bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular reactivity, tissue levels, and binding sites for endothelin: a comparison in the spontaneously hypertensive and Wistar–Kyoto rats
Authors: Bolger Gordon T. , Liard Francine , Jodoin Annette , Jaramillo Jorge
Published: April 2011

The role of endothelin (ET-1) in mediating the development of blood pressure was investigated in the spontaneously hypertensive (SHR) rat using the Wistar–Kyoto (WKY) rat as the normotensive control. The following were characterized in both rat strains: age-dependent changes in mean arterial blood pressure (MAP), tissue (blood, lung, heart, and kidney) levels of immunoreactive ET-1 like related peptides (ET-1RP), aortic ring responses to ET-1, and specific high-affinity tissue (lung, atrium, ventricle, aorta, and kidney) binding sites for 125I-labelled ET-1. Commencing at age 10 weeks through to 12 weeks, SHR rats but not WKY rats developed a significant increase in MAP (from 152 ± 7 to 189 ± 3 mmHg) (1 mmHg = 133.32 Pa). However, in both WKY and SHR rats immunoreactive levels of ET-1RP increased (100 and 80%, respectively) throughout the same measurement period. The potency of ET-1 to contract aortic rings from SHR rats was slightly but not significantly greater than that for aortic rings from WKY rats, although aortic rings from SHR rats contracted in the presence of 0.5 nM ET-1, while those from WKY rats did not. The levels of immunoreactive ET-1RP were significantly reduced (32%) in the kidney and unchanged in the heart and lung of SHR rats compared with WKY rats. Specific 125I-labelled ET-1 binding sites displayed an increase and a significant decrease (24%) of density in the atrium and ventricle, respectively, a significant increase (31%) of affinity in the lung, and were unchanged in the kidney and aorta of SHR rats compared with WKY rats following the development of hypertension. The lack of a correlation between circulating levels of immunoreactive ET-1RP and the development of hypertension coupled with a lack of significant differences in vascular reactivity suggest that ET-1 is not the sole mediator of hypertension in this animal model. However, the tissue-specific changes in immunoreactive ET-1RP and 125I-labelled ET-1 binding sites suggest that ET-1 may be a partial mediator of hypertension and is subject to compensatory changes in response to the increased total peripheral resistance in SHR rats.Key words: endothelin, hypertension, spontaneously hypertensive rat.
The 1990 Pharmaceutical Manufacturers Association of Canada Keynote Lecture. The role of the cytochromes P450 in the detoxication and activation of drugs and other chemicals
Authors: Parke Dennis V. , Ioannides Costas , Lewis David F. V.
Published: April 2011

The roles of the cytochromes P450 are reviewed, with emphasis on their involvement in the detoxication of drugs and chemicals, the activation of carcinogens, and the toxicity of drugs. Cytochromes P450 have different characteristics. P450I mostly activates carcinogens and other chemicals by forming oxygenated reactive intermediates, which are also associated with the formation of neoantigens and immunotoxicity. P450IIE has a propensity to form oxygen radicals, which are cytotoxic and carcinogenic; other cytochromes generate oxygen radicals by futile cycling when activated by difficultly metabolized substrates. Novel procedures for the safety evaluation of chemicals are described; COMPACT is based on the computer graphic determination of the spatial conformation and electronic structure of chemicals to enable their activating cytochromes P450, and hence their toxicity, to be established; ENACT is based on quantifying the induction of individual cytochromes P450, since the extent of induction of P450I, and possibly other activating cytochromes, is directly related to the carcinogenic potential of the chemical.Key words: cytochromes P450, oxygen radicals, enzyme induction, drug metabolism, chemical toxicity.
Effects of ethanol exposure on the embryo–fetus: experimental considerations, mechanisms, and the role of prostaglandins
Authors: Smith Graeme N. , Patrick John , Sinervo Ken R. , Brien James F.
Published: April 2011

The purpose of this review is to critically examine the effects of ethanol on the embryo–fetus. There has been a tremendous amount of human epidemiological and experimental animal research on the characterization of the anomalies produced by chronic prenatal ethanol exposure and the identification of critical periods of vulnerability and critical amounts of ethanol necessary to produce fetal effects and (or) abnormal development. Few studies have examined the underlying mechanism(s) of the action of ethanol, and even fewer studies have examined the effects of single-dose ethanol exposure on the embryo–fetus. In this review, the current state of knowledge of the effects of chronic use of ethanol on the embryo–fetus is summarized. The primary focus of the review is on the embryonic–fetal effects of acute ethanol exposure, with particular emphasis on the ethanol-induced suppression of fetal breathing movements, as this effect appears to be a very sensitive index of acute exposure of the near-term fetus to ethanol. Factors to be considered in the selection of experimental animals to investigate the mechanism of action of ethanol and to study the acute effects of ethanol are discussed. Postulated mechanisms of action of ethanol on the embryo–fetus are evaluated with a focus on the role of prostaglandins. Finally, future directions in this field of research are proposed.Key words: alcohol, ethanol, embryo, fetus, prostaglandins.
Effects of prostaglandins, cAMP, and changes in cytosolic calcium on platelet aggregation induced by a thromboxane A2 mimic (U46619)
Authors: Yun John C. H. , Öhman K. Peter , Gill Jr. John R. , Keiser Harry
Published: April 2011

