bluuebunny/crossref_metadata_2025 huggingface dataset:
Prorenin is present in human red blood cells
Authors: Troffa C. , Tonolo G. , Manunta P. , Pazzola A. , Soro A. , Madeddu P. , Pala F. , Melis M. G. , PinnaParpaglia P. , Patteri G. , Bacciu S. , Sabino G. , Glorioso N.
Published: April 2011

We looked for the presence of prorenin in erythrocytes from normal subjects (n = 8), hypertensive patients (n = 8), and pregnant women (n = 8). Angiotensin I generation was measured at 37 °C, pH 5.7, in the presence of homologous substrate (1400 ng/mL) before and after trypsin activation (100 μg/mL) in (A) haemolyzed erythrocytes, (B) supernatants of haemolyzed erythrocytes, and (C) in the sixth washing of erythrocytes diluted 1:1 with a 0.1 M Tris buffer containing 0.5% bovine serum albumin and protease inhibitors. Haemolyzed erythrocytes generated angiotensin I only after trypsin treatment, and the rate of generation was the same (A) before and (B) after centrifugation at 20000g, indicating the absence of prorenin bound to the cell membranes. When aliquots of the last washing of erythrocytes (C) were tested for angiotensin I generation before and after trypsin, they did not generate angiotensin I, indicating that residual prorenin from the plasma was no longer present in our preparation. Angiotensin I generation by trypsin-treated A and B was completely abolished by preincubation with anti-renin serum. The level of prorenin was not significantly different in the erythrocytes from normal, hypertensive, and pregnant subjects (68 ± 10, 58 ± 7 and 107 ± 17 pg angiotensin I∙mL−1∙h−1, ns) in spite of their very different plasma levels (21 ± 2.5, 17 ± 2.4 and 110 ± 12 ng angiotensin I∙mL−1∙h−1, p < 0.01 for pregnant women compared with both normal and hypertensive subjects). Our data show that prorenin is present in human erythrocytes in fairly constant and clearly detectable amounts, thus suggesting a possible intracellular role for it.Key words: inactive renin, intracellular prorenin, erythrocytes, prorenin.
Evidence against the involvement of a cytochrome P-450 mechanism in pulmonary hemodynamics in the newborn pig
Authors: Perreault Thérèse , Marte Josie De , Coceani Flavio
Published: April 2011

Control mechanisms operating through a cytochrome P-450 system have emerged lately as a possible important determinant of pulmonary hemodynamics. Their action may be expressed in the adjustment of vascular tone under both physiologic and pathophysiologic conditions. One such condition is the pulmonary constrictor response to hypoxia. The identity of the effector agent, or agents, is not known, though there are data implicating monooxygenase products of arachidonic acid. From this premise, we wanted to evaluate the effect of cytochrome P-450 inhibitors on basal pulmonary vascular tone during normoxia, and their effect upon hypoxic pulmonary vasoconstriction response. Experiments were performed in an isolated, perfused lung preparation from 1- and 7-day-old piglets, and the effects of two cytochrome P-450 inhibitors (metyrapone and ketoconazole) were tested on the perfusion pressure. At 10−5 and 10−4 M, metyrapone caused a modest, but significant, increase in pulmonary pressure (p < 0.05) in 7-day-old preparations, while it was without effect in the 1-day-old preparation. Similarly, ketoconazole at concentrations from 10−6 M upwards increased the perfusion pressure in the older animal (p < 0.01). Responses to the inhibitors were not seen in preparations that had been pretreated with a cyclooxygenase inhibitor (indomethacin, 2.8 × 10−6 M) or a dual cyclooxygenase–lipoxygenase inhibitor (BW755C, 10−5 M). Hypoxic vasoconstriction was marginally enhanced by 10−4 M metyrapone, while it was affected inconsistently by 10−5 M ketoconazole. We conclude that vasoactive agents formed through cytochrome P-450 reactions have a minor role, or no role at all, in the control of pulmonary hemodynamics in the newborn pig.Key words: neonatal pulmonary circulation, hypoxia, metyrapone, ketoconazole.
Interleukin-6 is a centrally acting endogenous pyrogen in the rat
Authors: Rothwell N. J. , Busbridge N. J. , Lefeuvre R. A. , Hardwick A. J. , Gauldie J. , Hopkins S. J.
Published: April 2011

Intracerebroventricular (i.c.v.) injection of human recombinant interleukin-6 (IL-6; 20–100 ng) caused significant increases in colonic temperature and resting oxygen consumption [Formula: see text] in conscious rats. These effects were prevented by pretreatment with a cyclooxygenase inhibitor (flurbiprofen, 1 mg/kg, i.p.) or a corticotrophin-releasing factor antagonist (α-helical CRF 9–41, 25 μg, i.c.v.). Higher doses of IL-6 (i.c.v.) caused only small changes in [Formula: see text] and temperature, and very high doses given intravenously (i.v.) (4 μg/kg) were required to stimulate these parameters. Central injection of anti-rat IL-6 antibody inhibited the effects of interleukin-1β (i.c.v.) or endotoxin injection (i.p.) on colonic temperature and [Formula: see text] in conscious rats. These data indicate that IL-6 is an important endogenous pyrogen that acts within the central nervous system.Key words: interleukin 6, fever, thermogenesis, brain, pyrogen.
A Decade of Atrial Natriuretic Factor Research
Authors: Bold Adolfo J. de
Published: April 2011

The papers that are summarized here and presented in full format in this issue address different aspects of atrial natriuretic factor (ANF) research discussed at the symposium entitled "A Decade of ANF Research" held in Ottawa on June 21–23, 1990. The papers are an excellent reflection of the progress made in basic and clinical research on natriuretic peptides during the time elapsed since the discovery of ANF.
23Na and flame photometric studies of the NMR visibility of sodium in rat muscle
Authors: Buist Richard J. , Deslauriers Roxanne , Saunders John K. , Mainwood Graham W.
Published: April 2011

