bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of adrenalectomy and acute replacement by corticosteroids on distal acidification
Authors: Damasco Maria Cristina , Ansaldo Martin , Malnic Gerhard
Published: April 2011

The role of adrenocortical steroids in distal nephron acidification was studied in rats by measuring urine minus blood [Formula: see text] differences (U – B [Formula: see text]) in control, sham-operated, and adrenalectomized (ADX) animals. Operations were performed 48 h before experiments. During the experiments, all rats received an infusion of 0.35–0.60 M NaHCO3, leading to urine bicarbonate concentrations in the order of 100–200 mM. Adrenalectomized rats had significantly decreased U – B [Formula: see text] (11.9 ± 1.99 mmHg; 1 mmHg = 133.3 Pa) with respect to sham-operated rats (39.9 ± 1.26 mmHg). In another series, ADX rats received supplements of the adrenal steroids corticosterone, aldosterone, and 18-hydroxycorticosterone 100 min before the experiment. U – B [Formula: see text] increased after hormone administration: corticosterone, 30.0 ± 2.13 mmHg; aldosterone, 26.6 ± 1.74 mmHg; 18-hydroxycorticosterone, 29.0 ± 1.60 mmHg; but none restored these values to normal. Combinations of two hormones were also used; only aldosterone + corticosterone restored U – B [Formula: see text] to normal: 39.0 ± 1.66 mmHg. Renal phosphate excretion (but not urine phosphate levels) decreased significantly in ADX as compared with sham-operated rats. Extracellular volume was not significantly affected in ADX rats, which received ad libitum 0.9% NaCl for drinking. It is concluded that distal tubular acidification, as evaluated by U – B [Formula: see text], is dependent on cortical steroids.Key words: urine minus blood [Formula: see text], urine acidification, distal nephron, adrenal steroids.
Comparison of the effects of botulinum toxin in adult and neonatal rats: neuromuscular blockade and toxicity
Authors: Bambrick L. L. , Gordon T.
Published: April 2011

A single dose of botulinum toxin (BoTX) was injected subcutaneously to induce neuromuscular blockade in the triceps surae muscles of the hindlimbs of neonatal and adult rats. The efficacy of the toxin in producing complete neuromuscular blockade of the lower limb muscles, assessed by blockade of (a) postural and flexor reflexes and (b) muscle contraction in response to nerve stimulation, was dose dependent at all ages over a BoTX dose range of 10–60 ng/kg. However, BoTX was dramatically more toxic in adult animals resulting in a decline in body weight and lethal consequences in 25% of adult animals 1 week after administration of BoTX doses as low as 40 ng/kg. In contrast, neonatal animals, given the same dosage, continued to grow and no mortalities were observed. The differences in toxicity of BoTX in adult and neonatal rats are readily accounted for by the short duration of effect in the younger animals, which, in turn, is probably the result of more rapid generation of new and functional nerve terminals.Key words: sprouting, toxin botulinism, botulinum toxin, neuromuscular blockade, neonatal muscle.
Reduced neuroexcitatory effect of domoic acid following mossy fiber denervation of the rat dorsal hippocampus: further evidence that toxicity of domoic acid involves kainate receptor activation
Authors: Debonnel Guy , Weiss Michel , Montigny Claude de
Published: April 2011

Domoic acid, an excitatory amino acid structurally related to kainic acid, has been shown to be responsible for the severe intoxication presented, in 1987, by more than one hundred and fifty people having eaten mussels grown in Prince Edward Island (Canada). Unitary extracellular recordings were obtained from pyramidal neurons of the CA3 region of the rat dorsal hippocampus. The excitatory effects of microiontophoretic applications of domoic acid and of the agonists of the two other subtypes of glutamatergic receptors, quisqualate and N-methyl-D-aspartate, were compared on intact and colchicine-lesioned sides. Similar to what has been previously found for kainate, the colchicine lesion of the mossy fiber projections induced a 95% decrease of the neuronal responsiveness to domoic acid, whereas the effect of quisqualate was unchanged and that of N-methyl-D-aspartate was only slightly decreased. These results provide further electrophysiological evidence that domoic acid is a potent agonist of kainate receptors and that it may produce its neuroexcitatory and neurotoxic effects, in the hippocampal CA3 region, through activation of kainate receptors located on the mossy fiber terminals.Key words: domoic acid, kainic acid, glutamic acid, N-methyl-D-aspartic acid, quisqualic acid, dorsal hippocampus, neurotoxins.
Synthesis and relevance of cardiac eicosanoids with particular emphasis on ischemia and reperfusion
Authors: Karmazyn Morris
Published: April 2011

