bluuebunny/crossref_metadata_2025 huggingface dataset:
Zinc deficiency impairs whole body accumulation of polyunsaturates and increases the utilization of [1-14C]linoleate for de novo lipid synthesis in pregnant rats
Authors: Cunnane S. C. , Yang J.
Published: April 2011

Zinc deficiency impairs the metabolism of polyunsaturates, but the degree to which its effects are independent of food intake are still in question. Identical amounts of a semiliquid control diet (26.4 mg zinc/kg) or moderately zinc deficient diet (3.2 mg zinc/kg) were tube fed to rats for 11 days during the second half of pregnancy to evaluate the specific effects of zinc deficiency on maternal utilization and fetal accumulation of polyunsaturates. The whole body fatty acid balance method was used to determine net accumulation of polyunsaturates and their whole-body disappearance. Incorporation of14C from [1-14C]linoleate into maternal and fetal lipid classes was also studied on days 20–21. At term, zinc-deficient rats had significantly higher whole-body disappearance of linoleate and α-linolenate and lower accumulation of n−6 and n−3 long-chain polyunsaturates. Zinc-deficient rats had higher14C activity in free cholesterol, saturates, and monounsaturates in several maternal organs but not in the fetuses. We conclude that during pregnancy, moderate zinc deficiency not affecting food intake or weight gain still alters whole-body metabolism of linoleate and α-linolenate towards increased β-oxidation and also increases the utilization of carbon from linoleate for de novo lipid synthesis.Key words: cholesterol, linoleate, α-linolenate, oxidation, polyunsaturates, pregnancy, zinc.
Phase II enzymes and bioactivation
Authors: Hinson Jack A. , Forkert Poh-Gek
Published: April 2011

A colloquium entitled Phase II enzymes and bioactivation was held during the 10th International Symposium on Microsomes and Drug Oxidations in Toronto, Ont., on July 20, 1994. This colloquium was a tribute in recognition of the contributions by Dr. James R. Gillette in advancing our understanding of drug metabolism and chemical toxicity. A major focus of the colloquium was formation of conjugates such as those with glutathione (GSH) that may not lead to detoxification but to bioactivation. The GSH conjugates may be further metabolized to reactive species that cause toxicity. The nephrotoxicity of hydroquinone and bromobenzene is mediated via quinine–glutathione conjugates, and is manifested in cellular changes, including induction of the gadd-153 and hsp-70 mRNA. The formation of GSH conjugates is also involved in the bioactivation of the vicinal dihalopropane 1,2-dibromo-3-chloropropane; cytotoxic lesions are observed in the kidney and testes. The evidence indicates that conjugation is mediated by the GSH S-transferases. The symposium also covered aspects of the importance of conjugation in the pharmacokinetics of certain drugs. Conjugation reactions including sulfation are markedly influenced by the manner in which the liver processes the drug. Characteristics such as erythrocyte binding, as in the case of acetaminophen, become limiting factors in the conjugation reactions. Conjugation reactions can lead to a different outcome, such as acquired drug resistance. Conjugation of metallothioneins with the alkylating mustard drugs melphalan and chlorambucil can lead to the formation of protein adducts. Conjugation of reactive intermediates with these small molecular weight proteins may be considered as a phase II reaction and a mechanism of detoxification. A different pathway for the metabolism of xenobiotics is catalyzed by the carboxylesterases, a family of enzymes that is involved in hydrolysis of chemical compounds, generally leading to detoxification. Three rat esterases have been purified, cloned, and characterized. Two forms, hydrolase A and hydrolase B, are present in liver microsomes in a number of species, including the human. These are also detected in extrahepatic tissues. A third esterase, hydrolase S, is found in rat liver microsomes and rat serum, and may be a serum carboxylesterase secreted from the liver. A better knowledge of esterases will advance our understanding of pharmacokinetics and mechanisms of the effects of chemicals such as phenacetin and acetaminophen, two drugs that Dr. Gillette has worked with extensively. The data presented herein reflect the new and innovative approaches that have been adopted to investigate various aspects of chemical toxicity and drug metabolism. These data also indicate that significant insights are likely to come from integrated approaches utilizing established toxicological techniques together with those from other disciplines, including molecular biology and analytical chemistry.Key words: drug metabolism, drug disposition, toxicity, conjugation.
Antihypertensive effect of corilagin in the rat
Authors: Cheng Juei-Tang , Lin Ta-Chen , Hsu Feng-Lin
Published: April 2011

The antihypertensive effect of corilagin, one of the ellagitannins purified from the seeds of Euphoria longana Lam. (Sapindaceae), was investigated in the spontaneously hypertensive rat (SHR). Administration of corilagin into conscious SHR at 5 mg/kg produced an antihypertensive effect equivalent to that induced by 1 mg/kg of guanethidine. This dose-dependent hypotensive effect was comparable with that observed in anesthetized SHR animals. Corilagin did not modify the baroreflex sensitivity in phenylephrine-challenged SHR. Corilagin reduced plasma noradrenaline in a dose-dependent fashion, an effect that was maintained in adrenalectomized rats. Failure of the antagonists for α2-adrenoceptors, idazoxan and yohimbine, as well as for dopamine receptors, haloperidol and domperidone, to reverse the antihypertensive actions of corilagin ruled out the participation of these receptors. Moreover, corilagin attenuated the pressor effects of methoxamine and Bay K8644 to a similar degree, indicating the direct effect of corilagin on vascular activity in rats. These results suggest that corilagin possesses the ability to lower blood pressure through the reduction of noradrenaline release and (or) direct vasorelaxation.Key words: corilagin, antihypertension, noradrenaline release, vasorelaxation.
Age-related changes in electrophysiological responses to muscarinic receptor stimulation in rat myocardium
Authors: Su N. , Duan J. , Moffat M. P. , Narayanan N.
Published: April 2011