23Na nuclear magnetic resonance spectroscopy (NMR) is increasingly being used to study Na+ gradients and fluxes in biological tissues. However, the quantitative aspects of 23Na NMR applied to living systems remain controversial. This paper compares sodium concentrations determined by 23Na NMR in intact rat hindlimb (n = 8) and excised rat gastrocnemius muscle (n = 4) with those obtained by flame photometric methods. In both types of samples, 90% of the sodium measured by flame photometry was found to be NMR-visible. This is much higher than previously reported values. The NMR measurements for intact hindlimb correlated linearly with the flame photometric measurements, implying that one pool of sodium, predominantly extracellular, is 100% visible. From measurements on excised muscle, in which extracellular space is more clearly defined, the NMR visibility of intracellular Na+ was calculated to be 70%, assuming an extracellular space of 12% of the total tissue water volume and an extracellular NMR visibility of 100%. 23Na transverse relaxation measurements were carried out using a Hahn spin echo on both intact hindlimb (n = 1) and excised muscle (n = 2) samples. These showed relaxation curves that could each be described adequately using two relaxation times. The rapidly relaxing component showed a T2 value of 3–4 ms and the slowly relaxing component a T2 of 21–37 ms. A spin lattice relaxation (T1) measurement on intact hindlimb yielded a value of 51 ms. These relatively long relaxation times show that the quadrupolar relaxation effect of Na+ complexing to large macromolecules or being otherwise motionally restricted is relatively weak. This is consistent with the high NMR visibilities reported here.Key words: Na+, rat hindlimb, gastrocnemius, nuclear magnetic resonance spectroscopy.
Distal tubule bicarbonate reabsorption during rebound metabolic alkalosis
Authors: Vandorpe David H. , Nadler Steven P. , Levine David Z.
Published: April 2011

Rebound metabolic alkalosis is a transient alkalemia that is seen during recovery from NH4Cl-induced metabolic acidosis. The persistent elevation of plasma bicarbonate concentration is the result of continuing excretion of net acid by the kidney. Bicarbonate transport by inner medullary collecting ducts has been reported by others to proceed normally (i.e., bicarbonate reabsorption continues in this segment) during rebound metabolic alkalosis. No other segmental responses have been evaluated. Since the surface distal tubule of the rat is known to both reabsorb and secrete bicarbonate in vivo, it was of interest to determine the response of this segment. Our results show that the distal tubule microperfused in vivo during rebound metabolic alkalosis continues to reabsorb significant amounts of bicarbonate, despite the presence of systemic alkalemia that we have previously shown to be associated with distal tubule bicarbonate secretion.Key words: rebound metabolic alkalosis, distal tubule, micropuncture, bicarbonate reabsorption.
Differences in α1-adrenoceptor mechanisms for phenylephrine and tizanidine in rabbit thoracic aorta and common iliac artery
Authors: Takayanagi Issei , Harada Mariko , Koike Katsuo , Satoh Mitsutoshi
Published: April 2011

Based on affinity for WB4101 and susceptibility to chloroethylclonidine, we evaluated the subtype of α1-adrenoceptors activated by phenylephrine (a full agonist) and tizanidine (a partial agonist). The rabbit thoracic aorta and common iliac artery contain both α1A- and α1B-adrenoceptors, but the α1B-subtype may be more predominantly in the common iliac artery than in the thoracic aorta. In rabbit thoracic aorta and common iliac artery, phenylephrine induced contraction through both α1A-and α1B-subtypes and tizanidine through only the α1A-subtype. The subtype activated by phenylephrine may be partly different from that activated by tizanidine in the preparations used herein.Key words: rabbit thoracic aorta, rabbit common iliac artery, α1A-subtype, α1B-subtype, α1-adrenoceptor mechanism.
Does adenosine modulate the natriuretic response to ANP in normal dogs?
Authors: Levy Mortimer , Legault Louis , Cernacek Peter , Farber David
Published: April 2011

To determine if the usual natriuretic response to ANP could be altered by raising intrarenal levels of adenosine, ANP was administered to normal anesthetized dogs at 100 ng∙kg−1∙min−1 i.v. before and after the administration of adenosine (3 μg∙kg−1∙min−1) into the left renal artery (n = 8). For each kidney, the group mean ΔUNaV in response to ANP was unchanged by the presence of adenosine. However, following intrarenal infusion of adenosine, this unaltered average response for the infused kidney was achieved by either attenuation or exaggeration of the natriuresis to ANP in half the dogs, respectively. When intrarenal levels of extracellular adenosine were elevated by the i.v. infusion of dipyridamole in seven dogs, there was uniform exaggeration of an ANP-induced natriuresis by an average of 145 μequiv./min. The provision of theophylline by itself (an adenosine antagonist) had no effect on UNaV but prevented the dipyridamole-induced exaggerated natriuresis to ANP. The infusion of adenosine deaminase into one renal artery reduced the natriuretic response to ANP. We conclude that elevated intrarenal levels of adenosine will exaggerate an ANP-induced natriuresis possibly by altering intracytosolic Ca2+.Key words: theophylline, dipyridamole, purine receptors.
Pre- and post-sinusoidal origin of hepatic exudate in anesthetized cats
Authors: Greenway C. V. , Innes I. R. , Scott G. D.
Published: April 2011