Eicosanoids represent a family of compounds derived primarily from arachidonic acid. It is now known that arachidonic acid can undergo metabolism via at least three distinct pathways, although the most readily understood are those resulting in prostaglandin or leukotriene formation via cyclooxygenase and 5-lipoxygenase, respectively. These products can be synthesized by the heart or can be released from accumulating neutrophils under various pathological conditions. Eicosanoids possess a wide array of pharmacological actions that could be of importance either in the initiation or modulation of various cardiac diseases. Here, we review the potential importance of eicosanoids to ischemic heart disease. Data are cited that examine the potential importance of these compounds to experimentally induced cardiac injury as well as clinically observed ischemic heart disease. Particular emphasis is placed on recent studies that document the relevance of endogenously synthesized arachidonic acid metabolites as well as the consequence of modulating eicosanoid synthesis through pharmacological or dietary means on cardiac injury under experimental or clinical situations.Key words: prostaglandins, leukotrienes, heart disease, ischemia, reperfusion.
Measurements of 6-keto-prostaglandin F1α and thromboxane B2 in bleeding time blood: relation to bleeding and vascular disorders?
Authors: Gerrard Jon M.
Published: April 2011

The body's ability to produce prostacyclin and thromboxane by blood vessels and platelets may be important in hemostatic and thrombotic disorders and in blood pressure regulation. There are limitations to the information that can be derived from measurement of the active substances or metabolites in plasma and urine. Assays for thromboxane and prostacyclin in bleeding time blood reflect production in response to a single standardized vascular injury, and show considerable promise in furthering our understanding of the production of these chemicals in vivo. These assays may improve the assessment of risk of developing thrombotic disorders and improve the ability to monitor treatment. Studies to date have focused largely on the influences of various doses of aspirin on the production of prostacyclin and thromboxane in bleeding time blood, but also suggest that smokers are high thromboxane producers. In addition, individuals who exhibit type A behavior, a behavior pattern characterized by a relatively high level of ambitiousness, hostility, and competitive drive and a chronic sense of urgency appear to be low prostacyclin producers. Diets enriched in sunflower oil were found to diminish thromboxane production, while diets high in canola oil enhanced prostacyclin formation.Key words: bleeding disorders, thrombotic disorders, prostacyclin, thromboxane, bleeding time.
Functional and electrophysiological effects of quinacrine on the response of ventricular tissues to hypoxia and reoxygenation
Authors: Moffat Margaret P. , Tsushima Robert G.
Published: April 2011

This study examined the effects of quinacrine on the functional and electrophysiological responses of isolated guinea pig hearts and isolated canine papillary muscle and Purkinje fibre preparations. A dose–response relationship for quinacrine (0.01–10.0 μg/mL) was studied in isolated guinea pig hearts perfused for 40 min. Quinacrine was found to exert a concentration-dependent negative inotropic effect (1.0 and 10 μg/mL); in the presence of the 10 μg/mL of the drug, hearts developed contracture, atrioventricular conduction block, and ventricular asystole. In hearts exposed to hypoxia, lactate acidosis, and glucose deprivation and then reoxygenated for 30 min, pretreatment with quinacrine (0.1 μg/mL) for 15 min prior to the initiation of hypoxia resulted in enhanced recovery of contractile function. Administration of the drug at any other time of the hypoxia–reoxygenation protocol was without effect. However, quinacrine reduced both the incidence and duration of reoxygenation arrhythmias. To examine the possible mechanistic basis for this antiarrhythmic action, isolated canine preparations were exposed to the same conditions and then reoxygenated. Quinacrine (1 μg/mL) significantly reduced the reoxygenation-associated loss in membrane potential and prevented inexcitability and depolarization-induced automaticity in Purkinje fibres. These results suggest that quinacrine exerts an antiarrhythmic action during reoxygenation and may do so by modifying some potential mechanisms of arrhythmia that occur in the specialized conduction system.Key words: hypoxia, reoxygenation, quinacrine, arrhythmias.
Gonadotropin-releasing hormone binding inhibitors in the ovary
Authors: Behrman Harold R. , Aten Raymond F. , Margolin Yael
Published: April 2011

A protein present in ovaries and other tissues of many species competitively and reversibly inhibits high affinity binding of gonadotropin-releasing hormone (GnRH) to rat ovarian membranes, but this protein is not GnRH. This protein has been partially purified and characterized from bovine ovaries. The absence of GnRH binding inhibitory (GBI) activity in plasma and follicular fluid indicates that this protein may act in a localized manner within or near its site of production or release. The bovine ovarian GBI protein evokes antigonadotropic activity in ovarian cells from both the rat and the bovine. The biological effect of GBI may occur independently of interaction with high affinity binding sites for GnRH, since these are absent from the bovine ovary. Thus, the GBI protein may abrogate gonadotropin-dependent responses in ovarian cells by mechanisms separate from interaction with GnRH receptors. A complete characterization of the GBI protein and evaluation of its mechanism of action in ovarian and pituitary cells will dictate conclusions on the physiological importance of this protein.Key words: gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, granulosa cells, luteal cells, ovary.
Plasma membrane changes during corpus luteum regression
Authors: Carlson John C. , Buhr Mary M. , Riley John C. M.
Published: April 2011