The effects of U46619, a thromboxane mimic, on cytosolic Ca2+ concentration and platelet aggregation were determined in human platelets. Cytosoiic Ca2+ concentration was determined by Quin-2 fluorescence and platelet aggregation quantitated with an aggregometer. Addition of U46619 (1 × 10−7 M) to the platelet suspension produced a rapid increase in cytosolic Ca2+ and platelet aggregation. Pretreatment of platelets with EGTA (3 × 10−3 M), verapamil (5 × 10−4 M), a calcium entry blocker, or 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (1 × 10−3 M), an inhibitor of intracellular Ca2+ release, either blunted or markedly delayed the rate, but not the magnitude, of increase in cytosolic Ca2+ and prevented platelet aggregation by U46619. Pretreatment of platelets with prostaglandin I2 (PGI2) (5 × 10−8 M), PGD2 (5 × 10−8 M), PGE1 (5 × 10−8 M), PGF2α (1 × 10−5 M), dibutyryl cAMP (5 × 10−3 M), or forskolin (1 × 10−6 M) prevented both the increase in cytosolic Ca2+ and the associated platelet aggregation induced by U46619. These data suggest that U46619 may induce platelet aggregation through an increase in cytosolic Ca2+, and that both Ca2+ entry and its release from intracellular storage sites probably contribute to the increase in cytosolic Ca2+. Furthermore, the rate of the increase in cytosolic Ca2+ concentration, as well as the magnitude of the increase, appear to be critical for platelet aggregation induced by U46619. Our data are consistent with the hypothesis that PGs inhibit U46619-induced platelet aggregation by preventing the increase in cytosolic Ca2+, and that these effects may be mediated via an increase in cAMP, since they were induced by PGs and cAMP.Key words: thromboxane, cytosolic calcium, platelet aggregation, prostaglandins, EGTA, verapamil, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride.
Chronic Musculoskeletal Pain Symposium
Authors: Lund James P. , Bushnell M. Catherine , Chapman C. Elaine
Published: April 2011

The aim of this year's symposium was to bring together basic and clinical scientists working towards the understanding of several chronic pain conditions of muscles and joints that are of unknown etiology. All of these are difficult to treat and their impact on the quality of life is wide-ranging.The organizers wish to acknowledge the financial support of Sterling-Winthrop, Fonds de la recherche en santé du Québec, Merck Frosst Canada, the Faculté de médecine and the Faculté de médecine dentaire of Université de Montréal, and to thank the following people for their assistance with the local organization: Helene Auzat, Gérald Beauchamp, Suzanne Cabana, Daniel Cyr, Michel Dumas, Giovanni Filosi, Claude Gauthier, and Claire Lamarche.The chairmen of the sessions have provided excellent introductions to the four themes: Basic Mechanisms, Arthritis and Headache, Muscle Pain Syndromes, and Pain Control. We are particularly grateful to our colleague, Dr. Gilles Lavigne, for his assistance and to Dr. Jonathan Dostrovsky, who agreed to help with the task of editing the papers.
The pain-adaptation model: a discussion of the relationship between chronic musculoskeletal pain and motor activity
Authors: Lund James P. , Donga Revers , Widmer Charles G. , Stohler Christian S.
Published: April 2011

Articles describing motor function in five chronic musculoskeletal pain conditions (temporomandibular disorders, muscle tension headache, fibromyalgia, chronic lower back pain, and postexercise muscle soreness) were reviewed. It was concluded that the data do not support the commonly held view that the pain of these conditions is maintained by some form of tonic muscular hyperactivity. Instead, it seems clear that in these conditions the activity of agonist muscles is often reduced by pain, even when this does not arise from the muscle itself. On the other hand, pain causes small increases in the level of activity of the antagonist. As a consequence of these changes, force production and the range and velocity of movement of the affected body part are often reduced. To explain how such changes in the behaviour come about, we propose a neuro-physiological model based on the phasic modulation of excitatory and inhibitory interneurons supplied by high-threshold sensory afferents. We suggest that the "dysfunction" that is characteristic of several types of chronic musculoskeletal pain is a normal protective adaptation and is not a cause of pain.Key words: pain, headache, temporomandibular disorders, fibromyalgia, chronic lower back pain, post-exercise muscle soreness.
Electrical stimulation of peripheral and central pathways for the relief of musculoskeletal pain
Authors: Bushnell M. Catherine , Marchand Serge , Tremblay Nicole , Duncan Gary H.
Published: April 2011

One method for the treatment of chronic musculoskeletal pain involves stimulation of the peripheral or central nervous system. Such stimulation includes transcutaneous electrical nerve stimulation, dorsal column stimulation, and deep brain stimulation. This review discusses the clinical use of electrical stimulation for the relief of musculoskeletal pain, and describes the results of studies conducted in our laboratory suggesting that such stimulation reduces pain transmission along sensory-discriminative pathways.Key words: pain, nociception, transcutaneous electrical nerve stimulation, dorsal column stimulation, deep brain stimulation.
Effects of isoflurane, halothane, and enflurane on myocardial flow and energy stores in the perfused rat heart
Authors: Blaise G. A. , Noël J. , Villeneuve E. , Hollman C. , Vinet B. , Boulanger Y. , Vinay P.
Published: April 2011

