Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 1: General considerations

The suitability of urethane anesthesia for physiopharmacological investigations is reviewed. Total dose administered and route of administration are recognized as factors having a great influence on both resting parameters and biological responses to drugs. A peculiar characteristic of urethane is represented by its ability to induce a surgical plane of anesthesia without affecting neurotransmission in various subcortical areas and the peripheral nervous system. This makes urethane a suitable general anesthetic for studying neural function in both central and peripheral nervous systems and accounts for the preservation of a number of reflex responses in urethane-anesthetized animals.     

Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 2: Cardiovascular system

Summary Urethane produces a level of surgical anesthesia characterized by preservation of a number of cardiovascular reflexes. When the proper route of administration is used, and the use of unnecessarily high doses is avoided, urethane anesthesia appears to be suitable for a number of investigations at cardiovascular level. However in certain types of studies involving pharmacological stimulation of peripheral adrenoceptors urethane affects markedly the magnitude of the response under study.     

Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 2: Cardiovascular system

Urethane produces a level of surgical anesthesia characterized by preservation of a number of cardiovascular reflexes. When the proper route of administration is used, and the use of unnecessarily high doses is avoided, urethane anesthesia appears to be suitable for a number of investigations at cardiovascular level. However in certain types of studies involving pharmacological stimulation of peripheral adrenoceptors urethane affects markedly the magnitude of the response under study.     

An analysis of the effects of urethane on cardiovascular responsiveness to catecholamines in terms of its interference with Ca++ mobilization from both intra and extracellular pools

Urethane (1 X 10(-2) - 1 X 10(-1) M) reduced, in a concentration-dependent manner, both intra and extracellular Ca++ dependent noradrenaline-induced contractions of perfused rabbit ear artery as well as the tonic contractions produced by perfusion with high K+ solution. However, a quantitative analysis of the data indicated that for urethane concentrations similar to those found in plasma during anesthesia urethane antagonism is confined to noradrenaline-induced contractions which depend upon the mobilization of Ca++ from intracellular storage sites. In KCl-contracted arteries, urethane enhanced the relaxant effects of isoprenaline. - Urethane reduced the amplitude of contractions of spontaneously beating guinea-pig right atrium at concentrations which have only a limited effect on frequency. In addition, it decreased in a concentration-dependent manner the amplitude of isoprenaline-activated electrically driven, and K+ depolarized guinea-pig right ventricular strips. Urethane had no effect on the chrono and inotropic actions of isoprenaline on cardiac preparations. In in vivo experiments the chronotropic response to low doses of isoprenaline was significantly higher in urethane-treated as compared to unanesthetized rats. The higher dose of isoprenaline tested produced a significant fall in systolic blood pressure in urethane-anesthetized rats. A significant correlation exists between the chronotropic response to isoprenaline and resting heart rate values in urethane-anesthetized rats. These results indicate that urethane, at concentrations similar to those found in plasma during anesthesia selectively interferes with mobilization of Ca++ from intracellular storage sites. In addition, the interference of urethane anesthesia with the isoprenaline chronotropic effect 'in vivo' cannot be explained by a direct interference of urethane with beta-adrenoceptors at cardiac level.     

Suitability of urethane anesthesia for physiopharmacological investigations. Part 3: Other systems and conclusions

The suitability of urethane anesthesia for physiopharmacological experiments in various systems is briefly reviewed. Urethane anesthesia appears to be suitable for various types of studies on respiratory function and on reflex activation of motility of the urinary bladder and some sections of the intestinal tract. However, urethane produces a variety of potentially disturbing side-effects at endocrine and renal level.     

Suitability of urethane anesthesia for physiopharmacological investigations. Part 3: Other systems and conclusions

Summary The suitability of urethane anesthesia for physiopharmacological experiments in various systems is briefly reviewed. Urethane anesthesia appears to be suitable for various types of studies on respiratory function and on reflex activation of motility of the urinary bladder and some sections of the intestinal tract. However, urethane produces a variety of potentially disturbing side-effects at endocrine and renal level.     