Structural and biochemical changes were examined in the plasma membrane of luteal cells during corpus luteum regression. Structural alterations as indicated by an increase in the liquid–crystalline to gel phase transition temperature and a decrease in plasma membrane fluidity were observed during luteolysis in microsomes and in plasma membranes prepared from prostaglandin F2α-treated rats, when samples were examined by wide angle x-ray diffraction and fluorescence polarization. In addition, a significant increase in activity of the lipolytic enzyme phospholipase A2 appeared during incubation of plasma membrane samples and dispersed luteal cells at 40 °C in the presence of 1.0 mM CaCl2. Similar incubation conditions also produced a drop in human chorionic gonadotropin (hCG) binding in luteal samples from prostaglandin F2α-treated rats. These results indicate that during luteolysis there are important structural changes in the plasmalemma of regressing luteal cells. These alterations appear related to an increase in phospholipase A2 activity and a decrease in hCG receptors. These modifications may account for the decrease in function during corpus luteum regression.Key words: structural changes, plasma membrane, luteolysis.
The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist
Authors: Ford-Hutchinson A. W. , Girard Y. , Lord A. , Jones T. R. , Cirino M. , Evans J. F. , Gillard J. , Hamel P. , Leveillé C. , Masson P. , Young R.
Published: April 2011

L-670,596 ((−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 × 10−9 M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 × 10−7 M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U-44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1–5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.Key words: thromboxane A2, thromboxane antagonist, prostaglandin endoperoxides, platelet aggregation.
Effects of endogenous calcium transport inhibitor from heart muscle on the active calcium uptake and passive calcium release properties of sarcoplasmic reticulum
Authors: Narayanan Njanoor , Bedard Philip , Waraich Trilochan S.
Published: April 2011

In the present study, the effects of the cytosolic Ca2+ transport inhibitor on ATP-dependent Ca2+ uptake by, and unidirectional passive Ca2+ release from, sarcoplassmic reticulum enriched membrane vesicles were examined in parallel experiments to determine whether inhibitor-mediated enhancement in Ca2+ efflux contributes to inhibition of net Ca2+ uptake. When assays were performed at pH 6.8 in the presence of oxalate, low concentrations (<100 μg/mL) of the inhibitor caused substantial inhibition of Ca2+ uptake by SR (28–50%). At this pH, low concentrations of the inhibitor did not cause enhancement of passive Ca2+ release from actively Ca2+-loaded sarcoplasmic reticulum. Under these conditions, high concentrations (>100 μg/mL) of the inhibitor caused stimulation of passive Ca2+ release but to a much lesser extent when compared with the extent of inhibition of active Ca2+ uptake (i.e., twofold greater inhibition of Ca2+ uptake than stimulation of Ca2+ release). When Ca2+ uptake and release assays were carried out at pH 7.4, the Ca2+ release promoting action of the inhibitor became more pronounced, such that the magnitude of enhancement in Ca2+ release at varying concentrations of the inhibitor (20–200 μg/mL) was not markedly different from the magnitude of inhibition of Ca2+ uptake. In the absence of oxalate in the assay medium, inhibition of Ca2+ uptake was observed at alkaline but not acidic pH. These findings imply that the inhibition of Ca2+ uptake observed at pH 6.8 is mainly due to decrease in the rate of active Ca2+ transport into the membrane vesicles rather than stimulation of passive Ca2+ efflux; at alkaline pH (pH 7.4), enhanced Ca2+ efflux contributes substantially, if not exclusively, to the decrease in Ca2+ uptake observed in the presence of the inhibitor. It is suggested that if the cytosolic inhibitor has actions similar to those observed in vitro in intact cardiac muscle, acid–base status of the intracellular fluid would be a major factor influencing the nature of its effects (inhibition of Ca2+ uptake or stimulation of Ca2+ release) on transmembrane Ca2+ fluxes across the sarcoplasmic reticulum.Key words: sarcoplasmic reticulum, Ca2+ uptake, Ca2+ release, endogenous inhibitor, heart muscle.
Acute hypothyroidism slows the rate of left ventricular diastolic relaxation
Authors: Wieshammer Siegfried , Keck Fritz S. , Waitzinger Josef , Henze Eberhard , Loos Ulrich , Hombach Vinzenz , Pfeiffer Ernst F.
Published: April 2011

The effect of acute thyroid hormone deficiency on left ventricular diastolic filling was studied by radionuclide ventriculography with simultaneous right heart catheterization in nine athyreotic patients without cardiovascular disease. The patients were studied when they were hypothyroid and when they were euthyroid on replacement therapy. Peak filling rate and the time to peak filling were used to characterize diastolic function. The time to peak filling was defined as the interval from end-systole on the radionuclide time–volume curve to the time of occurrence of peak filling. The peak filling rate was determined in absolute terms from the normalized radionuclide peak filling rate and from the end-diastolic volume, which was derived from the radionuclide ejection fraction and from the thermodilution stroke volume. In all patients, the values for peak filling rate were lower in the hypothyroid than in the euthyroid state (287 ± 91 mL/s vs. 400 ± 118 mL/s, Δ = 41 ± 13%, p < 0.01). Peak filling always occurred during the first half of the diastolic interval. The time to peak filling was not significantly affected by the thyroid state (170 ± 10 ms vs. 159 ± 21 ms, Δ = 7 ± 10%). Left ventricular filling pressure as reflected by the pulmonary capillary wedge pressure and end-systolic volume were similar in both thyroid states (6 ± 2 mmHg vs. 8 ± 2 mmHg (1 mmHg = 133.32 Pa) and 32 ± 11 mL vs. 32 ± 7 mL, respectively). The data suggest that the rate of active diastolic relaxation is decreased in short-duration hypothyroidism. This may be due to a depressed activity of the sarcoplasmic reticular calcium pump which is under thyroid control.Key words: hypothyroidism, left ventricular diastolic function, radionuclide ventriculography.
Maintenance of hepatic arterial blood flow during hemorrhage is mediated by adenosine
Authors: Lautt W. Wayne , McQuaker Janet E.
Published: April 2011