The effect of three volatile anesthetics (halothane, enflurane, and isoflurane) on coronary flow and metabolic state of isolated rat hearts was studied. These anesthetics are coronary dilators and their effects are dose dependent. At 2 MAC (minimum alveolar concentration), isoflurane, enflurane, and halothane increase coronary flow by 114 ± 5.9, 93 ± 6.1, and 77 ± 6.4%, respectively (p < 0.001). At these concentrations, they also have a modest but significant metabolic effect causing a 30% reduction in myocardial ATP and phosphocreatine levels, with no significant modification in ADP and AMP concentrations. Energy charge and lactate/pyruvate ratio were also unaffected by these anesthetics. The vascular and metabolic effects were reversible within 2 and 30 min, respectively. Perfusion of the hearts with a Krebs–Henseleit solution without Pi did not interfere with the vascular and the metabolic effect of the anesthetics; however, in this case, ATP and phosphocreatine concentration did not return to control levels after their discontinuation despite full recovery of the vascular effect. These data suggest that the volatile anesthetics have direct coronary vascular and myocardial metabolic effects and that these effects occur independently.Key words: anesthetics, volatile, coronary flow, metabolic equilibrium.
The effect of isoproterenol on fluid and electrolyte transport in the inner medullary collecting duct
Authors: Honrath U. , Wilson D. R. , Sonnenberg H.
Published: April 2011

In the late distal and cortical collecting tubule, which is the principal regulatory site for potassium (K) excretion, vasopressin stimulates, and epinephrine via β-adrenergic action, inhibits K secretion. In the inner medullary collecting duct (IMCD) we have shown that vasopressin also stimulates K secretion. The present experiments were designed to determine whether the β-adrenergic agonist, isoproterenol, would induce K reabsorption in the IMCD, and (or) prevent a secretory response to acute KCl infusion. Two groups of rats, with or without isoproterenol administration (3 μg/h), were subjected to retrograde microcatheterization of the IMCD before and during infusion of 0.83 mol/h KCl. Isoproterenol reduced plasma K concentration and urinary K excretion, but the response to acute KCl infusion was qualitatively similar to control. Isoproterenol decreased delivery of potassium, chloride, and fluid to the IMCD, there was no net transport of K along the duct in either group, and KCl infusion did not result in K secretion in either group. The results indicate that isoproterenol may inhibit K secretion in the late distal or cortical collecting tubule. However, there was no statistically significant difference in K transport along the IMCD between isoproterenol and control groups. Reduced sodium excretion, which was found during isoproterenol administration both before and after KCl infusion, was associated with no change in sodium delivery but with increased sodium reabsorption in the IMCD. This increased sodium reabsorption may be a direct effect of isoproterenol, or may be due to reflex cardiovascular adjustments associated with systemic actions of the drug.Key words: rat, KCl infusion, potassium transport, fluid reabsorption, sodium reabsorption, chloride reabsorption, catecholamines.
Inhibition of the acetylcholine-induced relaxation of canine isolated basilar artery by potassium-conductance blockers
Authors: Elliott D. A. , Gu M. , Ong B. Y. , Bose D.
Published: April 2011

Canine basilar artery rings precontracted with 5-hydroxytryptamine (0.1–0.5 μM) relaxed in the presence of acetylcholine (25–100 μM), sodium nitroprusside (0.1 μM), or stimulation of the electrogenic sodium pump by restoration of extracellular K+ (4.5 mM) after K+- deprivation. Acetylcholine-induced relaxation is believed to be caused by the release of endothelium-derived relaxing factor (EDRF) and is prevented by mechanical removal of the endothelium, while relaxations induced by sodium nitroprusside or restarting of the sodium pump are endothelium-independent. Acetylcholine-induced relaxation was selectively blocked by pretreatment of the tissue with the nonselective K+ conductance inhibitors, 4-aminopyridine (4-AP, 3 mM), Ba2+ (1 mM), and tetraethylammonium (20 mM). 4-AP also blocked ACh-mediated relaxation in muscles contracted with elevated external K+. Relaxation of 5-hydroxytryptamine-induced contraction by sodium nitroprusside, or by addition of K+ to K+-deprived muscle, was not affected by 4-AP. Relaxation of basilar artery with acidified sodium nitrite solution (containing nitric oxide) was reduced by 4-AP. These results suggest that 4-AP and possibly Ba2+ inhibit acetylcholine-induced endothelium-dependent relaxation by inhibition of the action of EDRF on the smooth muscle rather than through inhibition of release of EDRF. The increase in K+ conductance involved in acetylcholine-induced relaxation is not due to ATP-inhibited K+ channels, as it is not blocked by glyburide (10−6 M). Endothelium-derived relaxant factor(s) may relax smooth muscle by mode(s) of action different from that of sodium nitroprusside or by hyperpolarization due to the electrogenic sodium pumping. Since 4-AP and similar agents are used to increase myogenic tone, the absence of the endothelium may be mistakenly assumed in the presence of these agents.Key words: Ba2+, blood vessels, endothelium-derived hyperpolarizing factor, endothelium-derived relaxing factor, glyburide, K channel, pinacidil, relaxation.
Creatine kinase and mechanical and mitochondrial functions in hereditary and diabetic cardiomyopathies
Authors: Veksler V. I. , Murat I. , Ventura-Clapier R.
Published: April 2011