Recent studies have demonstrated that the negative chronotropic and inotropic responses of the heart to cholinergic muscarinic receptor stimulation are strikingly enhanced with aging in the rat model. The present study investigated the electrophysiological basis of this phenomenon by determining the effects of a muscarinic receptor agonist, carbachol, on transmembrane action potential parameters in right atrial tissue and right ventricular free wall preparations from adult (6–8 months old) and aged (26–28 months old) Fischer 344 rats. In addition, the effect of carbachol on atrioventricular conduction time (AVT) was determined in isolated perfused beating hearts. The results showed the following. The baseline maximum diastolic potential (MDP: adult, −76.4 ± 1.8 mV; aged, −66.8 ± 1.5 mV; p < 0.05; n = 5) but not the action potential duration measured at 95% repolarization (APD95: adult, 40.0 ± 5.0 ms; aged, 47.4 ± 6.7 ms; n = 5) differed significantly in aged compared with adult atrium. No significant age-related difference was evident in baseline MDP measured in ventricular epicardium (adult, −69.8 ± 0.5 mV; aged, −69.0 ± 1.1 mV; n = 6) or endocardium (adult, −72.5 ± 1.4 mV; aged, −73.0 ± 1.2 mV; n = 6). The baseline action potential duration measured at 50% repolarization (APD50) differed significantly with age in ventricular endocardium (adult, 11.6 ± 2.2 ms; aged, 23.0 ± 4.6 ms; p < 0.05; n = 6) but not in epicardium (APD50: adult, 8.1 ± 0.4 ms; aged, 13.0 ± 2.3 ms; n = 6). Superfusion with carbachol (0.1 nM – 10 μM) resulted in concentration-dependent hyperpolarization of MDP in atrium; the magnitude of hyperpolarization differed significantly with age (2.5-fold higher in the aged; p < 0.05; n = 5). Carbachol caused concentration-dependent shortening of APD50; this effect differed significantly with age in the ventricle (2-fold greater in the aged; p < 0.05; n = 6) but not in the atrium. Carbachol prolonged the AVT in atrial-paced (240 beats/min) hearts; the magnitude of carbachol-induced increase in AVT did not differ significantly with age. These results are consistent with the possibility that in the aging heart, greater hyperpolarization at the level of the right atrium (likely involving pacemaker cells) and greater shortening of APD50 at the level of ventricular myocytes may contribute to the enhanced cholinergic-triggered bradycardia and negative inotropic response, respectively.Key words: aging heart, action potential, cholinergic responses, carbachol.
Age of rat influences isolation of jejunal enterocytes from along the villus
Authors: Keelan M. , Wierzbiciki E. , Doring K. , Thomson A. B. R.
Published: April 2011

Aging is associated with alterations in the functions of the intestine. Also, the functions of the intestine vary along the length of the villus. A method is reported for the isolation of four fractions of enterocytes from along the villus of young (3 months, 300–350 g) and old (8 months, 700–750 g) male Wistar rats. Different qualitative patterns are seen when the activities of alkaline phosphatase (AP), invertase (INV), or [3H]methylthymidine incorporation are expressed on the basis of millimoles per gram protein, percentage of highest activity, percentage of total activity, cumulative activity for each fraction, or millimoles per gram protein versus cumulative percentage of total protein. When expressed on the basis of protein, AP is higher in upper (FI) versus lower (FIV) villus fractions, and in each fraction AP is higher in old versus young animals. INV varies little along the villus or between young and old rats; [3H]methylthymidine incorporation is highest in the crypt cells. The ratio mg protein/mg DNA varies along the villus and is twofold higher in young than in old rats. In contrast, when activities are expressed on the basis of DNA, the same qualitative patterns are seen along the villus, but INV and AP are both higher in young than in old rats. In summary (i) the qualitative and quantitative differences in the activities of AP and INV along the villus of old versus young rats vary when the data are expressed on the basis of DNA rather than protein; (ii) the ratio of protein to DNA varies along the villus in young and old animals, and for this reason it is appropriate to report enzyme activity on the basis of enterocyte DNA; and (iii) INV and AP, when expressed on the basis of DNA, are higher in young than in old animals. Thus, the isolation of rat jejunal enterocytes from along the villus is affected by the age of the animals.Key words: alkaline phosphatase, brush border membrane vesicles, crypt–villus axis, invertase, rat jejunum, techniques, thymidine kinase.
Involvement of cyclooxygenase 2 (COX-2) in intrinsic tone of isolated guinea pig
Authors: Charette L. , Misquitta C. , Guay J. , Riendeau D. , Jones T. R.
Published: April 2011

Indomethacin and related nonsteroidal anti-inflammatory drugs relax prostanoid-dependent intrinsic tone of isolated guinea pig trachea by inhibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX-2) was discovered, which differed from COX-1 with respect to protein structure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselectively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibitor of COX-2. In the present study we compared the activity of a selective (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrinsic tone of isolated guinea pig trachea. NS-398 ≥ indomethacin produced a reversal of intrinsic tone with a similar concentration-dependent (10 nM to 1 μM) time course (Tmaxapproximately 20–45 min), potency (EC501.7 and 5.6 nM, respectively), and maximal response. Contractions to cholinergic nerve stimulation (45 V, 0.5 ms, 0.1–32 Hz) and histamine were similarly modulated in tissues relaxed with the selective or nonselective COX-2 inhibitors. Immunoblot analyses showed that COX-2 protein synthesis was induced in both the cartilage and smooth muscle portions of the trachea during changes in intrinsic tone. These findings are consistent with pharmacological results and provide the first demonstration that prostanoid tone in isolated guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likely related to COX-2 inhibition.Key words: cyclooxygenase 2, relaxation, guinea pig trachea, cyclooxygenase 1.
Kinin B1and B2receptors in the mouse
Authors: Allogho S. Nsa , Gobeil F. , Pheng L. H. , Nguyen-Le X. K. , Neugebauer W. , Regoli D.
Published: April 2011