The effect of hemorrhage (1.91 mL/min, 10 mL/kg) on splanchnic blood flow was determined in cats anesthetized with pentobarbital. The hepatic artery (HA) is relatively protected during hemorrhage and does not constrict, whereas the superior mesenteric artery (SMA) undergoes significant vasoconstriction. Adenosine receptor antagonism with 8-phenyltheophylline blocks the dilator response to infused adenosine selectively (does not block responses to isoproterenol). The dilator response to reduced portal blood flow (the HA buffer response) is also antagonized and adenosine receptor blockade converts the HA response to hemorrhage to one similar to that of the SMA. Thus, the protective dilation of the HA during hemorrhage is mediated by adenosine. In contrast, the vasodilation of the HA seen with reinfusion of the shed blood is not altered by adenosine receptor antagonism.Key words: adenosine, hemorrhage, splanchnic blood flow, hepatic blood flow, hepatic arterial buffer response.
Effects of hyperbaric oxygen in circulatory shock induced by splanchnic artery occlusion and reperfusion in rats
Authors: Bitterman Haim , Bitterman Noemi , Melamed Yehuda , Cohen Leon
Published: April 2011

We studied the effects of hyperbaric oxygen in a severe model of circulatory shock induced by occlusion and reperfusion of major splanchnic arteries (splanchnic artery occlusion (SAO) shock). Pentobarbital-anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state, resulting in a uniformly fatal outcome after release of the occlusion. Exposure to hyperbaric oxygen at 2 ATA (atmosphere absolute) (1 ATA = 0.1 MPa) was initiated immediately after reperfusion. SAO shock rats exposed to hyperbaric oxygen maintained mean arterial blood pressure at significantly higher values throughout the postreperfusion period compared with untreated SAO shock rats (p < 0.01), with final mean arterial blood pressures of 88 ± 9 and 51 ± 4 mmHg, respectively. Treatment with hyperbaric oxygen attenuated the increase in plasma activities of the lysosomal hydrolase cathepsin D(p < 0.05), and diminished the increase of hematocrit (p < 0.01 from untreated shock rats). Splanchnic occlusion shock rats treated with hyperbaric oxygen also exhibited a significantly higher survival rate than the untreated shock group (77 vs. 0%, respectively; p < 0.01). Our results suggest that the beneficial effects of exposure to hyperbaric oxygen immediately after reperfusion of the splanchnic region outweigh its possible deleterious effect.Key words: mean arterial blood pressure, cathepsin D, hematocrit.
Characterization of α-adrenoceptor subtypes by [3H]prazosin and [3H]rauwolscine binding to canine venous smooth muscle membranes
Authors: Shi A. G. , Ahmad S. , Kwan C. Y. , Daniel E. E.
Published: April 2011

Postsynaptic α-adrenoceptor subtypes were studied using [3H]prazosin and [3H]rauwolscine binding to plasmalemma-enriched microsomal fractions isolated from dog saphenous veins and mesenteric veins. Both radioligands showed saturable binding consistent with the presence of a single homogeneous binding site in each case, based on Scatchard analysis. The Kd values of [3H]prazosin and [3H]rauwolscine, calculated from kinetic studies were similar to those from equilibrium binding data in both venous muscle membranes. The microsomal membranes of dog saphenous vein and mesenteric vein contained about a fourfold higher density of the high affinity [3H]rauwolscine binding sites than those for [3H]prazosin binding. In competition studies, IC50 values for displacement of rauwolscine or prazosin suggested that the sites of interaction for the antagonists prazosin and rauwolscine were independent. Phenylephrine, a functionally selective α-adrenoceptor agonist, competed with a similar IC50 value for the specific binding sites of [3H]prazosin and [3H]rauwolscine; but B-HT 920, a functionally selective α2-adreno-ceptor agonist, competed for [3H]rauwolscine and [3H]prazosin binding with distinctly different IC50 values. Our data show the existence of two populations of α-adrenoceptor antagonist binding sites in the plasma membranes of dog saphenous vein and mesenteric vein, and raise the question whether agonist selectively depends on different affinities or on differential efficacies at one or two sites.Key words: α-adrenoceptor subtype, B-HT 920, phenylephrine, receptor-response coupling.
Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension
Authors: Schiffrin Ernesto L.
Published: April 2011

Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K,1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar–Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K, 1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors. Receptor number in SHR did not vary inversely with plasma levels of ANP, in contrast to other hypertensive models. In experimental and spontaneous hypertensive rat models there are various abnormalities in the regulation of vascular binding sites for peptides (ANG II, AVP, and ANP) and in the coupling of receptors to intracellular signal transduction mechanisms, which may play a role in the development and maintenance of high blood pressure.Key words: receptor regulation, vasoactive peptides, blood vessels, high blood pressure.
Peripheral neurogenic mechanisms in deoxycorticosterone acetate – salt hypertension in the rat
Authors: Champlain J. de , Eid H. , Drolet G. , Bouvier M. , Foucart S.
Published: April 2011

The finding of elevated circulating catecholamine levels in experimental and human hypertension suggests an active sympathoadrenal participation in the the pathogenesis of hypertension. In deoxycorticosterone acetate (DOCA)–salt hypertensive rats and in spontaneously hypertensive rats (SHR) the sympathoadrenal reactivity was found to be potentiated in response to various stimuli suggesting alterations in baroreflex functions or in local modulatory mechanisms. Several studies have suggested an attenuation of the α2-presynaptic or local inhibitory mechanism and a potentiation of the β2-facilitatory presynaptic mechanism in the peripheral sympathetic system, thus possibly explaining the potentiated sympathoadrenal reactivity in those hypertensive animals. At postsynaptic adrenergic sites, β-adrenoceptor numbers were reported to be decreased, whereas α1-adrenoceptor numbers were unchanged in the cardiovascular system of DOCA hypertensive rats, thus favoring a dominance of α1-postsynaptic responses in those animals. In support of this concept, the production of inositol monophosphate, used as an index of inositol triphosphate production, was found to be markedly enhanced following norepinephrine-induced α1-stimulation in atria and ventricles as well as in mesenteric and femoral arteries of DOCA–salt hypertensive rats thus suggesting an increased reactivity of the second messenger system linked to α1-adrenoceptors. Since similar abnormalities were also observed in SHR and in human hypertension, it thus appears that an imbalance between a- and β-postsynaptic receptors may exist in various forms of hypertension. These studies therefore suggest the existence of multiple abnormalities in pre- and post-synaptic adrenergic mechanisms in experimental and human hypertension. All those abnormalities tend to favor the development of a dominance of α1-postsynaptic adrenoceptor functions, which could represent a major mechanism in the establishment of hypertension as well as in the development of cardiac and arterial wall hypertrophy.Key words: sympathetic tone, norepinephrine, experimental hypertension, presynaptic modulation, phosphoinositide.
Frontiers in cocaine research
Authors: Marwah Joe
Published: April 2011

In Canada and the United States, cocaine abuse has become a serious drug problem. Cocaine elicits a multitude of behavioural, biochemical, and physiological effects, which depend on the dose, pattern, and route of administration. The recent upsurge in cocaine abuse and the attendant psychiatric problems, the adverse effects, and the lack of knowledge regarding the underlying mechanisms have provided an impetus for investigations on its mechanisms of action and for discovering newer treatment approaches. To date no specific mechanism of action can fully account for the psychotropic actions of cocaine, since each of these is also elicited by several other pharmacological compounds that do not produce euphoria–reward, are not self-administered by test animals, and are not abused by humans. Cocaine is both a psychomotor stimulant and a potent local anesthetic. The psychomotor stimulation has traditionally been attributed to an augmentation of monaminergic neurotransmission in the CNS, since previous biochemical studies have reported that cocaine blocks the reuptake of endogenous catecholamines, and potentiates their synaptic actions. However, the mechanism(s) underlying cocaine's central actions might well involve interactions with several synaptic mechanisms including the monoaminergic mechanisms.This symposium, sponsored by the Pharmacological Society of Canada, brought together investigators in the area of cocaine pharmacology to discuss recent advances in this field. The four areas covered by the symposium were the pharmacokinetics and biotransformation of cocaine in man, autonomic actions of cocaine, biological aspects of cocaine addiction, and endocrine and neuroclinical actions of cocaine. The proceedings of the symposium published here provide important perspectives on a classical drag that has held the interest of pharmacologists and toxicologists for many years.
New perspectives on cocaine addiction: recent findings from animal research
Authors: Bozarth Michael A.
Published: April 2011

Research with laboratory animals has provided several insights into the nature of cocaine abuse and addiction. First, the nature of drug addiction has been reevaluated and the emphasis has shifted from physical dependence to compulsive drug-taking behavior. Second, animal studies suggest that cocaine is at least as addictive as heroin and possibly even more addictive. Third, cocaine is potentially more dangerous than heroin as evidenced by the higher fatality rate seen in laboratory animals given unlimited access to these drugs. Fourth, the neural basis of cocaine reinforcement has been identified and involves an enhancement of dopaminergic neurotransmission in the ventral tegmental dopamine system. Other addictive drugs (e.g., opiates) may also derive at least part of their reinforcing impact by pharmacologically activating this reward system. Fifth, although the biological consequences of repeated cocaine self-administration on central nervous system functioning are poorly understood, preliminary findings suggest that intravenous cocaine self-administration may decrease neural functioning in this brain reward system. This has important clinical implications because diminished functioning of an important brain reward system may significantly contribute to relapse into cocaine addiction. These and other findings from experimentation with laboratory animals suggest new considerations for the etiology and treatment of drug addiction.Key words: addiction, cocaine, dopamine, reward, withdrawal syndrome.
Autonomic actions of cocaine
Authors: Pitts D. K. , Marwah J.
Published: April 2011