To determine whether the development of cardiomyopathies is associated with alterations in creatine kinase function, the functional properties of cardiac contractile apparatus and mitochondria were studied in two different models of cardiomyopathies, the Syrian hamster (hereditary dilated cardiomyopathy, strain UM-X7.1, 200 days old) and the diabetic rat (4–6 weeks after injection of streptozotocin) using ventricular skinned fibers. After Triton X-100 treatment, the hereditary cardiomyopathic fibers demonstrated decreased maximal calcium-activated tension and unchanged calcium sensitivity, whereas fibers from diabetic hearts exhibited unchanged maximal tension and increased calcium sensitivity, when compared with their respective controls. In both cases myofibrillar creatine kinase appeared unchanged. The functional properties of total tissue mitochondria were evaluated using saponin-skinned fibers. Coupling between oxidation and phosphorylation was not altered in cardiomyopathies. Respiration rate (per unit of tissue dry weight) was normal in hereditary cardiomyopathy but was considerably lower in diabetic fibers compared with control fibers. In both models of cardiomyopathies, creatine-stimulated respiration was significantly lower than in controls, thus indicating the depression of functional activity of mitochondrial creatine kinase.Key words: diabetes, hereditary cardiomyopathy, myofibrils, mitochondria, creatine kinase.
Amiodarone antagonizes the effects of T3 at the receptor level: An additional mechanism for its in vivo hypothyroid-like effects
Authors: Paradis Pierre , Lambert Chantal , Rouleau Jean
Published: April 2011

Amiodarone is a diiodinated benzofuran derivative that has some structural similarities to the thyroid hormones and contains two iodine atoms per molecule. It has exhibited hypothyroid-like effects that are thought to be the result of an inhibition of thyroid hormone synthesis due to iodine load, a decrease in the T4 to T3 conversion, and (or) a competitive binding for T3 receptors. The aim of this study was to determine if this third mechanism contributes to the hypothyroid-like effects of amiodarone in vivo. To do so, some characteristic features known to be influenced by hypothyroidism were determined in surgically thyroidectomized rats (n = 48), which received replacement doses of T3 (0.5 and 1.0 μg∙100∙g−1∙day−1) with or without amiodarone (60 mg∙kg−1∙day−1). Thyroidectomy produced a hypothyroid state upon which amiodarone had no detectable effects except a negative body weight gain. T3 (0.5 μg) nearly normalized the thyroid status of the animals, but the concomitant administration of amiodarone induced hypothyroid-like effects suggesting that these effects are dependent on T3. Higher doses of T3 (1.0 μg) produced hyperthyroid-like effects and attenuated the effects of amiodarone. Unexpectedly, amiodarone decreased T3 plasma concentrations. To determine if the effects of amiodarone were the results of a decrease in T3 plasma and myocardial concentrations or a competition with T3 for its receptors, exogenous T3 pharmacokinetics were studied in thyroidectomized rats receiving T3 (0.5 μg) with or without amiodarone. The results suggested that amiodarone increased T3 cardiac concentrations. It was therefore concluded that, in addition to affecting thyroid hormone synthesis and T4 to T3 conversion, amiodarone seems to antagonize the effects of T3 at the receptor level by a competitive mechanism.Key words: amiodarone, hypothyroid-like effects, T3 receptors.
Interaction of glyceryl trinitrate and sodium nitroprusside with bovine pulmonary vein homogenate and 10 000 × g supernatant: biotransformation and nitric oxide formation
Authors: Marks Gerald S. , McLaughlin Brian E. , Brown Leslie B. , Beaton Danielle E. , Booth Brian P. , Nakatsu Kanji , Brien James F.
Published: April 2011

The current proposed mechanism of action of nitrovasodilator drugs involves biotransformation to nitric oxide, which is postulated to be the active vasodilator substance. Our objective was to determine whether nitric oxide was formed from two prototype nitrovasodilator drugs, glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), after incubation with bovine pulmonary vein (BPV) preparations. GTN or SNP was incubated in an argon atmosphere with phosphate buffer, BPV homogenate, or the 10 000 × g supernatant fraction of the homogenate. Nitric oxide formation, as determined by a chemiluminescence – headspace gas method, was measurable following the incubation of SNP with BPV homogenate and 10 000 × g supernatant. There was no detectable formation of nitric oxide from the incubation of GTN with the two BPV preparations, although GTN was biotransformed to glyceryl dinitrate, as determined by gas–liquid chromatography. There was decreased recovery of nitric oxide during the incubation of authentic nitric oxide with the two BPV preparations as compared with buffer. In conclusion, formation of nitric oxide was measured for the interaction of SNP, but not GTN, with BPV preparations. However, the data do not exclude the possible formation of nitric oxide from GTN, as nitric oxide was shown to be sequestered or transformed by the BPV preparations.Key words: glyceryl trinitrate, sodium nitroprusside, nitric oxide formation, bovine pulmonary vein.
The 1989 Borden Award Lecture. Some effects of dietary components (amino acids, carbohydrate, folic acid) on brain serotonin synthesis, mood, and behavior
Authors: Young Simon N.
Published: April 2011