In cats anesthetized with pentobarbital, hepatic venous pressure was increased to cause drops of exudate to appear on the surface of the liver. These drops were collected during steady-state infusions of small doses of ethanol and galactose when there was a large arteriovenous gradient across the liver. Comparison of the concentrations of these substances in arterial, portal, and hepatic venous blood and exudate showed that the exudate concentrations were slightly higher than the hepatic venous concentrations but markedly lower than arterial and portal blood concentrations. We conclude that the exudate cannot be entirely formed in the space of Mall (presinusoidal) but a substantial part is postsinusoidal in origin. If the exudate is a mixture of fluids equilibrated with inflowing and outflowing blood, then 75–80% of the exudate is postsinusoidal and 20–25% is presinusoidal in origin.Key words: lymph, ascites, galactose, ethanol.
K+-channel blockers do not decrease acetylcholine depolarizations in canine trachealis
Authors: Daniel E. E. , Jury J. , Serio R. , Jager L. P.
Published: April 2011

Using the double sucrose gap, we have examined the role of K+ channels in the cholinergic depolarizations in response to field stimulation and acetylcholine (Ach) in canine trachealis. Acetylcholine-like depolarization per se decreased electrotonic potentials from hyperpolarizing currents. The net effect of acetylcholine (10−6 M) depolarization on membrane conductance was a small increase after the depolarization was compensated by current clamp. Reversal potentials for acetylcholine depolarization and for the excitatory junction potential (EJP) were determined by extrapolation to be 20–30 mV positive to the resting potential, previously shown to be approximately −55 mV. They were shifted positively by tetraethylammonium ion (TEA) at 20 mM or Ba2+ at 1 mM. TEA or Ba2+ initially depolarized the membrane and increased membrane resistance. Repolarization of the membrane restored any reductions in EJP amplitudes associated with depolarization. After 15 min, the membrane potential partially repolarized, and acetylcholine-induced depolarization and contractions were then increased by TEA. 4-Aminopyridine depolarized the membrane but decreased membrane resistance. Apamin (10−6 M), charybdotoxin (10−7 M), and glybenclamide (10−5 M) each failed to significantly depolarize membranes, increase membrane resistance, or reduce EJP amplitudes or depolarization to 10−6 M Ach. Glybenclamide reduced depolarizations to added acetylcholine slightly. TEA occasionally reduced the EJP markedly, but this was shown to be most likely a prejunctional effect mediated by norepinephrine release. TEA alone among K+-channel blockers slowed the onset and the time courses of the EJP as well as the acetylcholine-induced depolarization. K+-channel closure cannot be a complete explanation of acetylcholine-induced membrane effects on this tissue. Acetylcholine must have increased the conductance of an ion with a reversal potential positive to the resting potential in addition to any effect to close K+ channels.Key words: acetylcholine, tracheal smooth muscle, trachea, chloride channels, sucrose gap, potassium channels, tetraethylammonium, Ba2+.
Flow-dependent antiarrhythmic properties of ammonia during catecholamine-driven ventricular tachycardia
Authors: Malootian A. , Friedrichs G. S. , Merrill G. F.
Published: April 2011

Fifteen mongrel dogs weighing 22–34 kg were instrumented to investigate the antiarrhythmic effects of ammonia (0.1 – 0.2 mmol/min ammonium hydroxide), adenosine (1.87 μmol/min), and saline (0.9% NaCl) during norepinephrine-driven ventricular tachycardia, under conditions of controlled and natural coronary blood flow. Under natural flow conditions, the severe ectopy caused by norepinephrine (100–800 ng∙kg−1∙min−1) was reduced by 42 ± 4% after 30 s of ammonia infusion. Adenosine infusion reduced percent ectopy by 97 ± 2% at 30 s. Ammonia also significantly increased coronary blood flow by 26 ± 4%, while adenosine increased blood flow by 72 ± 14%. Saline infusion had no significant effect on either the severity of ventricular tachycardia or coronary blood flow. Norepinephrine consistently caused coronary functional hyperemia as previously reported. When coronary blood flow was controlled by a peristaltic pump to match natural coronary blood flow and to prevent norepinephrine-induced coronary functional hyperemia, the antiarrhythmic effects of ammonia were lost while those of adenosine were unaffected. Additionally, increasing coronary blood flow manually during norepinephrine-induced ventricular tachycardia, to a level seen with combined norepinephrine and ammonia under natural flow conditions, appeared to worsen the venticular arrhythmias. We conclude that the antiarrhythmic properties of ammonia against norepinephrine-driven ventricular tachycardia might be dependent on coronary blood flow, while those of adenosine are independent of coronary blood flow.Key words: coronary flow, ammonium hydroxide, cardiac, norepinephrine.
Ammonia and amino acid metabolism in human skeletal muscle during exercise
Authors: Graham T. E. , MacLean D. A.
Published: April 2011

This review focuses on the ammonia and amino acid metabolic responses of active human skeletal muscle, with a particular emphasis on steady-state exercise. Ammonia production in skeletal muscle involves the purine nucleotide cycle and the amino acids glutamate, glutamine, and alanine and probably also includes the branched chain amino acids as well as aspartate. Ammonia production is greatest during prolonged, steady state exercise that requires 60–80% [Formula: see text] and is associated with glutamine and alanine metabolism. Under these circumstances it is unresolved whether the purine nucleotide cycle (AMP deamination) is active; if so, it must be cycling with no IMP accumulation. It is proposed that under these circumstances the ammonia is produced from slow twitch fibers by the deamination of the branched chain amino acids. The ammonia response can be suppressed by increasing the carbohydrate availability and this may be mediated by altering the availability of the branched chain amino acids. The fate of the ammonia released into the circulation is unresolved, but there is indirect evidence that a considerable portion may be excreted by the lung in expired air.Key words: glutamine, branched chain amino acids, glutamate dehydrogenase, purine nucleotide cycle.
Cocaine hepatotoxicity during protein undernutrition of retrovirally infected mice
Authors: Odeleye Olalekan E. , Lopez Maria C. , Smith Bruce T. , Eskelson Cleamond D. , Watson Ronald R.
Published: April 2011