A systematic study has been performed in various segments of the intestine and in the urinary bladder of the mouse to identify tissues that respond to kinins and possess B1and (or) B2receptors. The stomach was found to contain B1and B2functional sites that show pharmacological profiles compatible with B1and B2receptors, whereas the urinary bladder possesses only B2sites. Myotropic responses mediated by B1receptors show slow onset and reversibility compared with responses evoked by the activation of B2receptors. The order of potency of agonists is bradykinin (BK) ≥ [Hyp3]BK > [Aib7]BK on the B2of both the stomach and urinary bladder, while desArg9-BK is inactive. The order of potency of agonists on the B1receptor is [Lys]desArg9BK ≤ desArg9BK, while BK and the other B2agonists are inactive. B2antagonists of the first generation, such as DArg[Hyp3,DPhe7]BK, act as partial agonists and show residual agonistic activities higher than 0.5, while HOE-140 shows high affinity and very little residual agonistic activity; WIN 64338 is almost inactive. On the B1receptor, classical antagonists, such as [Leu8]desArg9BK and Lys[Leu8]desArg9BK, act as partial agonists. A modification of their structures has led to a new compound (R-715) that shows fairly high affinity (pA27.0) and little residual agonistic effect. This compound has been used for B1receptor characterization in the stomach. Residual agonistic activities of both B2and B1antagonists appear to be mediated by B2and B1receptors, respectively. Data presented in this paper provide the pharmacological basis for sensitive and selective preparations to be used for studying B1and B2receptors in the mouse.Key words: mouse, stomach, urinary bladder, bradykinin, B1and B2receptors, antagonists.
Effect of endurance training on muscle activation and force sensation
Authors: Cafarelli E. , Liebesman F. , Kroon J.
Published: April 2011

One of the consequences of endurance training is a reduction in force sensation in trained muscles at any exercise intensity. To study the central and peripheral contributions to this adaptation, we trained six male subjects with single-leg cycling at 60% [Formula: see text] peak (30 min/day × 3 days/week × 8 weeks); six others were matched controls. Measurements were made during separate 20-min, single-leg rides at 70% pre-training [Formula: see text] peak, with trained (TR), untrained (UT), and control (CT) legs, before and after training. No pre–post differences were observed in the control group. [Formula: see text] peak increased 18% (p < 0.05) in the TR leg and 6% (p < 0.05) in the UT leg of the trained subjects. Force sensation was significantly less in both the TR (70%; p < 0.05) and UT (50%; p < 0.05) legs during 20 min of single-leg cycling after training. Vastus lateralis EMG, plasma lactate, and heart rate were all significantly (p < 0.05) lower when cycling with either the TR or UT leg, which were both lower than when cycling with the CT leg, at the end of each 20-min ride. These data reflect an intramuscular environment that is better adapted to endurance performance by virtue of both central and peripheral mechanisms. Thus, there is less need to recruit additional motor units to maintain the same power output, and this reduced motor outflow leads to a decline in force sensation.Key words: kinesthesia, proprioception, electromyography, single-leg training, endurance training.
Effects of short-term exposure to hydroxyflutamide in utero on the development of the reproductive tract in male mice
Authors: Silversides David W. , Price Christopher A. , Cooke Gerard M.
Published: April 2011

To determine if and when short-term ablation of androgen action compromises the development of the male reproductive tract in mice, the androgen receptor antagonist hydroxyflutamide was administered orally to pregnant FVB/N mice and the reproductive tracts of the male offspring were examined when adult. Hydroxyflutamide (30 mg per day) for 5 days from day 11 to day 15 of gestation caused hypospadias in all male progeny. However, testis weights, seminal vesicle weights, and serum testosterone levels were not affected (p > 0.05) but caput–corpus epididymal weights were 15% lower than controls (p < 0.02). Shorter periods of treatment that included day 14 or 15 caused hypospadias, but treatments that did not include days 14 and 15 did not (p < 0.002). Hydroxyflutamide (30 mg, once or twice daily for 2 consecutive days) between days 15 and 20 of gestation demonstrated that androgen ablation on days 15&16 caused hypospadias, absence of prostate, and scrotal location of the seminal vesicles with abdominal testes (p < 0.05). Males exposed later in pregnancy had prostates, but the weights were reduced (p < 0.001); testes were scrotal and seminal vesicles were abdominal; caput–corpus epididymal weights were 15–30% lower than controls (p < 0.05), but the tubule contained large numbers of spermatozoa. Furthermore, testis weights, serum testosterone, and the response of the testis to a human chorionic gonadotropin (hCG) challenge in vitro were not compromised by hydroxyflutamide, and seminiferous tubules exhibited normal spermatogenesis. When males that had been exposed to hydroxyflutamide on days 13&14, 15&16, 17&18, and 19&20 were housed with sexually mature females, pregnancies resulted only from the day 19&20 treatment group. Thus, there are long-term effects caused by short-term blockade of androgen action at critical times during pregnancy and such effects could result in the inability to impregnate, irrespective of any externally visible indications of developmental anomalies.Key words: antiandrogen, sexual development, fetus, male, mouse.
Mechanical and electrophysiological effects of a hydroxyphenyl-substituted tetrahydroisoquinoline, SL-1, on isolated rat cardiac tissues
Authors: Chang Gwo-Jyh , Su Ming-Jai , Lee Pei-Hong , Lee Shoei-Sheng , Liu Karin Chiung-Sheue
Published: April 2011