This review covers three areas in which dietary components may influence brain serotonin synthesis, mood, and behavior. In the first, tryptophan-deficient amino acid mixtures have been used to lower brain tryptophan and serotonin in normal human subjects for experimental purposes. Results suggest that low serotonin can cause lowered mood and increased aggression, but that it is probably not involved in any simple way in carbohydrate craving. Low serotonin levels can block the analgesic effect of morphine in humans. The second area concerns deficiencies of folic acid, which can cause low brain serotonin and lowered mood. Folate supplements may be useful in some depressed patients. The third area concerns the effect of carbohydrate meals. Although it is well established that carbohydrate meals raise brain tryptophan and serotonin in the rat, and that protein meals lower them, any effects of carbohydrate or protein meals on human brain serotonin are likely to be negligible under most circumstances. Carbohydrate meals can have definite effects on mood and behavior in humans, and there are a variety of mechanisms, other than alterations in brain serotonin, that might mediate these effects.Key words: tryptophan, serotonin, folic acid, carbohydrate, protein, mood.
Use-dependent decline in rat aorta sensitivity to contraction by potassium
Authors: Wright Gary
Published: April 2011

Aortic rings excised from rats at 12 weeks of age showed a decrease in responsiveness during repeated contraction by increasing potassium concentration. By comparison, aortic rings obtained from rats at 22 and 26 weeks exhibited less loss or an increase in responsiveness to high potassium concentration during repeated contraction. The decrease in responsiveness to potassium in aortae of young rats was not due to the extended interval of incubation of the tissue in vitro. Aortic rings incubated without stimulation for 4 h following a reference contraction showed no change in contractile response to potassium. However, the magnitude of loss in responsiveness to potassium did appear to be related to the potassium concentration and the length of time the tissues were exposed to the high potassium solutions. Contraction of the tissue at 60 versus 30 mM KCl or extending the interval in depolarizing solution from 15 to 60 min significantly enhanced the decline in tissue responsiveness to potassium. The interruption of a series of potassium-induced contractions by exposure of the tissue to contractile (serotonin, norepinephrine) or relaxant (acetylcholine, isoproterenol) stimuli had no effect on the loss in responsiveness to potassium. However, injection of the calcium channel agonist, Bay K 8644, into the incubation media restored responsiveness to potassium. Concentration–response curves indicated that both sensitivity and the maximal response to potassium were reduced in aortic rings repeatedly contracted with potassium. Bay K 8644 addition immediately following the control contraction significantly increased sensitivity and the maximal response to potassium compared with the control contraction. After tissues had been repeatedly contracted by potassium, Bay K 8644 restored tissue sensitivity and the maximum response to the control level. The results indicate that aortic tissues of young rats are subject to desensitization to potassium stimulation during repeated exposure in vitro. The restoration of tissue sensitivity by Bay K 8644 suggests that this desensitization centers on decreased effectiveness of the voltage-dependent mechanism for increasing intracellular concentration of free calcium and the activation of the contractile protein.Key words: concentration–response, depolarization, vascular smooth muscle, tension.
Characterization of bradykinin receptors in peripheral organs
Authors: Rhaleb Nour-Eddine , Rouissi Noureddine , Drapeau Guy , Jukic Daniela , Regoli Domenico
Published: April 2011

Bradykinin (BK) and related kinins are potent stimulants of the rabbit jugular vein, the hamster urinary bladder, and the guinea pig trachea. The characterization of kinin receptors in these tissues was made with agonists and antagonists. Results obtained with agonists indicate that bradykinin and kallidin are much more active than des-Arg9-BK and suggest the presence of B2 receptors in the three organs. Some new agonists were also tested and the BK analogue, [Hyp3,Tyr(Me)8]BK, was found to be a potent and selective stimulant of the three preparations, with pD2 values of 8.56, 8.00, and 8.39, respectively, but inactive on the rabbit aorta (a B1-receptor system). Contractile effects of kinins in the rabbit jugular vein and hamster urinary bladder were reduced or eliminated by B2-receptor antagonists but at different concentration levels; e.g., acetyl-D-Arg[Hyp3,D-Phe7]BK showed pA2 values of 7.78 on the rabbit jugular vein but only 5.72 on hamster urinary bladder. This compound contracted the guinea-pig trachea and was found to be inactive as an antagonist on this preparation. Contractions of the hamster urinary bladder and the guinea-pig trachea in response to bradykinin were markedly reduced or eliminated by indomethacin and by BW 755C, while those of the rabbit jugular vein were not modified. The present findings indicate that the myotropic effect of kinins on the rabbit jugular vein depends on the activation of B2 receptors and suggest that B2 receptors are largely responsible also for the response of the hamster urinary bladder. B2 receptors and (or) a nonreceptor mechanism appear to be involved in the stimulant effects of the kinin agonists and some antagonists in the guinea-pig trachea.Key words: bradykinin, B2 receptors, agonists, antagonists, smooth muscles, arachidonic acid cascade, indomethacin, BW 755C.
Amino Acids as Neurotransmitters.: A Symposium to honour Hugh McLennan on his retirement
Authors: Ledsome J. R.
Published: April 2011