Effects of cocaine administration on lipid peroxidation and liver damage in immunocompromised mice fed different levels of dietary proteins were investigated. Indices of lipid peroxidation and serum aminotransferases as evidence of free radical attack and liver damage were compared in mice fed a low protein (4%) or regular protein diet (20% protein) for 3 weeks and then infected with murine leukemia virus and given daily intraperitoneal injections of increasing progressive doses of 5–45 mg∙kg−1∙day−1 of cocaine for 11 weeks. Cocaine administration significantly increased hepatic triglycerides, serum aminotransaminases, conjugated dienes, lipid fluorescence, and malondialdehyde levels. These changes were exacerbated by retroviral infection and also by protein undernutrition. Retroviral infection additiveiy increased indices of cocaine-induced lipid peroxidation and hepatic damage. Significant increases in indices of lipid peroxidation and greater liver injury were also detected in similarly treated mice that received the low protein diet compared with well-nourished mice. These results show that immunocompromised mice fed low levels of dietary protein form significantly increased immunogenic lipid peroxidation adducts during cocaine treatment.Key words: lipid peroxidation, retroviral infection, cocaine, protein nutrition, liver, AIDS.
Plasma amino acid and ammonia responses to altered dietary intakes prior to prolonged exercise in humans
Authors: MacLean D. A. , Spriet L. L. , Graham T. E.
Published: April 2011

This study examined the effects of altered dietary intakes on amino acid and ammonia (NH3) responses prior to and during prolonged exercise in humans. Six male recreational cyclists rode to exhaustion at 75% of [Formula: see text] following 3 days on a low carbohydrate (LC), mixed (M), or high carbohydrate (HC) diet in a latin square design. There were differences (p < 0.05) in exercise times among all treatments (58.8 ± 3.7, 112.1 ± 7.3, and 152.9 ± 10.3 min for the LC, M, and HC treatments, respectively). The rate of increase in plasma NH3 during exercise was greater (p < 0.05) during the LC trial. The LC trial was also characterized by higher (p < 0.05) resting plasma concentrations of branched chain amino acids (BCAA) and a greater decrease in these amino acids during exercise (p < 0.05), as compared with the other two treatments. Both plasma BCAA and NH3 were susceptible to dietary manipulations. These findings suggest that limited carbohydrate availability in association with increased BCAA availability results in enhanced BCAA metabolism during exercise. This is reflected in a greater rate of increase in plasma NH3 and is consistent with the hypothesis that a significant fraction of the NH3 released during a prolonged, submaximal exercise bout is from amino acid catabolism.Key words: AMP deaminase, branched chain amino acids, branched chain keto acid dehydrogenase, glycogen, purine nucleotide cycle.
Developments in the study of smooth muscle research: reflections on 42 years
Authors: Daniel E. E.
Published: April 2011

This review of smooth muscle research in my laboratory covers over 40 years. It focuses on research on the control of myometrium, blood vessels, gastrointestinal muscle, and airway muscle and highlights the major findings and those who made them. My goal is to show how science can be rewarding both in terms of findings and in terms of the people who make them.Key words: myometrium, gastrointestinal motility, airway hyperresponsiveness, neuropeptides, neural control.
In vivo airway reactivity: predictive value of morphological estimates of airway smooth muscle
Authors: Martin J. G. , Opazo-Saez A. , Du T. , Tepper R. , Eidelman D. H.
Published: April 2011

Airway responsiveness to methacholine and other bronchoconstrictors is highly variable within and among species. The aim of the experiments in this report was to evaluate the importance of the quantity of airway smooth muscle as a determinant of intra- and inter-species variability in airway responsiveness. To do this we established concentration–response curves to methacholine in a sample of normal guinea pigs as well as in rat, rabbit, and dog. After challenge we excised the lungs for the quantitation of smooth muscle by morphometry. Animals were anesthetized with pentobarbital and mechanically ventilated using a Harvard ventilator. Aerosols of methacholine were administered in progressively doubling concentrations from 0.0625 to 256 mg/mL for a period of 30 s for each concentration. The maximal response, determined from pulmonary resistance (RL), and the concentration of methacholine required to effect 50% of the maximal RL were determined. After provocation testing the lungs were removed and fixed with 10% Formalin. Midsagittal sections and parahilar sections were stained with hematoxylin–phloxine–saffron for microscopic examination of smooth muscle. The images of all airways in the sections were traced using a camera lucida side-arm attachment and digitized using commercial software. The area of the airway wall occupied by smooth muscle was determined and standardized for airway size by dividing it by the square of the epithelial basement membrane length. The variability in airway smooth muscle in the intraparenchymal airways was significantly greater between than within individual guinea pigs (n = 13). This was not true of extraparenchymal airways. There was a significant relationship between the quantity of airway smooth muscle in the intraparenchymal cartilaginous airways and the EC50 but not the maximal value of resistance (Rmax). In contrast there was a statistically significant positive correlation between Rmax and airway smooth muscle for all species. There was also a significant inverse correlation between EC50 and airway smooth muscle for all species. We conclude that airway smooth muscle appears to be an important determinant of inter-animal differences in sensitivity of guinea pigs to aerosolized methacholine. Smooth muscle also appears to be a determinant of interspecies differences in both sensitivity and maximal responses to methacholine.Key words: airways responsiveness, mechanical determinants, limited bronchoconstriction, methacholine, morphometry.
Physiological mechanisms mediating enhanced force generation during development and immune sensitization
Authors: Mitchell Richard W. , Murphy Thomas M. , Leff Alan R.
Published: April 2011