The mechanisms of the positive inotropic action of a new synthetic tetrahydroisoquinoline compound, SL-1, were investigated in isolated rat cardiac tissues and ventricular myocytes. SL-1 produced a rapidly developing, concentration-dependent positive inotropic response in both atrial and ventricular muscles and a negative chronotropic effect in spontaneously beating right atria. The positive inotropic effect was not prevented by pretreatment with reserpine (3 mg/kg) or the α-adrenoceptor antagonist prazosin (1 μM), but was suppressed by either the β-adrenoceptor antagonist atenolol (3 μM) or the K+ channel blocker 4-aminopyridine (4AP, 1 mM). In the whole-cell recording study, SL-1 increased the plateau level and prolonged the action potential duration in a concentration-dependent manner and decreased the maximum upstroke velocity [Formula: see text] and amplitude of the action potential in isolated rat ventricular myocytes stimulated at 1.0 Hz. On the other hand, SL-1 had little effect on the resting membrane potential, although it caused a slight decrease at higher concentrations. Voltage clamp experiments revealed that the increase of action potential plateau and prolongation of action potential duration were associated with an increase of Ca2+ inward current (ICa) via the activation of β-adrenoceptors and a prominent inhibition of 4AP-sensitive transient outward K+ current (Ito) with an IC50 of 3.9 μM. Currents through the inward rectifier K+ channel (IKl) were also reduced. The inhibition of Ito is characterized by a reduction in peak amplitude and a marked acceleration of current decay but without changes on the voltage dependence of steady-state inactivation. In addition to the inhibition of K+ currents, SL-1 also inhibited the Na+ inward current (INa) with an IC50 of 5.4 μM, which was correlated with the decrease of [Formula: see text]. We conclude that the positive inotropic effect of SL-1 may be due to an increase in Ca2+ current mediated via partial activation of β-adrenoceptors and an inhibition of K+ outward currents and the subsequent prolongation of action potentials.Key words: SL-1, tetrahydroisoquinoline, inotropic and chronotropic action, action potential, Na+, Ca2+, and K+ currents.
Regional differences in vasculotoxic effects of cyclosporin in rats
Authors: Verbeke Marleen , Ridder Leo de , Voorde Johan Van de , Lameire Norbert
Published: April 2011

Studies on cyclosporin-induced vasculotoxicity often yielded discrepant results, possibly as a result of differences in study protocols. The aim of the present study was to analyse cyclosporin-induced vasculotoxicity in arteries of different size and origin. Therefore, rats were treated with cyclosporin, 20 mg∙kg−1∙day−1, by gastric gavage for 10 days. In our previous studies, this treatment schedule induced renal functional impairment in vivo and an impaired relaxation response of thoracic aortic rings in vitro. Relaxation of various arteries (thoracic and abdominal aorta and carotid, renal, and interlobar arteries) from cyclosporin-treated and control rats in response to endothelium-dependent and -independent vasodilators was analysed. The thoracic aorta showed diminished endothelium-dependent and -independent relaxations; in the abdominal aorta no impairment was observed. Moreover, the dysfunction of the thoracic aorta seemed to be homogeneous along its length and showed an abrupt termination at the level of the diaphragm. In all other segments studied, no impairment of the relaxation responses was found. A similar pattern of vascular damage was found in rats treated with a very toxic cyclosporin treatment (50 mg∙kg−1∙day−1 s.c. × 7 days). The results indicate regional differences in cyclosporin-induced vasculotoxicity. The thoracic aorta, and in view of the fall of the renal blood flow, most likely also the renal resistance vessels, could be more susceptible than other vessels to cyclosporin-induced vascular dysfunction.Key words: cyclosporin, rat, arteries, vasorelaxation.
The 1994 Veylien Henderson Award of the Society of Toxicology of Canada. Mechanisms in the pathogenesis of amiodarone-induced pulmonary toxicity
Authors: Massey Thomas E. , Leeder Randall G. , Rafeiro Elizabeth , Brien James F.
Published: April 2011

Although amiodarone is a highly efficacious antidysrhythmic agent, the drug produces numerous adverse effects. The most critical of these is pulmonary toxicity because of the potential for mortality. This review examines the experimental model systems used to study amiodarone toxicity, summarizes the current state of knowledge regarding the processes involved in amiodarone-induced pulmonary toxicity (AIPT), and includes a discussion of potential future directions. Possible contributing processes to initiation of AIPT include phospholipidosis, altered calcium ion regulation, generation of reactive oxygen species, formation of an amiodarone aryl radical, and perturbation of cellular energy production. In addition, an immune response to the parent compound or to a metabolite could play a role. It is expected that elucidation of the mechanism(s) of AIPT will lead to safer antidysrhythmic agents and (or) to effective treatments for the prevention or amelioration of AIPT.Key words: amiodarone, pulmonary fibrosis, oxidative stress, pulmonary toxicity, pneumonitis.
Possible role of protein kinase C in regulation of 5-hydroxytryptamine 2A receptors in rat brain
Authors: Rahimian Roshanak , Hrdina Pavel D.
Published: April 2011