A meeting was held at the University of British Columbia on May 28–29, 1990 to honour the many important scientific contributions made by Dr. Hugh McLennan to our understanding of chemical neurotransmission in the brain and spinal cord. The invited speakers were those with whom Dr. McLennan has at one time or another collaborated, and their presentations reflected Hugh's early interest in GÀBA (factor I) as an inhibitory transmitter and his research over the last two decades into the physiology and pharmacology of acidic amino acid receptors.The session on GABA opened with an intriguing discussion by Professor Florey of the history of the isolation and identification of GABA as a neurotransmitter and was followed by papers dealing with the electrophysiological actions of GABA. Professor Curtis discussed its pre- and post-synaptic actions in the spinal cord, while Dr. Mathers presented data derived from GABA-gated chloride channels isolated from cultured neurones. Professor Krnjević was unfortunately unable to attend the symposium.Work presented by Professors Watkins and Lodge and Dr. Curry provided an excellent historical perspective on the birth and rapid development of excitatory amino acid pharmacology, a field to which Dr. McLennan has contributed enormously.Among the topics pertaining to the electrophysiological actions of acidic amino acids was the role of the NMDA receptor both in long-term potentiation (Dr. Collingridge) and in synaptic transmission in the kainic acid-lesioned hippocampus (Dr. Wheal), the effects of antagonists on synaptic transmission in the thalamus (Dr. Hicks), and the modulation by catecholamines of glutamate-induced neuronal excitations (Dr. Marshall).In his closing address Dr. McLennan, with characteristic grace and style, acknowledged the efforts of his co-workers in his many achievements. Those of us who have had the great pleasure of collaborating with Hugh here at UBC or within the scientific community wish him all the best in his retirement.
Modulation of amino acid neurotransmitter actions by other neurotransmitters: some examples
Authors: Marshall Kenneth C. , Xiong Huangui
Published: April 2011

Developments in the field of central neurotransmission indicate that amino acids serve as important and widespread transmitters throughout the central nervous system. There are increasing indications from recent experimental studies that several of the other central neurotransmitters may exert potent effects on central neurons by modulating the actions of amino acids. Noradrenaline and serotonin have received particular attention as potential modulators, and a wide variety of actions has been reported for them. Modulatory actions have been reported at both pre- and post-synaptic levels, including both short- and long-term effects and facilitation or inhibition of amino acid actions. Selectivity has been found both for specific receptor subtypes of the neuromodulator and for specific effects of amino acids. Examples of such selectivity are modification of actions of an amino acid with little effect on spontaneous activity or membrane properties of the target cell, or in comparison to the actions of other neurotransmitters, or even other selective amino acid analogs. Modulatory actions on amino acids have also been reported for several other neurotransmitters including acetylcholine and various peptides. Recent studies of angiotensin II demonstrate that when iontophoretically applied, it can potently and selectively block the depolarizing action of glutamate on locus coeruleus neurons. It is possible that physiological influences of these various transmitter substances are expressed through modification of amino acid actions, rather than through direct effects on central neurons.Key words: neuromodulation, neurotransmitters, glutamic acid, noradrenaline, angiotensin II.
Cytochrome P450 enzymes: ubiquitous "receptors" for drugs
Authors: LaBella Frank S.
Published: April 2011

Most foreign compounds bind to one or more cytochrome P450 drug-metabolizing isozymes. These heme monooxygenases are most concentrated in the endoplasmic reticulum of liver cells but are present in virtually all biological membranes and in all cells. Some radioligands for known hormone receptors have been found to label, with comparable affinities, specific P450 enzymes. A characteristic feature of P450 enzymes is their broad and overlapping drug specificities, with affinity constants ranging over several orders of magnitude. Because fatty acid derivatives and steroids are endogenous substrates for the P450 enzymes, drugs may interfere with the generation of functional cellular lipids. The functional significance of high-affinity binding of drugs to the oxygenases may, on the one hand, be minimal and reflect extraneous or trivial drug–protein interactions. On the other hand, the drug–P450 union may in other cases mediate the major pharmacological response.Key words: cytochrome P450, radioligand binding, microsomes, sigma receptor, antiestrogen receptor.
Adaptation of intestinal glucose transport in rats with diabetes mellitus occurs independent of hyperphagia
Authors: Fedorak Richard N. , Thomson Alan B. R. , Porter Valerie M.
Published: April 2011

Chronic diabetes enhances intestinal absorption of glucose and induces hyperphagia. We examined the enhanced intestinal absorption of glucose in ad libitum-fed rats with streptozocin-induced diabetes mellitus and compared these results with those obtained from pair-fed diabetic animals. Maximal transport capacity (Vmax) and carrier affinity (K0.5) were determined by measuring jejunal and ileal short circuit current (Isc) responses to varying concentrations of 3-O-methyl-D-glucopyranose and D-glucose. Pair-fed diabetic animals maintained the same body weight as animals fed ad libitum, although ad libitum-fed diabetic rats had an increased oral chow intake. Age-matched control rats maintained a constant jejunal and ileal Vmax and K0.5 throughout the study. Diabetic rats fed ad libitum demonstrated an enhanced Vmax and K0.5 in both jejunum and ileum. Pair feeding diabetic animals further enhanced jejunal Vmax while lowering jejunal K0.5 levels. In contrast, pair feeding diabetic animals delayed and blunted changes in ileal Vmax and prevented changes in ileal K0.5. In conclusion, signals other than those of hyperphagia regulate kinetic changes in glucose absorption during diabetes mellitus. Furthermore, these changes have differing effects on jejunum and ileum.Key words: 3-O-methyl-D-glucose, absorption, streptozocin, pair feeding, ad libitum, hyperphagia, diabetes.
Acute severe carbon monoxide exposure in the rat: effects of hyperglycemia and hypoglycemia on mortality, recovery, and neurologic deficit
Authors: Penney David G. , Helfman C. Clough , Dunbar Jr. Joseph C. , McCoy Lowell E.
Published: April 2011