An analysis of the effects of urethane on cardiovascular responsiveness to catecholamines in terms of its interference with Ca++ mobilization from both intra and extracellular pools

Summary Urethane (1×10^–2–1×10^–1 M) reduced, in a concentration-dependent manner, both intra and extracellular Ca⁺⁺ dependent noradrenaline-induced contractions of perfused rabbit ear artery as well as the tonic contractions produced by perfusion with high K⁺ solution. However, a quantitative analysis of the data indicated that for urethane concentrations similar to those found in plasma during anesthesia urethane antagonism is confined to noradrenaline-induced contractions which depend upon the mobilization of Ca⁺⁺ from intracellular storage sites. In KCl-contracted arteries, urethane enhanced the relaxant effects of isoprenaline.—Urethane reduced the amplitude of contractions of spontaneously beating guinea-pig right atrium at concentrations which have only a limited effect on frequency. In addition, it decreased in a concentration-dependent manner the amplitude of isoprenaline-activated electrically driven, and K⁺ depolarized guinea-pig right ventricular strips. Urethane had no effect on the chrono and inotropic actions of isoprenaline on cardiac preparations. In in vivo experiments the chronotropic response to low doses of isoprenaline was significantly higher in urethane-treated as compared to unanesthetized rats. The higher dose of isoprenaline tested produced a significant fall in systolic blood pressure in urethane-anesthetized rats. A significant correlation exists between the chronotropic response to isoprenaline and resting heart rate values in urethane-anesthetized rats. These results indicate that urethane, at concentrations similar to those found in plasma during anesthesia selectively interferes with mobilization of Ca⁺⁺ from intracellular storage sites. In addition, the interference of urethane anesthesia with the isoprenaline chronotropic effect in vivo cannot be explained by a direct interference of urethane with -adrenoceptors at cardiac level.     

Unsuitability of urethane anesthetized rats for testing potential β-adrenoreceptor blockers

Summary Isoprenaline induced tachycardia in urethane, but not sodium barbital anesthetized rats depends upon resting heart rate values. This makes urethane anesthesia unsuitable for testing -blockers.     

Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis

The central nervous system (CNS) is capable of gathering information on the body’s nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.     

Central IL-1 differentially regulates peripheral IL-6 and TNF synthesis

Centrally given interleukin (IL)-1 is known to induce a rapid rises in blood IL-6. To extend this and to examine the mechanism by which this occurs, the effects of intracerebroventricular (icv) injection of human recombinant IL-1β on mRNA expression of IL-6 and tumour necrosis factor (TNF) in the spleen and liver were examined in rats. Icv injection of IL-1 produced a rapid rise of the tissue mRNA levels of IL-6 and TNF in both organs, prior to and/or in parallel with an increase in their serum levels. Pretreatment with chlorisondamine, a ganglionic blocking agent, inhibited the IL-6 responses, while it had little influence on the TNF responses. The results suggest that brain IL-1 induces peripheral production of IL-6, but not of TNF, through autonomic nervous system activation. Received 27 October 1997; received after revision 15 December 1997; accepted 12 January 1998     

Sex-peptides: seminal peptides of the <Emphasis Type="Italic">Drosophila</Emphasis> male