We examined the development of acetylcholinesterase (AChase) activity and tracheal smooth muscle (TSM) contraction elicited by acetylcholine (ACh) in a swine model of maturation and a dog model of allergic bronchospasm. Strips of TSM were tethered isometrically at optimal length and responses were expressed as a percentage of the maximum to KCl-substituted perfusate (% KCl). Maximal contraction (ATmax) to ACh in 2-week-old swine (168 ± 8% KCl) was greater than in 10-week-old swine (142 ± 2% KCl; p < 0.02). The AChase inhibitor, physostigmine, augmented ACh-elicited ATmax in 10-week-old (27% increase; p < 0.01) but not in 2-week-old swine (2% increase; p is NS) and caused a greater increase in sensitivity to muscarinic activation in 2 versus 10 week-old swine (p < 0.02), thus demonstrating increased contraction of TSM in 2 versus 10-week-old swine, which results at least in part from reduced AChase activity in immature animals. In another study, TSM from ragweed-sensitized dogs demonstrated augmented efficacy to ACh-elicited contraction (180 ± 6% KCl) compared with TSM from sham-sensitized, littermate controls (163 ± 4% KCl; p < 0.05). In the presence of physostigmine, ATmax was not different between ragweed-sensitized and control TSM. Direct measurement of AChase activity demonstrated reduced enzyme activity in TSM homogenates from ragweed-sensitized dogs (0.86 ± 0.09 absorbance units∙min−1∙mg−1 protein (AU∙min−1∙mg−1)) versus control dogs (1.59 ± 0.13 AU∙min−1∙mg−1; p < 0.001), but similar Michaelis constants (KM = 0.36 ± 0.06 for ragweed-sensitized dogs vs. 0.34 ± 0.06 for control; p is NS). These data demonstrate that immune sensitization reduces AChase activity in TSM by a mechanism consistent with reduction in enzyme content. Together, our data suggest the functional expression of AChase activity increases with age, but may be inhibited by immune sensitization.Key words: canine, porcine, tracheal smooth muscle, maturation, acetylcholinesterase.
Indomethacin worsens and a leukotriene biosynthesis inhibitor accelerates mucosal healing in rat colitis
Authors: Empey Lonnie R. , Walker Keith , Fedorak Richard N.
Published: April 2011

The implication of leukotrienes as mediators of inflammation and recent evidence that prostaglandin analogues provide a beneficial effect during experimental colitis led to the speculation that (i) leukotrienes may be injurious and (ii) prostaglandins may be protective to colonic mucosa. Using a 2% acetic acid induced rat colitis model, we administered specific cyclooxygenase (indomethacin) and leukotriene biosynthesis inhibitors (MK-886) to examine the effect of endogenous prostaglandins and leukotrienes on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, net in vivo intestinal fluid absorption, and colonic PGE2 and LTB4 levels as measured by in vivo rectal dialysis. Indomethacin treatment prior to induction of colitis reduced endogenous mucosal PGE2 levels and exacerbated macroscopic ulceration and net fluid absorption. Addition of the exogenous PGE1 analogue misoprostol to the indomethacin-exacerbated colitis completely healed colonic macroscopic ulceration and inflammation but only partially improved fluid absorptive injury. The specific leukotriene biosynthesis inhibitor MK-886 administered prior to induction of colitis healed macroscopic ulceration and inflammation but not fluid absorptive injury. This mucosal reparative effect of MK-886 occurred at a dose that reduced colonic LTB4 synthesis while concomitantly enhancing PGE2 levels. Combining MK-886 with misoprostol treatment improved not only macroscopic ulceration and inflammation but also provided a synergistic effect that maintained net colonic fluid absorption at noncolitic control levels. These studies suggest that, during the induction of experimental colitis, endogenous prostaglandins play a pivotal role in providing a mucosal healing effect, and that leukotriene biosynthesis inhibitor may manifest part of its beneficial effect by shifting arachidonic acid metabolism towards production of prostaglandins.Key words: cyclooxygenase, eicosanoids, indomethacin, inflammatory bowel disease, leukotrienes, lipoxygenase, MK-886, misoprostol, prostaglandins.
Influence of pregnancy on mean systemic filling pressure and the cardiac function curve in guinea pigs
Authors: Cha S. C. , Aberdeen G. W. , Nuwayhid B. S. , Quillen Jr. E. W.
Published: April 2011

To assess the degree of circulatory fullness and to evaluate the influence of peripheral and cardiac factors in the regulation of cardiac output during pregnancy, the following studies were conducted using pentobarbital-anesthetized, open-chest nonpregnant and late term pregnant guinea pigs. Mean circulatory filling pressure was taken as the equilibrium pressure when the pulmonary artery was constricted. Total vascular compliance was assessed by ±5-mL changes in blood volume performed while this constriction was maintained. A separate group of guinea pigs was prepared with a pulmonary artery electromagnetic flow probe and right atrial catheter. Rapid infusion of saline was used to increase right atrial pressure while the cardiac output was determined. Pregnancy was characterized by the following changes relative to nonpregnant controls: 51Cr-labelled RBC blood volume increased from 55 ± 3 to 67 ± 3 mL/kg; mean circulatory filling pressure increased from 7.1 ± 0.2 to 8.0 ± 0.5 mmHg (1 mmHg = 133.322 Pa); right atrial pressure decreased from 3.4 ± 0.2 to 2.1 ± 0.3 mmHg; and cardiac output increased from 71.8 ± 3.9 to 96.8 ± 3.3 mL∙min−1∙kg−1. Total vascular compliance was not changed (2.1 ± 0.1 mL∙kg−1∙mmHg−1) and most of the expanded blood volume was accommodated as unstressed volume. The cardiac function curve was shifted upwards in pregnant animals. The resistance to venous return, as determined from the slope of the venous return curves, was not changed. These data suggest that the circulation of the pregnant guinea pig is slightly overfilled. The pressure gradient for venous return was increased, but a more important contribution to the increased levels of cardiac output is made by the increase in cardiac pumping ability.Key words: blood volume, mean circulatory filling pressure, vascular compliance, venous return.
Intratracheal injection of nickel chloride and copper–zinc superoxide dismutase activity in lung of rats
Authors: Novelli Ethel L. B. , Rodrigues Ney L. , Ribas Bartolomé O. , Curi Paulo R.
Published: April 2011