The development of our knowledge of the physiological, pharmacological, and biochemical actions of cocaine has in essence occurred in parallel with the development of our knowledge about the function of the autonomic nervous system. Cocaine is a sympathomimetic compound with potent local anesthetic properties. The principal hypothesis accepted to date to explain the sympathomimetic effects of cocaine is that this drug inhibits neuronal monoamine neurotransmitter reuptake by binding to a transporter or uptake site thereby increasing the effective concentration of neurotransmitter at adrenergic receptor sites. Much of the available evidence for this hypothesis has come from studies utilizing in vitro or in situ techniques. There have been relatively fewer studies examining the impact of cocaine on the autonomic nervous system in the intact animal. In addition, few studies have examined the effects of cocaine on central autonomic function. Past studies concerning the mechanism of action of cocaine are reviewed and recent data addressing the cardiovascular, respiratory, and central autonomic effects of cocaine are discussed.Key words: cocaine, autonomic nervous system.
Effects of inhaled cadmium on breathing in the mouse
Authors: Ueda Fukiko , Nagata Midori , Nagata Toshifumi , Umeda Masaki
Published: April 2011

Effects of intranasally administered cadmium (3.67 μg Cd ~ 36.7 mg per mouse) on breathing were investigated in mice under pentobarbital anesthesia. Cd levels found in the respiratory tract were dependent on the amount administered. Cd mainly caused degeneration and desquamation of the bronchial epithelium and pulmonary congestion, while the carrier solvent had no effects. On the other hand, the carrier solvent decreased respiratory frequency and enhanced its amplitude. These effects were absent 24 h later. However, Cd strongly affected respiration; frequency and amplitude were decreased and recovery at 24 h was not complete at the higher concentrations. These effects by Cd on respiration were dependent on the concentration of administered Cd and the Cd level in lung. Therefore, these results suggest that intranasally administered Cd has inhibitory effects on mouse respiration, perhaps owing to its acute toxicity to pulmonary tissues.Key words: cadmium, mouse, inhalation, lung, respiration.
Further investigation of a potential calcium channel modulator isolated from rat erythrocytes
Authors: Huang Bing S. , McCumbee William D. , Wright Gary L.
Published: April 2011

The contractile effects of a peptide isolated from rat erythrocytes were further studied in rat aortic rings. Previous data showed that preincubation of aortic tissue with the peptide had no effect on resting tension, but significantly enhanced K+ and norepinephrine (NE) induced contraction. The calcium channel antagonist verapamil noncompetitively blocked the effect of the peptide, whereas nifedipine blockage appeared to be competitive. In the present study the peptide enhanced K+, NE, and phenylephrine (PE) induced contraction in a concentration-dependent manner, with a maximum enhancement at peptide concentrations of 10−7–10−6 M. At a concentration as low as 10−9 M, the peptide significantly enhanced K+-induced, but not NE- or PE-induced, contraction. The magnitude of maximal enhancement was greater for K+-induced contraction than that for NE- or PE-induced contraction. Preincubation of the tissues with the peptide caused a leftward shift of cumulative concentration–response curves to K+ and NE. The peptide enhancement of contraction increased with increasing K+ and NE concentration. The peptide potentiated the contractile response to Ca2+ in K+-depolarizing medium. It also enhanced the contractile response to NE in intracellular Ca2+-pool-depleted tissue following the replenishment of extracellular Ca2+, but had no apparent effect on the mobilization of intracellular calcium. Addition of nifedipine caused a rightward shift of both the peptide and Bay K 8644 concentration–response curves. Schild analysis for nifedipine antagonism, however, showed that the slope of the plot was significantly different from unity in both the Bay K 8644 and peptide responses, invalidating the use of this technique for conclusions regarding the nature of the nifedipine antagonism and site of action of the peptide. These data indicate that this peptide, like Bay K 8644, may influence the contractile sensitivity of aortic smooth muscle by acting as an endogenous modulator of voltage-dependent calcium channels.Key words: peptide, rat aortic ring, contractility, Bay K 8644.
The effect of adenosine and adenosine analogues on methylxanthine-induced hypercaliuria in the rat
Authors: McPhee M. Derrick , Whiting Susan J.
Published: April 2011

