical areas of the brain could account for the preservation of visual memories in monkeys that have had area TE removed in infancy.Key words: limbic structures, association cortex, amygdala, transient connections, compensatory potential.
Suppression of sympathetic nervous system is involved in hypotension and bradycardia during hemofiltration in anesthetized dogs
Authors: Hayashi Tetsuya , Shibamoto Toshishige , Yamaguchi Yoshihiro , Wang Hong-Gang , Tanaka Satoshi
Published: April 2011

Hypotension occurring during hemodialysis is often accompanied by paradoxical bradycardia. However, the mechanism is poorly understood. This study was designed to determine the role of the sympathetic nervous system in hemodialysis-induced hypotension and bradycardia. We measured efferent sympathetic nerve activities to the heart (CNA), kidney (RNA), liver (HNA), spleen (SpNA), and adrenal gland (AdNA), along with heart rate (HR), blood pressure (BP), central venous pressure (CVP), and left atrial pressure (LAP) during hemofiltration performed at a rate of 0.3 mL∙kg−1∙min−1 for 30 min in anesthetized dogs. The response to hemorrhage was also studied at the same bleeding speed. Hemorrhage caused a decrease in BP (−18 ± 1 mmHg; 1 mmHg = 133.3 Pa) with reflex increases in HR (7 ± 2 beats/min) and sympathetic nerve activities. In contrast, hemofiltration caused a decrease in CNA (85 ± 18%), HNA (86 ± 11%), and SpNA (88 ± 11%) with greater decreases in BP (−43 ± 10 mmHg) and HR (−27 ± 14 beats/min) than hemorrhage. During hemofiltration, the decreases in BP, HR, CNA, HNA, and SpNA were attenuated after vagotomy. Hematocrit increased by 6.5% at 30 min after hemofiltration, whereas it decreased by 4.3% after hemorrhage. These results suggest that hemofiltration suppresses the sympathetic nervous system, resulting in decreases in HR and BP. Furthermore, this sympathetic suppression during hemofiltration is mediated by vagal afferents.Key words: hemodialysis, baroreceptor reflex, sympathetic nerve activity, hemorrhage, vagus nerve.
Diurnal variation of intensive running in food-deprived rats
Authors: Morse Allen D. , Russell James C. , Hunt Terry W. M. , Wood George O. , Epling W. Frank , Pierce W. David
Published: April 2011

Manipulation of the food supply can induce either intense hyperactive wheel running or a fatal activity anorexia in rats that is strongly analogous to that seen in humans. The abnormal behaviour is accompanied by alterations in the diurnal pattern of activity. As part of a detailed study of hyperactivity and anorexia, spontaneous wheel running by male rats was studied under three conditions: ad libitum feeding; restriction to 15 g of food per day; and restriction to a single 90-min meal per day. Ad libitum fed rats increased their running at the rate of 440 ± 60 m/day per day, stabilizing after day 10 at 6045 ± 3010 m/day. The running occurred in short bursts throughout the dark period and at the beginning of the light period. Rats restricted to 15 g/day increased their running at the significantly greater (p < 0.001) rate of 1230 ± 120 m/day per day, reaching 12 200 ± 4090 m/day by day 10 and thereafter stabilizing at 13 600 ± 4 160 m/day. The running was initially triphasic and confined to the dark period but eventually progressed to a biphasic pattern. The rats restricted to a single 90-min access period to food each day showed an even greater rate of increase in running, attaining 1930 ± 288 m/day per day (p < 0.02 vs. 15 g/day group). These animals decreased eating and decompensated by day 4. The diurnal pattern of activity was disturbed from day 1 of the protocol, and by day 4 the rats ran essentially continuously throughout the daily cycle. The sensitivity to hyperactivity is a function of the severity of food restriction in this animal model of hyperactivity. It is paralleled by a marked disturbance of the diurnal pattern of activity, suggesting that the hyperactivity is related to a basic central nervous system dysfunction.Key words: hyperactivity, diurnal variation, rat.
Cellular mechanisms involved in brain ischemia
Authors: Sweeney Marva I. , Waiz Wolfgang , Yager Jerome Y. , Juurlink Bernhard
Published: April 2011