Superoxide radical [Formula: see text] is a free radical that may be involved in various toxic processes. Cu–Zn superoxide dismutase catalyses the dismutation of the superoxide free radical and protects cells from oxidative damage, and it has been used clinically. The concentration of Ni2+ and Cu–Zn superoxide dismutase activity were measured in lungs of rats at time intervals of 5, 12, 19, 26, 33, and 40 days following an intratracheal injection of 127 nmol of NiCl2. Nickel chloride increased nickel content and resulted in a significant increase of Cu–Zn superoxide dismutase activity in lungs. This elevation of Cu–Zn superoxide dismutase activity was highest on the 12th day (approximately threefold) and is at levels comparable to controls rats on day 40 onwards. Since Cu–Zn superoxide dismutase activity was increased in lung throughout our experimental period without corresponding increases of Cu2+ and Zn2+, we speculate that the elevation of Cu–Zn superoxide dismutase activity might be due to an increased half-life of the enzyme, induced by nickel.Key words: nickel chloride, intratracheal, Cu–Zn superoxide dismutase, lung.
The indirect negative inotropic effects of the P1-receptor agonist, L-phenylisopropyladenosine, in guinea-pig isolated cardiac preparations: comparison with cromakalim
Authors: Urquhart Robert A. , Broadley Kenneth J.
Published: April 2011

The possible mechanisms of the indirect negative inotropic responses to the P1-receptor agonist, L-phenylisopropyladenosine (L-PIA) were evaluated in electrically paced (2 Hz, 5 ms pulse width, voltage 50% above threshold) left atria and papillary muscles of guinea pigs. The responses were compared in naive tissues (direct effects) or after prestimulation with submaximal concentrations of either cAMP-dependent positive inotropes (isoprenaline or forskoiin) or the cAMP-independent inotrope Bay K 8644. Cumulative concentration – response curves were obtained in naive or prestimulated preparations for L-PIA or the potassium channel activator, cromakalim, for comparison. L-PIA and cromakalim exerted negative inotropy in naive atrial tissues, whereas only cromakalim was active in naive papillary muscles. In atria prestimulated with isoprenaline (31 nM) or forskolin (1.4 μM), the negative inotropy of L-PIA was enhanced compared with naive tissues. In contrast, prestimulation with Bay K 8644 (1 μM) exerted a significant functional antagonism of the response to L-PIA. In the case of cromakalim, prestimulation with isoprenaline exerted a functional antagonistic effect. In papillary muscles, an indirect negative inotropic effect of L-PIA was only seen in tissues prestimulated with the cAMP-dependent inotropes isoprenaline (31 nM) or forskolin (2.4 μM), and not in naive tissues or those prestimulated by Bay K 8644 (333 nM). As with atria, prestimulation with isoprenaline exerted a functional antagonistic effect on the response to cromakalim. These results suggest that the P1-receptor agonist, L-PIA, exerts its indirect negative inotropic effects in left atria by two mechanisms. One mechanism is common to the direct inhibition of naive tissues and an additional component is seen after prestimulation with cAMP-dependent positive inotropes. Where prestimulation is cAMP-independent, this component is absent and functional antagonism is observed. Similarly, the negative inotropic effect of the potassium channel activator, cromakalim, is cAMP-independent and functionally antagonized in both atria and papillary muscles by isoprenaline.Key words: L-phenylisopropyladenosine, atria, papillary muscles, guinea pig, cromakalim, isoprenaline, forskolin, Bay K 8644 prestimulation.
Catecholamine-induced changes in vascular capacitance and sympathetic nerve activity in dogs
Authors: Arimura Hiroyuki , Bosnjak Zeljko J. , Hoka Sumio , Kampine John P.
Published: April 2011

The effects of three catecholamines, dopamine, epinephrine, and dobutamine, on the systemic circulation, especially on systemic vascular capacitance, were studied using cardiopulmonary bypass in dogs anesthetized with pentobarbital. Venous outflow was divided into three compartments: splanchnic, renal, and other; changes in systemic blood volume (SBV) were calculated from the changes in total venous outflow. To examine the contribution of sympathetic discharge to these vascular responses, sympathetic efferent nerve activity (SENA) from the ventral ansa subclavian nerve was recorded simultaneously. Experiments were done under three conditions: control, after baroreceptor deafferentation, and after hexamethonium injection with low and high doses of each catecholamine. During control and after baroreceptor deafferentation, dopamine- and epinephrine-induced changes in SBV were less than those after hexamethonium, and not significant except with low dose epinephrine. After hexamethonium, dopamine (200 μg/kg), epinephrine (10 μg/kg), and dobutamine (100 μg/kg) reduced SBV by 10.6 ± 3.4, 13.1 ± 1.7, and 1.9 ± 0.3 mL/kg, respectively. Splanchnic outflow increased significantly with dopamine and epinephrine after hexamethonium. High dose dopamine and epinephrine significantly suppressed SENA to 38 ± 9 and 15 ± 6% of baseline, respectively. Low dose dopamine decreased arterial pressure and SENA. This suppression in SENA was attenuated but still observed after baroreceptor deafferentation. Dobutamine reduced SBV, but had no effect on SENA. These results suggest that dopamine and epinephrine primarily decrease SBV by venoconstriction in the splanchnic region, however, these effects are greatly modified by basal sympathetic discharge and changes in SENA and vascular tone.Key words: catecholamines, dopamine, epinephrine, dobutamine, vascular capacitance, venoconstriction.
Neurally mediated gastric mucosal damage in hypophysectomized rats
Authors: Hierlihy Lynn E. , Wallace John L. , Ferguson Alastair V.
Published: April 2011