Mating affects the reproductive behaviour of insect females: the egg-laying rate increases and courting males are rejected. These post-mating responses are induced mainly by seminal fluid. In Drosophila melanogaster, males transfer two peptides (sex-peptides, = Sps) that reduce receptivity and elicit increased egg laying in their mating partners. Similarities in the open reading frames of the genes suggest that they have arisen by gene duplication. In females, Sps bind to specific sites in the central and peripheral nervous system, and to the genital tract. The binding proteins of the nervous system and genital tract are membrane proteins, but they differ molecularly. The former protein is proposed to be a receptor located at the top of a signalling cascade leading to the two post-mating responses, whereas the latter is a carrier protein moving Sps from the genital tract into the haemolymph. Sps bind to sperm. Together with sperm they are responsible for the persistence of the two post-mating responses. But Sps are the molecular basis of the sperm effect; sperm is merely the carrier.Received 10 February 2003; received after revision 25 April 2003; accepted 1 May 2003This article is dedicated to the 85th birthday of the discover of the sex-peptide, Prof. Dr. Pei Shen Chen, Zoological Institute, University of Zürich, Switzerland. P. S. Chen has served on the Editorial Board of Experientia (now CMLS) from 1974 to 1988.     

Effect of cyproheptadine on the octopamine-induced responses in the mammalian central nervous system

Summary Extracellular recordings have been made from rat thalamic neurones anaesthetized with urethane, 1.5–2 g/kg i.p. Iontophoretically applied octopamine excited certain thalamic neurones in the ventral basal complex while inhibiting others. Both effects were reversibly antagonized by iontophoretically applied cyproheptadine without affecting responses to noradrenaline and dopamine.Acknowledgment. We are grateful to Merck, Sharp and Dohme for a gift of cyproheptadine HCl.     

Pheromone behavioral responses in unusual male European corn borer hybrid progeny not correlated to electrophysiological phenotypes of their pheromone-specific antennal neurons

In genetic studies on the sex pheromone communication system of two races of European corn borer, which use opposite pheromone blends of the E and Z compounds, it was found that antennal olfactory cell response amplitudes to the two compounds were controlled by an autosomal factor, whereas behavioral responses to the blends were controlled by a sex-linked locus. Because of the difference in genetic controls, it was postulated that some unusual males would be produced in F₂ crosses between these two races. These unusual males would have antennal olfactory cells that respond as the Z-race males, but would respond behaviorally to the E blend. The present studies combined behavioral studies in a flight tunnel and single cell electrophysiological studies to show that these unusual males do indeed exist. These findings show that the spike amplitude of peripheral olfactory cells is not important in regulating species- or race-specific pheromone responses, as compared to some central nervous system factor assesses the spike frequencies from different pheromone-component-specific cells on the antenna. This factor seems to be essential in governing the pheromone-blend specific behavioral responses of male moths.     

Breathing at high altitude

Acclimatization to long-term hypoxia takes place at high altitude and allows gradual improvement of the ability to tolerate the hypoxic environment. An important component of this process is the hypoxic ventilatory acclimatization (HVA) that develops over several days. HVA reveals profound cellular and neurochemical re-organization occurring both in the peripheral chemoreceptors and in the central nervous system (in brainstem respiratory groups). These changes lead to an enhanced activity of peripheral chemoreceptor and re-inforce the central translation of peripheral inputs to efficient respiratory motor activity under the steady low O₂ pressure. We will review the cellular processes underlying these changes with a particular emphasis on changes of neurotransmitter function and ion channel properties in peripheral chemoreceptors, and present evidence that low O₂ level acts directly on brainstem nuclei to induce cellular changes contributing to maintain a high tonic respiratory drive under chronic hypoxia. (This study is part of a multi-author review.)     

Peptide YY enhances NaCl and water absorption in the rat colon in vivo

Peptide YY (PYY) is thought to possess paracrine and endocrine functions. The highest concentrations of this peptide are in the colonic mucosa. The effect of PYY on electrolyte and water transport in the rat colon was studied in vivo. Under urethane anesthesia, rat colonic loops were perfused at a constant rate with physiological buffer solution containing phenol red as a nonabsorbable volume marker, and net movements of water, sodium, chloride and potassium in the perfused colon were determined every 10 min. Intravenous administration of PYY produced a dose-dependent increase in the net absorption of sodium chloride and water, as well as a decrease in the net secretion of potassium. PYY inhibited the reduction in net absorption of sodium chloride and water evoked by vasoactive intestinal peptide (VIP), but did not affect the VIP-evoked increase in net potassium secretion.These findings suggest that PYY acts as an enhancer of sodium chloride and water absorption and as an antagonist to VIP-induced secretion in the colon.     