Cellular mechanisms, both destructive and protective, that are associated with cerebral ischemia are reviewed in this paper. Central to understanding the evolution of stroke are the concepts of ischemic core and surrounding penumbral region damage, delayed neuronal death, and neuronal rescue. The role of spreading depression in the evolution of subsequent ATP depletion, ion shifts, glutamate release, activation of glutamate receptors, intracellular Ca2+ changes, and generation of reactive oxygen species in the penumbra in relationship to neuronal and glial cell damage are discussed. We conclude that the most fruitful areas for future stroke research include traditional approaches as well as novel approaches. Traditional approaches include stroke prevention and examination of the effects of combinations of proven and promising effective therapeutic interventions. Novel approaches include delineating mechanisms whereby growth factors and compounds such as deprenyl and staurosporine afford neuroprotection, ultimately leading to direct manipulation of the signal transduction pathways that lead to neuronal dysfunction and death. This includes determining which genes are activated and repressed in specific response to hypoxia–ischemia and determining how such alterations in gene expression affect survival and function of neurons. We also suggest that advantage be taken of the blood–brain barrier compromise during stroke in designing neuroprotective therapies.Key words: development and ageing, free radicals, neural protection, signal transduction, spreading depression, stroke.
Uniform characterization of potentiation in simple and complex situations when agents bind to different molecular sites
Authors: Pöch G. , Köck P. , Reiffenstein R. J. , Pancheva S. N.
Published: April 2011

There is general agreement about potentiation in dose–response studies, characterized by a left shift of the dose–response curve of A by a fixed dose of B when B is causing no effect by itself (simple situation). When B causes an effect similar to A (complex situation) by binding to different molecular sites, we propose an analogous analysis. This approach is based on comparison of experimental effects of A and B in combination with theoretical, independent effects, representing an effect of A that is not affected by B. We argue here that comparison of experimental effects with those of dose-additive (additive) combinations is inappropriate. Theoretical considerations and several practical examples show that the magnitude of effects due to additive combinations widely varies with the slope of dose–response curves of A. Consequently, it is also shown that one and the same theoretical effect may appear overadditive, additive, or underadditive. These situations are demonstrated by the experimental examples: inhibition of cytopathic effects in virus-infected cells, loss of righting reflex in mice, and smooth muscle relaxant effects of organic solvents.Key words: dose–response curves, ED50, slope, independent effects, enhancement.
Functional evidence for the involvement of GABAA receptors in cholecystokinin-induced ileal contraction
Authors: Alican İ. , Yeğen B. Ç. , Oktay Ş. , Ulusoy N. B.
Published: April 2011

To determine the role of GABAergic neurotransmission in cholecystokinin octapeptide (CCK-8) induced contraction of the guinea pig ileal longitudinal muscle – myenteric plexus preparation, CCKA or CCKB receptors were protected by L 364,718 and L 365,260, respectively. GABAA receptors were protected with bicuculline and the remainder of the receptors were inactivated by N-ethylmaleimide. Following the specific treatments isometric contractions in response to CCK-8 (0.1 nM – 1.0 μM) were obtained. CCKB receptor protection alone abolished responses to CCK-8. Additional GABAA receptor protection restored the responses. CCKA receptor protection alone decreased contractile responses to CCK-8, and additional protection of GABAA receptors resulted in restoration of the contractile responses at high concentrations of CCK-8. The results suggest that the CCKA and CCKB receptors that mediate the contractile action of CCK differ with regard to GABAergic neurotransmission. CCKB receptors appear to be dependent upon intact GABAergic neurotransmission, whereas CCKA receptors partially utilize this pathway.Key words: cholecystokinin receptors, L 364,718, L 365,260, GABAA receptors, PD 135 158, ileum, cholecystokinin antagonists.