This study was undertaken to evaluate the effect of acute in vivo treatment with 1-(2,5-dimethoxy-4-iodo-phenyl)2-aminopropane (DOI), a selective 5-hydroxytryptamine 2A/2C (5HT2A/2c) receptor agonist, on the kinetic parameters of [3H]ketanserin binding to 5HT2A receptors and on the protein kinase C (PKC) activity in subcellular fractions of rat brain tissue. A single injection of DOI (10 mg/kg i.p.) downregulated (by 50%) 5HT2A receptor density in a cortical synaptosomal preparation assayed 24 h later. This effect was dose dependent, since a single injection of 5 mg/kg of DOI reduced the Bmax of [3H]ketanserin binding by 23% (without a change in Kd) and a single 1 mg/kg dose of DOI was without effect. Repeated doses of DOI (10 mg/kg for 3 days) further downregulated (by 63%) 5HT2A sites in cortical synaptosomes. A similar degree (50%) of downregulation of 5 HT2A receptors by DOI (10 mg/kg) was seen in p-chloroamphetamine (PCA) lesioned rats, suggesting that the site of action of DOI in downregulation of 5HT2A receptors in rat brain is postsynaptic. An increase (by 38%) of PKC activity in the particulate fraction of the cortical synaptosomal preparation following a single injection of DOI (10 mg/kg) paralleled the decrease in 5HT2A receptor density, suggesting that 5HT2A sites may be downregulated as a result of phosphorylation of the receptor by activation of PKC after receptor stimulation with agonist. This possibility is further supported by the observation that three consecutive daily injections of DOI resulted in a significant decrease (by 19%) in cytosolic PKC activity and an increase (by 24%) of PKC activity in the particulate fraction. A single injection of DOI also induced a translocation of PKC activity from the cytosolic to the membrane fraction in PCA-lesioned rats. The present investigation has shown that downregulation of 5HT2A receptors in rat cerebral cortex by in vivo DOI treatment is accompanied by translocation of PKC activity from the cytosolic to the membrane fraction.Key words: protein kinase C, 5-hydroxytryptamine 2A/2C (5HT2A/2C) receptor, 1-(2,5-dimethoxy-4-iodo-phenyl)2-aminopropane, p-chloroamphetamine, rat cerebrocortical synaptosomes.
Responses of gull kidneys and salt glands to NaCl loading
Authors: Hughes Maryanne R.
Published: April 2011

Glomerular filtration rate was measured in Glaucous-winged Gulls, Larus glaucescens, acclimated to freshwater or saline and was also measured (along with salt gland secretion) following intravenous and intragastric infusion of 700 mM sodium chloride (NaCl). Freshwater- and saline-acclimated gulls had the same mean glomerular filtration rate, 5.6 ± 0.8 and 6.1 ± 1.0 mL ∙ min−1 ∙ kg−1; urine flow rate, 44 ± 20 and 46 ± 19 μL ∙ min−1 ∙ kg−1; urine/plasma osmolality ratio, 1.2 ± 0.2 and 1.7 ± 0.1; urine/plasma [14C]polyethylene glycol ratio, 210 ± 69 and 211 ± 64; and Na+reabsorption, 99.6 ± 0.2 and 99.6 ± 0.3%, respectively. Renal function during 143 mM NaCl infusion (glomerular filtration rate, 3.4 ± 0.3 mL ∙ min−1 ∙ kg−1; urine flow rate, 19.7 ± 2.8 μL ∙ min−1 ∙ kg−1; urine/plasma osmolality ratio, 1.7 ± 0.1; urine/plasma [14C]polyethylene glycol ratio, 223 ± 26, and Na+reabsorption 99.9 ± 0.0%) was not affected by subsequent infusion of 700 mM NaCl, although plasma osmolality was significantly increased. The urine/plasma ratio for [14C]polyethylene glycol, but not osmolality, was higher in gulls than in other avian species. Intravenously infused NaCl elicited less concentrated salt gland secretion at a significantly lower threshold plasma osmolality than intragastric NaCl infusion. Salt gland secretion and glomerular filtration rates were inversely related.Key words: bird, gull, Larus glaucescens, kidneys, salt glands, gut, sodium chloride, glomerular filtration rate, saline acclimation.
Correlation between cardiac remodelling, function, and myocardial contractility in rat hearts 5 weeks after myocardial infarction
Authors: Gosselin H , Qi X , Rouleau J L
Published: April 2011

Early after infarction, ventricular dysfunction occurs as a result of loss of myocardial tissue. Although papillary muscle studies suggest that reduced myocardial contractility contributes to this ventricular dysfunction, in vivo studies indicate that at rest, cardiac output is normal or near normal, suggesting that contractility of the remaining viable myocardium of the ventricular wall is preserved. However, this has never been verified. To explore this further, 100 rats with various-sized myocardial infarctions had ventricular function assessed by Langendorff preparation or by isolated papillary muscle studies 5 weeks after infarction. Morphologic studies were also done. Rats with large infarctions (54%) had marked ventricular dilatation (dilatation index from 0.23 to 0.75, p << 0.01) and papillary muscle dysfunction (total tension from 6.7 to 3.2 g/mm2, p << 0.01) but only moderate left ventricular dysfunction (maximum developed tension from 206 to 151 mmHg (1 mmHg = 133.3 Pa), p << 0.01), a decrease less than one would expect with an infarct size of 54%. The contractility of the remaining viable myocardium of the ventricle was also moderately depressed (peak systolic midwall stress 91 to 60 mmHg, p << 0.01). Rats with moderate infarctions (32%) had less marked but still moderate ventricular dilatation (dilatation index 0.37, p << 0.001) and moderate papillary muscle dysfunction (total tension 4.2 g/mm2, p << 0.01). However, their decrease in ventricular function was only mild (maximum developed pressure 178 mmHg, p << 0.01) and less than one would expect with an infarct size of 32%. The remaining viable myocardium of the ventricular wall appeared to have normal contractility (peak systolic midwall stress = 86 mmHg, ns). We conclude that in this postinfarction model, in large myocardial infarctions, a loss of contractility of the remaining viable myocardium of the ventricular wall occurs as early as 5 weeks after infarction and that papillary muscle studies slightly overestimate the degree of ventricular dysfunction. In moderate infarctions, the remaining viable myocardium of the ventricular wall has preserved contractility while papillary muscle function is depressed. In this relatively early postinfarction phase, ventricular remodelling appears to help maintain left ventricular function in both moderate and large infarctions.