The chronic effects of dietary caffeine, theophylline, and theobromine on urinary calcium excretion were investigated in the adult male rat. The effect of acutely administered adenosine and adenosine analogues on methylxanthine-induced hypercalciuria was concurrently investigated. When rats were fed equimolar amounts of theobromine, caffeine, and theophylline, it was found that urinary calcium excretion increased; on day 7 values were increased over controls (p < 0.05) by 54, 146, and 208%, respectively. On day 20, an injection of adenosine reduced calcium excretion in methylxanthine-treated rats to levels not different from control values. In another series of experiments, theophylline was fed to a group of rats to establish hypercalciuria. Three adenosine analogues N6-(L-2-phenylisopropyl)adenosine (R-PIA), N6-(D-2-phenylisopropyl)adenosine (S-PIA), and 5′-(N-ethylcarboxamido)adenosine (NECA) with different adenosine receptor specificities (A2, A1, and weakly A2, respectively) were administered to different groups of theophylline-fed and control rats, and their calcium excretions were measured. It was found that the order of efficacy of the analogues in reducing calcium excretion was NECA > R-PIA > S-PIA, which is consistent with the receptor being A2. A proportion of the methylxanthine-induced hypercalciuria may be due to adenosine antagonism.Key words: caffeine, theobromine, theophylline, calcium, adenosine.
Developmental changes in the effects of carbachol and morphine on cGMP contents of plasma, heart, and lung of mice
Authors: Muraki Takamura , Nomoto Teruko , Kato Ryuichi
Published: April 2011

It is considered that carbachol increases plasma cGMP levels by acting on muscarinic receptors and morphine increases these levels by acting on opioid receptors, followed by stimulation of muscarinic receptors. We investigated the ability of carbachol and morphine to increase cGMP contents of plasma, heart, and lung and the guanylate cyclase activity of heart and lung homogenate in 1-, 2-, 3-, and 7-week-old mice. The increase in plasma cGMP levels induced by carbachol showed a peak at 2 and 3 weeks of age. The basal cGMP contents in heart and lung and their rise induced by carbachol, as well as the guanylate cyclase activity of these organs, were decreased in 7-week-old mice. The effects of morphine on the cGMP contents showed a similar developmental change, except for no effect in 1-week-old mice. These changes in the effects of carbachol and morphine may be the result of developmental changes of the muscarinic receptor – guanylate cyclase system and opioid receptors.Key words: cGMP, mouse development, carbachol, morphine.
Ontogeny of the insulin response to glucose in fetal and adult sheep
Authors: Houghton Pamela E. , McDonald Thomas J. , Challis John R. G.
Published: April 2011

The purpose of the present experiments was to examine in sheep whether the fetal insulin response to glucose was present by day 110 (d110) of pregnancy and whether the magnitude of the fetal insulin response changed between d110 and d145 (term). We also compared the responses observed in fetuses to those of adult nonpregnant sheep. Basal concentrations of glucose measured in plasma collected from the fetal femoral artery rose progressively between d110 and d145 of gestation, but did not attain the plasma glucose concentrations measured in adult sheep. Peak glucose concentrations in fetuses were achieved 10 min following the bolus injection of glucose (0.8 g/kg estimated fetal body weight) into the fetal femoral vein, and peak values increased with gestational age. Significantly higher peak glucose concentrations were achieved in adult sheep. The concentration of insulin rose rapidly in fetuses at d110, and a similar time course of insulin release in plasma was seen at all gestational ages. The peak plasma insulin concentrations were achieved at 20 min and were significantly greater in older (d140–145) than younger (d125–130) fetuses (p < 0.05). Peak insulin values in fetuses were much less than in adult sheep. In adult sheep glucose and insulin concentrations remained elevated at 120 min following the injection of glucose, whereas in the fetus the concentration of insulin had returned to preinjection values by 60 min. The insulin/glucose ratio did not change in fetal lambs over the last one third of gestation and was not different from the adult sheep. We conclude that (1) the fetal insulin response to an acute glucose load is present by d110 of gestation, and (2) the ratio of insulin released per unit glucose elevation did not change in fetal sheep over the last one third of gestation, nor between fetal and adult sheep.Key words: glucose, insulin, fetal sheep.
Altered release of growth hormone from dispersed adenohypophysial cells of streptozotocin diabetic rats. I. Effects of growth hormone releasing factor and somatostatin
Authors: Sheppard M. S. , Eatock B. A. , Bala R. M.
Published: April 2011

As growth hormone has been implicated in the "dawn phenomenon," an early morning rise in serum glucose, we have studied the control of growth hormone release in diabetes using an acutely dispersed system of adenohypophysial cells from normal or diabetic rats (65 mg/kg streptozotocin, 8 days before sacrifice; serum glucose, 490 ± 17 mg/dL). Growth hormone release is normally controlled by the two hypothalamic hormones, growth hormone releasing factor and somatostatin. We have found cells of the diabetic rats exhibit changes in sensitivity that result in increased growth hormone release in static incubation. In normal cells, rat growth hormone releasing factor increases growth hormone release three- to four-fold with an EC50 of 151 ± 27 pM (n = 7). In contrast, in cells from diabetic rats, there was a significant (twofold) increase in sensitivity to growth hormone releasing factor (EC50 = 75 ± 15 pM, n = 7) which resulted in increased growth hormone release with lower but not maximal (10 nM) growth hormone releasing factor. Basal nonstimulated release was unchanged. Somatostatin inhibition of stimulated growth hormone release was reduced (n = 7); half-maximal inhibition occurred with 0.21 ± 0.03 nM (normal) and 0.76 ± 0.17 nM somatotatin (diabetic). In perifusion the peak secretion rate was significantly lower for diabetic cells stimulated by a maximal dose of growth hormone releasing factor. These studies suggest somatotrophs of diabetic rats have altered sensitivity in vitro to the controlling hormones growth hormone releasing factor and somatostatin.Key words: growth hormone, diabetes, streptozotocin, growth hormone releasing factor, somatostatin.
The effect of intestinal anaphylaxis on postprandial motility in the rat
Authors: Diamant S. C. , Gall D. G. , Scott R. B.
Published: April 2011