Human and animal studies suggest a poorer outcome in the presence of abnormal blood glucose concentration during cerebral hypoxia–ischemia. It is unknown whether this is also the case in acute severe carbon monoxide poisoning. Using Levine-prepared rats, three groups were established and exposed to CO to answer this question: (1) hyperglycemics resulting from the administration of a 50% glucose solution, (2) hypoglycemics resulting from the administration of normal saline, and (3) untreated controls. The rats inhaled 2400 ppm CO for 90 min in the absence of anesthesia. Blood glucose was raised to a mean value of 402 mg/dL just prior to CO exposure in group 1. This resulted in an increased mortality rate (i.e., 54%), and during 4 h of room air recovery an impaired ability to regain body temperature, an increased plasma lactate dehydrogenase activity, and an increased neurologic deficit as compared with group 3. Hypoglycemia, which developed during CO exposure in group 2 (mean minimum glucose after 90 min, 44 mg/dL), resulted in an increased mortality rate (i.e., 46%), and during 4 h of room air recovery an impaired ability to regain body temperature and an increased neurologic deficit as compared with group 3. Blood glucose concentration in the rats in groups 2 and 3 that died during or shortly after CO exposure was significantly depressed relative to the survivors of those groups. Plasma insulin activity was elevated during CO exposure in group 1 as compared with group 3, but fell during recovery; insulin remained low throughout CO exposure and recovery in group 2. The results demonstrate the deleterious effects of both a very high and a very low blood glucose concentration during acute CO exposure.Key words: blood pressure, body temperature, carbon monoxide, glucose, heart rate, hematocrit, hyperglycemia, hypoglycemia, insulin, lactate dehydrogenase, mortality, morbidity, neurologic deficit.
Reduction of tissue noradrenaline content in the isolated perfused rat heart during ischemia: importance of monoamine oxidation
Authors: Lamontagne Daniel , Yamaguchi Nobuharu , Ribuot Christophe , Champlain Jacques de , Nadeau Réginald
Published: April 2011

The effect of ischemia on myocardial noradrenaline concentration and endogenous noradrenaline output was studied in the isolated perfused rat heart. Following a 15-min stabilization period, regional ischemia was produced by coronary artery ligation. After 60 min of ischemia, noradrenaline concentrations were significantly reduced in the interventricular septum and left ventricle but not in the right ventricle. The reduction in tissue noradrenaline concentration was not prevented when the 60-min ischemia was replaced by a 10-min ischemia followed by a 50-min perfusion. No modification in noradrenaline output was observed during a 60-min ischemia. In contrast, reperfusion was accompanied by a washout of noradrenaline in the coronary effluent, corresponding to only 2% of the amount lost by the tissue. The effect of monoamine oxidase inhibition during the whole ischemic period was studied by perfusing the preparation with pargyline starting 10 min before the artery ligation. Although the administration of pargyline did not alter the noradrenaline output, it did prevent a reduction in myocardial noradrenaline concentration. It was concluded that monoamine oxidase may contribute to the elimination of the noradrenaline lost by the cardiac tissue during ischemia.Key words: tissue noradrenaline, myocardial ischemia, monoamine oxidase, isolated rat heart.
Early adaptations in blood substrates, metabolites, and hormones to prolonged exercise training in man
Authors: Green H. J. , Jones S. , Ball-Burnett M. , Fraser I.
Published: April 2011

This study was designed to investigate the effect of short-term, submaximal training on changes in blood substrates, metabolites, and hormonal concentrations during prolonged exercise at the same power output. Cycle training was performed daily by eight male subjects ([Formula: see text], [Formula: see text]) for 10–12 days with each exercise session lasting for 2 h at an average intensity of 59% of [Formula: see text]. This training protocol resulted in reductions (p < 0.05) in blood lactate concentration (mM) at 15 min (2.96 ± 0.46 vs. 1.73 ± 0.23), 30 min (2.92 ± 0.46 vs. 1.70 ± 0.22), 60 min (2.96 ± 0.53 vs. 1.72 ± 0.29), and 90 min (2.58 ± 1.3 vs. 1.62 ± 0.23) of exercise. The reduction in blood lactate was also accompanied by lower (p < 0.05) concentrations of both ammonia and uric acid. Similarly, following training lower concentrations (p < 0.05) were observed for blood β-hydroxybutyrate (60 and 90 min) and serum free fatty acids (90 min). Blood glucose (15 and 30 min) and blood glycerol (30 and 60 min) were higher (p < 0.05) following training, whereas blood alanine and pyruvate were unaffected. For the hormones insulin, glucagon, epinephrine, and norepinephrine, only epinephrine and norepinephrine were altered with training. For both of the catecholamines, the exercise-induced increase was blunted (p < 0.05) at both 60 and 90 min. As indicated by the changes in blood lactate, ammonia, and uric acid, a depression in glycolysis and IMP formation is suggested as an early adaptive response to prolonged submaximal exercise training.Key words: exercise, training, blood metabolites, substrates, hormones.
Effect of renal denervation on plasma renin activity after aortic baroreceptor deafferentation
Authors: Ciriello John , Simon James K. , Mercer Paul F.
Published: April 2011