The role of the pituitary hormones in the development of neurally mediated gastric mucosal damage was examined in both normal and hypophysectomized urethane-anaesthetized male Sprague–Dawley rats. Gastric mucosal damage was elicited either by electrical stimulation of intact vagal nerves or by electrical stimulation in the paraventricular nucleus. Macroscopic damage was scored following the stimulation period and samples of the stomach were fixed for histological assessment. Damage scores were assigned based on a 0 (normal) to 3 (severe) scale. Control experiments in which the vagi were not stimulated did not result in any significant gastric damage in either normal (0.56) or sham surgery (0.14) animals, whereas hypophysectomized animals were observed to have significant damage (1.44, p < 0.05). Stimulation of the vagi in hypophysectomized animals resulted in damage that was not significantly different compared with the hypophysectomized control animals (1.25, p > 0.05). In normal animals, stimulation of vagal nerves resulted in mean damage scores of 2.00, values that were not significantly different from those observed in hypophysectomized animals (1.25, p > 0.05). Similarly, stimulation in the paraventricular nucleus of hypophysectomized animals resulted in gastric lesions (2.00) that were not significantly different from those observed in normal animals (1.91, p > 0.05). These data suggest that such neurally mediated gastric damage does not depend upon neurosecretory projections to the pituitary gland, but that the maintenance of an intact gastric mucosa under normal conditions requires the presence of pituitary hormones.Key words: vagus, paraventricular nucleus, hypophysectomy, gastric.
Characterization of a novel variant of amino acid transport system asc in erythrocytes from Przewalski's horse (Equus przewalskii)
Authors: Fincham Daron A. , Ellory John Clive , Young James D.
Published: April 2011

In thoroughbred horses, red blood cell amino acid transport activity is Na+-independent and controlled by three codominant genetic alleles (h, l, s), coding for high-affinity system asc1 (L-alanine apparent Km for influx at 37 °C [Formula: see text] 0.35 mM), low-affinity system asc2 (L-alanine Km[Formula: see text] 14 mM), and transport deficiency, respectively. The present study investigated amino acid transport mechanisms in red cells from four wild species: Przewalski's horse (Equus przewalskii), Hartmann's zebra (Zebra hartmannae), Grevy's zebra (Zebra grevyi), and onager (Equus hemonius). Red blood cell samples from different Przewalski's horses exhibited uniformly high rates of L-alanine uptake, mediated by a high-affinity asc1-type transport system. Mean apparent Km and Vmax values (± SE) for L-alanine influx at 37 °C in red cells from 10 individual animals were 0.373 ± 0.068 mM and 2.27 ± 0.11 mmol (L cells∙h), respectively. As in thoroughbreds, the Przewalski's horse transporter interacted with dibasic as well as neutral amino acids. However, the Przewalski asc1 isoform transported L-lysine with a substantially (6.4-fold) higher apparent affinity than its thoroughbred counterpart (Km for influx 1.4 mM at 37 °C) and was also less prone to trans-stimulation effects. The novel high apparent affinity of the Przewalski's horse transporter for L-lysine provides additional key evidence of functional and possible structural similarities between asc and the classical Na+-dependent system ASC and between these systems and the Na+-independent dibasic amino acid transport system y+. Unlike Przewalski's horse, zebra red cells were polymorphic with respect to L-alanine transport activity, showing high-affinity or low-affinity saturable mechanisms of L-alanine uptake. Onager red cells transported this amino acid with intermediate affinity (apparent Km for influx 3.0 mM at 37 °C). Radiation inactivation analysis was used to estimate the target size of system asc in red cells from Przewalski's horse. The transporter's in situ apparent molecular weight was 158 000 ± 2500 (SE).Key words: amino acid transport, erythrocyte, Przewalski's horse.
Inhibitory and excitatory mechanisms of neurotensin action in canine intestinal circular muscle in vitro
Authors: Christinck F. , Daniel E. E. , Fox-Threlkeld J. E. T.
Published: April 2011

The effect of neurotensin on canine ileal circular muscle devoid of myenteric plexus was investigated using single and double sucrose gap techniques. Similar results were obtained with microelectrode techniques. Neurotensin caused a temperature-sensitive and dose-dependent biphasic response, an initial hyperpolarization associated with inhibition of contractile activity, followed by an excitatory phase, usually consisting of spike discharge and tonic and phasic contractions, for which depolarization was not required. Neither response was affected by tetrodotoxin, phentolamine, propranolol, or atropine. The hyperpolarization was associated with decreased membrane resistance, blocked by 10−7 M apamin, and converted to tonic depolarization by apamin (10−6 M). Tachyphylaxis to neurotensin occurred when the stimulation interval was less than 20 min. After Ca2+ depletion, depolarization was observed instead of the hyperpolarization; this depolarization was not affected by nitrendipine and was gradually abolished with repetitive stimulations at 20-min intervals. When Ca2+ was present, nifedipine did not alter the hyperpolarizing phase of the response but inhibited spiking and blocked all contractions. The excitatory phase of the response was enhanced by Bay K-8644. Neuromedin N elicited a response identical with that of neurotensin. The responses of the two peptides were completely cross tachyphylactic. Inhibitory junction potentials were not affected by neurotensin tachyphylaxis. It is concluded that neurotensin and neuromedin N activate apamin-sensitive, calcium-dependent potassium channels in circular muscle, causing membrane hyperpolarization and inhibition of muscle contraction. Release of intracellular calcium is involved in the activation of these potassium channels. When opening of potassium channels was inhibited, release of intracellular calcium caused depolarization. Neurotensin also activates L-type calcium channels, resulting in muscle contraction. Neurotensin does not appear to contribute to the compound inhibitory nerve response represented by the inhibitory junction potential.Key words: neurotensin, apamin, inhibitory junction potentials, ileum, circular muscle.
Tissue distribution, elimination, and metabolism of [3H]leukotriene C4 by the conscious marine toad, Bufo marinus
Authors: Pfeifer Cynthia A. , Furilla Robert A. , Gronert Karsten , Goss DeNa D. , Herman Ceil A.
Published: April 2011