Key words: postinfarction, contractility, ventricular function, ventricular remodelling.
Changes in [K+]o evoked by baclofen in guinea pig hippocampus
Authors: Obrocea G V , Morris Mary E
Published: April 2011

K+-sensitive microelectrodes were used to record changes evoked by baclofen in extracellular potassium concentration ([K+]o) and field potentials in the stratum pyramidale (SP) and stratum radiatum (SR) in the CA1b region of guinea pig hippocampal slices in vitro. Bath applications of ( ±)-baclofen (1 µM - 3 mM for approx 5 min) evoked changes in [K+]o, which were in most cases sustained throughout agonist application and reversed during washout. The maximal (Rmax) values for curves fitted to the concentration-response data were for SP and SR, respectively, 0.59 ± 0.03 and 0.65 ± 0.03 mM, and EC50 values were 39.7 and 39.4 µM, respectively. The evoked K+ and field potential changes were significantly correlated and could be blocked by 2-OH-saclofen (50 µM) and CGP 35348 (50 µM). In <= 10% of experiments baclofen (10-50 µM) induced either a decrease or a transient increase ( <= 1 min duration) in [K+]o; in some slices with concentrations >=20 µM an initial decrease preceded a progressive increase. Pressure ejection of baclofen (100 µM for 100-900 ms) evoked increases in [K+]o and field potentials, which were larger in SR than in SP. In <= 10% of slices brief and (or) sustained application of baclofen (by either bath perfusion or pressure ejection) also evoked synchronous, repetitive interictal and ictal discharges at frequencies approx 1/s and 1/12 s, respectively, an observation that affirms a proconvulsant capacity. It is concluded that (i) although increases in [K+]o evoked by baclofen in SR compared with SP are slightly larger, they are not significantly different, (ii) GABAB receptor subtype(s) in SR and SP appear similar, as they have identical affinities, and (iii) [K+]o accumulations evoked by GABA likely include a contribution from a GABAB receptor activated K+ conductance, especially in dendritic regions.Key words: brain slices, stratum pyramidale, stratum radiatum, GABAB receptors, ion-selective microelectrodes, epileptiform activity.
Muscarinic inhibition of substance P induced ion secretion in piglet jejunum
Authors: Blumenthal Jeffrey A , Onorato James J , Carey Hannah V
Published: April 2011

We examined the effects of the muscarinic agonist carbachol on ion secretion induced by substance P (SP) in piglet jejunal tissues mounted in Ussing chambers. Tetrodotoxin was present in all solutions to inhibit neural activity. Carbachol added 10 min prior to 0.75 µM SP dose dependently inhibited subsequent SP responses, with 90% inhibition at 10 µM carbachol. Addition of an equipotent dose of SP (7.5 µM) had no effect on subsequent carbachol-induced secretion. Carbachol's inhibition of SP-induced secretion was evident for at least 45 min and was abolished by prior addition of the M3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), but remained intact in the presence of the M2 antagonist gallamine or the nicotinic antagonist mecamylamine. Atropine added 10 min after carbachol restored subsequent SP responses toward control levels. Carbachol also reduced secretory responses to histamine and, to a lesser extent, prostaglandin E2 (PGE2). SP-induced secretion was not affected by prior addition of histamine and was reduced by PGE2 only at the highest PGE2 concentration. The results suggest that activation of the epithelial M3 receptor by carbachol inhibits subsequent secretory responses to the calcium-mediated agonists SP and histamine in piglet jejunum. This may reflect muscarinic activation of a negative messenger in epithelial cells that limits Cl- secretion.Key words: substance P, muscarinic receptor, carbachol, desensitization, piglet, jejunum, intestine, ion secretion.
Effect of endothelium removal on prostaglandin and nitric oxide function in pulmonary resistance arteries in the lamb
Authors: Theis JGW , Toyoda O , Coceani F
Published: April 2011

We have recently shown that isolated pulmonary resistance arteries of the fetal lamb have prostaglandin (PG) I2 based and nitric oxide (NO) based relaxing mechanisms, which are activated by oxygen (at neonatal levels) and bradykinin. The present study was carried out to ascertain whether these mechanisms remain operational after removal of the endothelium. Endothelium-denuded vessels pre-equilibrated at a neonatal PO2 were not affected by indomethacin (2.8 µM), while they contracted weakly to NG-nitro-L-arginine methyl ester (L-NAME, 100 µM). However, the latter response did not reach significance and resembled that of intact vessels at fetal PO2. Bradykinin (0.1-100 nM) dose dependently (from 1-3 nM upwards) relaxed endothelium-denuded arteries that had been precontracted with a thromboxane (TX) A2 analog (ONO-11113, 0.1 µM) or excess potassium (5 mM Ca2+ in K+-Krebs) at a neonatal PO2. The response was the same under the two conditions, but it was smaller than that of intact arteries. Bradykinin relaxation of ONO-11113-contracted arteries was completely or nearly completely inhibited by indomethacin and L-NAME. We conclude that endothelium-denuded, pulmonary resistance arteries maintain PG (conceivably PGI2) mediated and NO-mediated relaxing mechanisms. These extra-endothelial mechanisms are activated by bradykinin but not by oxygen.Key words: perinatal pulmonary circulation, endothelium, nitric oxide, prostaglandin, oxygen.
Presence of NK1receptors on a mucosal-like mast cell line, RBL-2H3 cells
Authors: Cooke Helen J , Fox Paula , Alferes Lisa , Fox Charity C , Wolfe, Jr. Seth A
Published: April 2011