Peptide YY enhances NaCl and water absorption in the rat colon in vivo.

Peptide YY (PYY) is thought to possess paracrine and endocrine functions. The highest concentrations of this peptide are in the colonic mucosa. The effect of PYY on electrolyte and water transport in the rat colon was studied in vivo. Under urethane anesthesia, rat colonic loops were perfused at a constant rate with physiological buffer solution containing phenol red as a nonabsorbable volume marker, and net movements of water, sodium, chloride and potassium in the perfused colon were determined every 10 min. Intravenous administration of PYY produced a dose-dependent increase in the net absorption of sodium chloride and water, as well as a decrease in the net secretion of potassium. PYY inhibited the reduction in net absorption of sodium chloride and water evoked by vasoactive intestinal peptide (VIP), but did not affect the VIP-evoked increase in net potassium secretion. These findings suggest that PYY acts as an enhancer of sodium chloride and water absorption and as an antagonist to VIP-induced secretion in the colon.     

Myelin sheaths: glycoproteins involved in their formation,maintenance and degeneration

Myelin sheaths are formed around axons by extending, biochemically modifying and spiraling plasma membranes of Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). Because glycoproteins are prominent components of plasma membranes, it is not surprising that they have important roles in the formation, maintenance and degeneration of myelin sheaths. The emphasis in this review is on four integral membrane glycoproteins. Two of them, protein zero (P0) and peripheral myelin protein-22 (PMP-22), are components of compact PNS myelin. The other two are preferentially localized in membranes of sheaths that are distinct from compact myelin. One is the myelin-associated glycoprotein, which is localized at the inside of sheaths where it functions in glia-axon interactions in both the PNS and CNS. The other is the myelin-oligodendrocyte glycoprotein, which is preferentially localized on the outside of CNS myelin sheaths and appears to be an important target antigen in autoimmune demyelinating diseases such as multiple sclerosis. Received 8 April 2002; received after revision 13 May 2002; accepted 22 May 2002     

Wnt signaling: multiple functions in neural development

Wnt signaling has proven to be essential for neural development at various stages and across species. Wnts are involved in morphogenesis and patterning, and their proliferation-promoting role is a key function in stem cell maintenance and the expansion of progenitor pools. Moreover, Wnt signaling is involved in differentiation processes and lineage decision events during both central and peripheral nervous system development. Additionally, several reports point to a role of Wnt signaling in axon guidance and neurite outgrowth. This article reviews and consolidates the existing evidence for the functions of Wnt signaling in neural development.Received 10 December 2004; received after revision 19 January 2005; accepted 21 January 2005     

Schwann cell mitochondria as key regulators in the development and maintenance of peripheral nerve axons

Formation of myelin sheaths by Schwann cells (SCs) enables rapid and efficient transmission of action potentials in peripheral axons, and disruption of myelination results in disorders that involve decreased sensory and motor functions. Given that construction of SC myelin requires high levels of lipid and protein synthesis, mitochondria, which are pivotal in cellular metabolism, may be potential regulators of the formation and maintenance of SC myelin. Supporting this notion, abnormal mitochondria are found in SCs of neuropathic peripheral nerves in both human patients and the relevant animal models. However, evidence for the importance of SC mitochondria in myelination has been limited, until recently. Several studies have recently used genetic approaches that allow SC-specific ablation of mitochondrial metabolic activity in living animals to show the critical roles of SC mitochondria in the development and maintenance of peripheral nerve axons. Here, we review current knowledge about the involvement of SC mitochondria in the formation and dysfunction of myelinated axons in the peripheral nervous system.