We have previously utilized a rat animal model to demonstrate that challenge of fasted sensitized animals with antigenic food protein is associated with diarrhea and altered intestinal myoelectric and motor activities. In this paper we examine the effect of intestinal anaphylaxis on postprandial motility in the same animal model. Hooded Lister rats were sensitized (S) by intraperitoneal injection of 10 μg egg albumin (i.e., antigen (Ag)) and compared with sham-sensitized controls (C). Seven days later, three bipolar jejunal electrodes and a jejunostomy tube, for motility recording and Ag administration, were implanted. On day 14, intestinal myoelectric and motor activities were measured in fed animals before and after intraluminal challenge with Ag (100 mg egg albumin/0.5 mL saline) or placebo (P; 0.5 mL saline). Specific immunoglobulin E serum titres were [Formula: see text] in S animals, while C animals showed no response. None of the C animals challenged with P or Ag and none of the S animals challenged with P defecated after challenge, but all the S animals challenged with Ag developed diarrhea (p < 0.001). There was no disruption or alteration of the fed motility pattern in C animals challenged with P or Ag, or S animals challenged with P. In fed S animals challenged with Ag the fed motility pattern persisted, but there was a significant (p < 0.05) increase in the number of high-amplitude aborally propagating clustered contractions, where the phasic contractile activity was superimposed on a sustained tonic elevation of intraluminal pressure lasting 5–10 s. In this animal model, an immune-mediated reaction to food protein was associated with diarrhea and alteration of postprandial intestinal motility.Key words: small intestine, motility, myoelectric activity, immunoglobulin E, anaphylaxis, immediate hypersensitivity, gut allergy, food allergy.
Stimulus-dependent pacemaker activity in the distal canine lower esophageal sphincter
Authors: Walton P. D. , Huizinga J. D.
Published: April 2011

Electrical and mechanical properties of the distal canine lower esophageal sphincter were studied in vitro to investigate possible means of inducing pacemaker activity. Both direct excitation and block of potassium conductance were investigated. The acetylcholine analog, carbachol, induced tissue depolarization and increase in tone but no electrical slow waves. Tetra-ethylammonium (TEA) chloride induced depolarization and evoked continuous spiking activity and increase in tone. BaCl did not depolarize the tissue but low amplitude spiking activity developed and increased tone. The putative potassium channel blocker, aminacrine at 2 × 10−4 M, induced electrical slow wave activity in the distal lower esophageal sphincter, with or without superimposed spikes, accompanied by phasic contractile activity. This activity closely resembled the spontaneous pacemaker activity observed previously in the proximal lower esophageal sphincter. The aminacrine-induced activity was abolished by calcium influx blockers. Aminacrine, but not TEA or BaCl, abolished the nonadrenergic nerve-mediated inhibitory junction potentials. In conclusion, block of inhibitory innervation, and induction of electrical slow waves as a control mechanism for phasic contractile activity, seems to require blockade of an aminacrine- but not TEA-sensitive potassium conductance.Key words: smooth muscle, potassium conductance, slow waves, aminacrine, lower esophageal sphincter.
Effects of an analogue of thyrotrophin-releasing hormone, RX77368, on infarct size and cerebral blood flow in focal cerebral ischaemia in the rat
Authors: O'Shaughnessy C. T. , Rothwell N. J. , Shrewsbury-Gee J.
Published: April 2011

Effects of a stable analogue of thyrotrophin-releasing hormone, RX77368, on cerebral blood flow and infarct size have been studied in an acute model of cerebral ischaemia in the rat. Two hours after electrocoagulation of the left middle cerebral artery (MCA), the mean area of ischaemia (± SEM), determined histochemically, was 11.5 ± 2.2% of a single hemisphere and blood flow, determined using radiolabeled microspheres, was reduced by 40% in the left forebrain (p < 0.001 compared with sham-operated animals). Administration of RX77368 (50 μg/kg, intracerebroventricularly) within 10 min of arterial occlusion caused a significant (p < 0.01) reduction in mean lesion size to 3.7 ± 1.8% and stimulation of blood flow to the left ischaemic forebrain (60% above saline treated). Peripheral administration of RX77368 (1 mg/kg intraperitoneally) also significantly stimulated blood flow to the ischaemic forebrain and caused an apparent decrease in frequency of large infarcted areas of brain tissue, although mean lesion size was not significantly affected. These findings indicate that RX77368 ameliorates tissue damage in acute focal cerebral ischaemia. Such effects may be related to stimulation of cerebral blood flow.Key words: middle cerebral artery, focal cerebral ischaemia, cerebral blood flow, thyrotrophin-releasing hormone analogue.