Reverse transcription - polymerase chain reaction of mRNA from rat RBL-2H3 cells yielded a 316 base pair band consistent with that predicted for the neurokinin-1 (NK1) receptor. Saturation and competition binding with125I-labeled Bolton-Hunter substance P, substance P fragments, and a series of selective tachykinin receptor agonists and antagonists demonstrated that RBL-2H3 cells express high affinity binding sites for substance P on their surfaces with the kinetic and pharmacological properties of NK1receptors. The pharmacology of these125I-labeled substance P binding sites was (from most to least potent) [Sar9,Met(O2)11]substance P > substance P 4-11 >> GR82334 >> MEN 10,376. However, substance P 1-4, substance P 8-11, substance P 9-11, and [Trp7, beta -Ala8]neurokinin A 4-10 failed to compete for binding. The metabolically stable NK1receptor agonist, [Sar9,Met(O2)11] substance P, caused a 49% increase in 5-hydroxytryptamine release above basal levels. The results demonstrate the presence of functional NK1receptors on RBL-2H3 cells, a mucosal-like mast cell line.Key words: substance P, receptors, mast cells, 5-hydroxytryptamine, tachykinins.
Opioid receptor and peptide mRNA expression in proliferative zones of fetal rat central nervous system
Authors: Leslie Frances M , Chen Yiling , Winzer-Serhan Ursula H
Published: April 2011

There is increasing evidence to suggest that opioid peptides may have widespread effects as regulators of growth. To evaluate the hypothesis that endogenous opioids control cellular proliferation during neural development, we have used in situ hybridization to examine opioid peptide and receptor mRNA expression in neuroepithelial zones of fetal rat brain and spinal cord. Our data show that proenkephalin mRNA is widely expressed in forebrain germinal zones and choroid plexus during the second half of gestation. In contrast, prodynorphin mRNA expression is restricted to the periventricular region of the ventral spinal cord. Little µ or delta receptor mRNA expression was detected in any regions of neuronal proliferation prior to birth. However, kappa receptor mRNA is widely expressed in hindbrain germinal zones during the 3rd week of gestation. Our present findings support the hypothesis that endogenous opioids may regulate proliferation of both neuronal and non-neuronal cells during central nervous system development. Given the segregated expression of proenkephalin mRNA in forebrain neuroepithelium and kappa receptor mRNA within hindbrain, different opioid mechanisms may regulate cell division in rostral and caudal brain regions.Key words: enkephalin, dynorphin, ontogeny, neurogenesis.
Properties of specific binding site of myotoxin a, a powerful convulsant, in brain microsomes
Authors: Katagiri Chikako , Ishikawa Hiro-Hide , Ohkura Masamichi , Nakagawasai Osam , Tadano Takeshi , Kisara Kensuke , Ohizumi Yasushi
Published: April 2011

Myotoxin a, a small basic polypeptide from prairie rattlesnakes (Crotalus viridis viridis), induces myonecrosis and binds to a single class of binding sites in skeletal muscle sarcoplasmic reticulum. In the present study, [125I]myotoxin a with a high specific activity was prepared and it was shown to bind mainly to microsomes in rat whole brain. [125I]Myotoxin a was further shown to bind to microsomes prepared from all regions tested in brain. Its specific binding to whole brain microsomes was of approximately 1.9 times lower affinity (KD = 0.76 µM; Bmax = 13.1 nmol/mg) than that to skeletal muscle sarcoplasmic reticulum. [125I]Myotoxin a binding to brain microsomes was displaced by unlabeled myotoxin a with an IC50 value of 4.5 µM. [125I]Myotoxin a binding was markedly reduced by treatment of microsomes with trypsin, suggesting that the binding site of [125I]myotoxin a is partially proteins. The binding was significantly inhibited by Mg2+ at concentrations above 1 mM. Having looked at several drugs, we noted that [125I]myotoxin a binding was noncompetitively inhibited by spermine, whereas it was enhanced by heparin. On the other hand, the i.c.v. injection of myotoxin a in mice induced potent convulsive effects at 0.05 nmol/mouse or more. This paper is the first to show that the specific binding site of myotoxin a is present in mouse brain and that myotoxin a is a novel peptidic convulsant in mice.Key words: myotoxin a, specific binding site, brain microsomes, powerful convulsion, central nervous system.
Heparin-releasable lipoprotein lipase activity is increased in cardiomyocytes after culture
Authors: Anderson Lorraine G , Carroll Rogayah , Acharya Anjli , Severson David L
Published: April 2011