Tissue distribution, elimination, and metabolism of 3H-labelled leukotriene (LT) C4 were studied in ureter-catheterized conscious marine toads, Bufo marinus. Six and 24 h after injection, organs containing the highest percent of injected radioactivity were small intestine, liver, and kidney. Radioactivity declined in these organs at 24 h by approximately threefold. Peak elimination time for radioactivity in the urine was between 2 and 4 h after the injection. During the 24-h collection period, 55.2 ± 0.2% of the injected radioactivity was eliminated in the urine. Polar metabolites represented 40.3 ± 1.1, 57.3 ± 5.6, and 62.8 ± 1.6% of the radioactivity at 2, 4, and 6 h, respectively. The primary urinary polar metabolite was 20-carboxy-LTE4, with 18-carboxydinor-LTE4 and 20-hydroxy-LTE4 also present. [3H]LTE4 decreased from 37.2 ± 1.8% at 2 h to 15.8 ± 3.3 and 15.0 ± 2.1% of the radioactivity at 4 and 6 h, respectively. Bile radioactivity was low. N-Acetyl-LTE4 was not detected in urine or bile samples. Radioactivity in the pan water was 14.3 ± 2.4 and 15.8 ± 2.5% of the injected radioactivity, at 6 and 24 h, respectively, suggesting that the skin was a route for excretion of leukotrienes. The marine toad is an interesting model demonstrating both similarities and differences from mammals in distribution, elimination, and metabolism of peptide leukotrienes.Key words: leukotriene, metabolism, elimination, distribution, Bufo marinus.
Erythrocyte ion regulation across inactive muscle during leg exercise
Authors: McKelvie R. S. , Lindinger M. I. , Jones N. L. , Heigenhauser G. J. F.
Published: April 2011

Ion concentration changes in whole blood, plasma, and erythrocytes across inactive muscle were examined in eight healthy males performing four 30-s bouts of maximal isokinetic cycling with 4 min rest between each bout. Blood was sampled from the arm brachial artery and deep antecubital vein during the intermittent exercise period and for 90 min of recovery. Arterial and venous erythrocyte lactate concentration ([Lac−]) increased from 0.3 ± 0.1 to 12.5 ± 1.3 (p < 0.01) and 1.1 ± 0.4 to 8.5 ± 1.5 mmol/L (p < 0.01), respectively, returning to control values during recovery. Arterial and venous plasma [Lac−] increased from 1.5 ± 0.2 to 27.7 ± 1.8 and from 1.3 ± 0.4 to 25.7 ± 3.5 mmol/L, respectively, and was greater than erythrocyte [Lac−] throughout exercise and recovery. Arterial and venous [K+] increased in erythrocytes from 119.5 ± 5.1 to 125.4 ± 4.6 (p < 0.01) and from 113.6 ± 1.7 to 120.6 ± 7.1 mmol/L, respectively, decreasing to control during recovery. In arterial and venous plasma, [K+] increased from 4.3 ± 0.1 to 6.1 ± 0.2 (p < 0.01) and from 4.5 ± 0.2 to 5.3 ± 0.2 mmol/L (p < 0.01), respectively, decreasing to control during recovery. The efflux of Lac− out of erythrocytes against an electrochemical concentration gradient suggests the presence of an active transport system. Efflux of K+ from erythrocytes as blood passes across inactive muscle affords an important adaptation to the K+ release from muscle activated in heavy exercise.Key words: isokinetic cycle ergometer, potassium, lactate, red cell volume, arteriovenous difference.
Synaptic mechanisms in sympathetic preganglionic neurons
Authors: Dun N. J. , Wu S. Y. , Shen E. , Miyazaki T. , Dun S. L. , Ren C.
Published: April 2011

Intracellular recordings from sympathetic preganglionic neurons (SPNs) in adult cat and neonatal rat spinal cord slices reveal four types of synaptic potentials, namely, excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs), and slow EPSPs in both preparations, and a slow IPSP in cat SPNs. Pharmacological studies show that glutamate or a related excitatory amino acid and glycine are the probable mediators of EPSPs and IPSPs. There may be heterogenous mediators of slow EPSPs; substance P, serotonin, norepinephrine, and epinephrine are all probable mediators of slow EPSPs in subpopulations of SPNs. In the case of slow IPSPs, norepinephrine appears to be the likely transmitter. Finally, stimulation of ventral roots elicits a synaptic potential that appears to be caused by glutamate released from afferent fibers in the ventral roots. Our results indicate that a multitude of synaptic mechanisms exist in the rat SPNs by means of which inputs arising from sensory and supraspinal neurons are processed in a timely and orderly manner, thus ensuring highly organized but differentiated outputs to multiple peripheral target cells.Key words: sympathetic preganglionic neurons, excitatory postsynaptic potentials, inhibitory postsynaptic potentials, slow excitatory postsynaptic potentials, glutamate, glycine.