Renal nerves are thought to play an important role in cardiovascular regulation under both normotensive and hypertensive conditions. In the present study the effect of renal denervation on the changes in plasma renin activity (PRA) after aortic baroreceptor deafferentation (tADN) were investigated in the rat. Bilateral renal denervation did not alter arterial pressure (AP, 100 ± 4 mmHg; 1 mmHg = 133.32 Pa), heart rate (HR, 363 ± 12 bpm), or PRA (2.9 ± 0.6 ng∙mL−1∙h−1) compared with the respective sham renal denervation values of 106 ± 3 mmHg (AP), 385 ± 13 bpm (HR), and 3.3 ± 0.7 ng∙mL−1∙h−1 (PRA). On the other hand, bilateral tADN resulted in significant increases in AP, HR, and PRA. One and 3 days after tADN, AP was 130 ± 4 and 127 ± 6 mmHg, HR was 461 ± 15 and 463 ± 20 bpm, and PRA was 9.1 ± 3.0 and 11.9 ± 4.5 ng∙mL−1∙h−1, respectively. Renal denervation before tADN prevented the increases in AP and PRA, but it did not affect the increase in HR. These data indicate that renal denervation does not alter basal PRA in normotensive animals but prevents the increased renin release observed in neurogenic hypertension. These data suggest that the increased PRA may be one of several factors that contributes to the elevated AP after tADN.Key words: aortic depressor nerve, afferent renal nerves, cardiovascular regulation, hypertension.
Tissue levels of glyceryl trinitrate and cGMP after in vivo administration in rat, and the effect of tolerance development
Authors: Torfgård Krishna , Ahlner Johan , Axelsson Krister L. , Norlander Björn , Bertler Åke
Published: April 2011

The present study compares the tissue distribution of glyceryl trinitrate (GTN) in plasma, heart, brain, aortic tissue, and adipose tissue from GTN tolerant and GTN nontolerant rats at various time points. Furthermore, the cGMP levels in brain, heart, and aortic tissue were studied at various time points as well as the concentration–effect relationship for GTN in aorta isolated at different time points after the last exposure to GTN. Concentrations of GTN were found to be higher in all tissues studied as compared with plasma, and the concentrations of GTN were higher in tissues from tolerant rats as compared with nontolerant rats, except for aortic tissue. Concentration–effect curves obtained in vitro showed that aortic smooth muscle was still tolerant 24 h after the last dose of GTN. The cGMP level in brain was significantly increased by 40% 2 h after a single dose of GTN (50 mg/kg) and in aortic tissue by 50% at 15 min and at 2 h after a single dose of GTN (50 mg/kg). There was no effect on cGMP in brain, while an increase was seen in aortic tissue 15 min after the last dose in tolerant animals. No change in cGMP level was seen in heart neither in nontolerant nor in tolerant animals at 15 min and at 2 h. No effect on cGMP levels in brain, heart, and aortic tissue was seen 8, 16, and 24 h after exposure to GTN in either tolerant or nontolerant rats. In conclusion, GTN does not involve the cGMP system in heart, and tolerance development caused a less pronounced GTN-induced cGMP increase in aortic tissue. Furthermore, the cGMP elevation in tissues does not correlate with GTN levels in tissues.Key words: glyceryl trinitrate, cGMP, tolerance, tissue distribution, rat.
Effects of inactivation of oxytocin receptor and inhibition of prostaglandin synthesis on uterine oxytocin receptor and gap junction formation and labor in the rat
Authors: Chan W. Y. , Berezin Irene , Daniel E. E. , Russell K. C. , Hruby Victor J.
Published: April 2011

Normal term labor is associated with a surge in myometrial oxytocin receptor formation and gap junction development. We have previously shown that inhibition of prostaglandin synthesis by naproxen sodium, 2.0 mg/day, suppressed oxytocin receptor formation but not gap junction formation and prolonged gestation. In this study, we investigated the effects of a specific oxytocin antagonist on oxytocin receptor formation, gap junction formation, and labor in the rat. [Pen1Phe(Me)2,Thr4,Orn8]oxytocin, a specific oxytocin antagonist, was infused subcutaneously during the last 3 days of pregnancy at 300 μg/day. Measurements of myometrial oxytocin receptor concentrations and gap junction formation on days 21 and 22 and days 22–23 (in labor) pregnant uteri showed no significant differences in the Bmax and Kd values between the control and the treated group. Gestation period was not prolonged by the oxytocin antagonist. However, in a separate group of day 23 pregnant rats, the uterine contractile response to 60 mU of oxytocin i.v. was found completely blocked by 10 μg of the oxytocin antagonist. These findings suggest that although functional oxytocin receptors did not appear to be essential for the initiation of labor, oxytocin antagonists may still be effective in the prevention of premature contractions. We also examined the effects of a higher dose of naproxen sodium, 5.0 mg/day, on gap junction formation. At this dose, naproxen sodium suppressed both oxytocin receptor and gap junction formation, prolonged gestation, and delayed parturition by 24 h or longer. Prostaglandin appears to be an important regulator or mediator of oxytocin receptor and gap junction formation and plays a critical role in the initiation of labor.Key words: oxytocin, prostaglandin, oxytocin receptor, gap junction, labor.