The activity of lipoprotein lipase (LPL) in adult rat heart cardiomyocytes after overnight culture on laminin-coated plates for 18-22 h was compared with enzyme activity in freshly isolated cardiomyocytes. LPL activity in cellular homogenates from cultured cardiomyocytes and freshly isolated cells was 240 and 233 nmol oleate released ·h-1·mg-1protein, respectively. LPL specific activity (mU/ng LPL protein) was 0.07 in cultured cells compared with 0.42 in freshly isolated cells, indicating an increased content of inactive LPL mass after overnight culture. The heparin-induced release of LPL activity into the medium of cultured cardiomyocytes (198 nmol ·h-1·mg-1) was much greater than heparin-releasable LPL (HR-LPL) activity (59 nmol ·h-1·mg-1) from freshly isolated cells. HR-LPL activity from cultured cardiomyocytes was dependent on serum (16.3-fold activation) and was inhibited by high ionic strength (1 M NaCl) and by a polyclonal antibody to LPL. Cultured cardiomyocytes also had more immunodetectable LPL on the cell surface compared with freshly isolated cardiomyocytes, consistent with increased HR-LPL activity. Therefore, overnight culture may permit cardiomyocytes time to recover from the stress of isolation by increasing the content of LPL on the cell surface.Key words: lipoprotein lipase, cardiac myocytes.
Immune function in aged women is improved by ingestion of vitamins C and E
Authors: De la Fuente M , Ferrández M D , Burgos M S , Soler A , Prieto A , Miquel J
Published: April 2011

We have investigated the effects of supplementation of the diet with the antioxidant vitamins C and E on several functions of the immune response of aged women. Ten healthy women and 20 women (72 ± 6 years old) suffering two diseases often associated with age (10 with major depression disorders, MDD, and 10 with coronary heart disease, CHD) were administered 1 g of vitamin C and 200 mg of vitamin E daily for 16 weeks. Blood samples were collected before and after treatment for measurement of several immunological functions, namely proliferative response of lymphocytes to the mitogen phytohemagglutinin (20 mg/L) and phagocytic functions of polymorphonuclear (PMN) neutrophils, i.e., adherence to vascular endothelium, chemotaxis, phagocytosis of latex beads, and superoxide anion production. In addition, we also determined the levels of serum cortisol and lipid peroxides. Intake of vitamins resulted in a significant increase in the lymphoproliferative capacity and in the phagocytic functions of PMN neutrophils as well as in a significant decrease of serum levels of lipid peroxides and cortisol, both in the healthy aged women and in the aged women with MDD or CHD. These findings suggest an important role of antioxidant supplementation in the improvement of immune function in aged females as well as in the prevention and treatment of specific diseases associated with age that are quite prevalent in the developed countries.Key words: vitamins C and E, ageing, lymphocytes, neutrophils, lipid peroxides, cortisol.
Interaction between prostanoids and nitric oxide in the control of tubular function in rats with chronic bile duct ligation
Authors: Criado Manuela , Flores Olga , Hidalgo Froilán , López-Novoa José M , Sánchez-Rodríguez Angel
Published: April 2011

Recent work indicates that both nitric oxide and cyclooxygenase products play an important role in the renal alterations of liver cirrhosis, although the interactions between them have not been completely established. The purpose of this study was to assess the effect of simultaneous blockade of nitric oxide synthase and cyclooxygenase in rats with chronic bile duct ligation and in control, sham-operated rats. Compared with control rats, chronic bile duct ligation rats, 23-25 days after surgery, showed a decreased mean arterial pressure, natriuresis, and kaliuresis, without differences in glomerular filtration rate, and an increased urinary nitrite excretion. Nitric oxide synthesis inhibition by administration of NG-nitro-L-arginine methyl ester induced, in control rats, an increase in mean arterial pressure, without significant changes in natriuresis or glomerular filtration rate. In chronic bile duct ligation rats, NG-nitro-L-arginine methyl ester induced an increase in mean arterial pressure, natriuresis, and kaliuresis, together with a reduction in urinary nitrite excretion and an increase in prostaglandin E2excretion. Cyclooxygenase inhibition with indomethacin induced in both experimental groups a marked inhibition in urinary prostaglandin E2excretion without significant changes in Na+or K+excretion, and a significant increase in urinary nitrite excretion in control rats. NG-Nitro-L-arginine methyl ester in addition to indomethacin prevented the indomethacin-induced increase in nitrite excretion and dramatically reduced sodium excretion in both experimental groups. Thus, the present study suggests that both nitric oxide and cyclooxygenase products interact in the control of urinary sodium excretion and that each system is activated in the absence of the other one.Key words: kidney, biliary cirrhosis, nitric oxide synthase, cyclooxygenase.
Do local immune-neuroendocrine disturbances initiate diabetes?
Authors: Murzenok Petr , Goranov Vitaly
Published: April 2011

It has been suggested that there exists a local immune-neuroendocrine self-regulating system in the pancreas. The system consists of β-cells, nerve ganglia, intercellular fluid, connective tissue, and endothelial and immunocompetent cells. The local immune-neuroendocrine system governs the background level of insulin production by intrinsic mechanisms both in normal conditions and in a recovery period after different kinds of stress. The activity of this system by a complex of metabolic, environmental, nerve, and nonspecific immune factors has been determined. The local immune-neuroendocrine system is partially autonomous as a result of local integrative nerve circuits, morphological and functional substrates. Increased or decreased synthesis and release of some cytokines or biologically active substances (neurotransmitters, neuropeptides, γ-aminobutyric acid, metabolites, nitric oxide, ions, etc.) by various cell types in the local immune-neuroendocrine system above usual levels may result in disturbances of sensitivity and functions of β-cells. If the capability of the local immune-neuroendocrine system is insufficient for their compensation, the islet cell autoantigens may occur, the specific immune mechanisms are involved, and the pathological process becomes irreversible. Some ways for prevention of disturbances in the local immune-neuroendocrine system during the early and late phases of diabetes are presented.Key words: β-cells, diabetes, local immuneneuroendocrine system.