Clenbuterol activates the central IL-1 system via the β2-adrenoceptor without provoking inflammatory response related behaviours in rats

Brain, Behavior, and Immunity

Volumn 56, Issue , 2016, Pages 114-129

  Ryan, Karen M ^a   Griffin, Éadaoin W ^a   Ryan, Katie J ^a   Tanveer, Riffat ^a   Vanattou Saifoudine, Natacha ^b   McNamee, Eoin N ^a   Fallon, Emer ^a   Heffernan, Sheena ^a   Harkin, Andrew ^b   Connor, Thomas J ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

^b TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Anhedonia; Anxiety; Clenbuterol; Cytokine; Depression; Food consumption; IL 1 ; Locomotor activity; Sickness behaviour; 2 Adrenoceptor

Indexed keywords

BETA 2 ADRENERGIC RECEPTOR; CLENBUTEROL; INTERLEUKIN 1; INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; INTERLEUKIN 1 RECEPTOR TYPE II; INTERLEUKIN 1BETA; LIPOPOLYSACCHARIDE; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; IL1B PROTEIN, RAT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANXIETY DISORDER; ARTICLE; CHRONIC DRUG ADMINISTRATION; CONTROLLED STUDY; DEPRESSION; DISEASE ASSOCIATION; DRUG EFFECT; FOOD INTAKE; IMMUNOREGULATION; IMMUNOSTIMULATION; LOCOMOTION; MALE; MENTAL STRESS; MOTOR DYSFUNCTION; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; RAT; RODENT; SYMPTOM; TREATMENT DURATION; UPREGULATION; ANIMAL; ANIMAL BEHAVIOR; ANXIETY; CHEMICALLY INDUCED; DRUG EFFECTS; ILLNESS BEHAVIOR; SPRAGUE DAWLEY RAT;

ADRENERGIC BETA-2 RECEPTOR AGONISTS; ANIMALS; ANXIETY; BEHAVIOR, ANIMAL; CLENBUTEROL; DEPRESSION; ILLNESS BEHAVIOR; INTERLEUKIN-1BETA; MALE; RATS; RATS, SPRAGUE-DAWLEY;

EID: 84959451078     PISSN: 08891591     EISSN: 10902139     Source Type: Journal    
DOI: 10.1016/j.bbi.2016.02.023     Document Type: Article

References (104)

1. Allan S.M., Tyrrell P.J., Rothwell N.J. Interleukin-1 and neuronal injury. Nat. Rev. Immunol. 2005, 5:629-640.
2. Arend W.P. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 2002, 13:323-340.
3. Aschner M. Immune and inflammatory responses in the CNS: modulation by astrocytes. Toxicol. Lett. 1998, 102-103:283-287.
4. Baronti A., Grieco A., Vibelli C. Oral NAB 365 (clenbuterol) and terbutaline in chronic obstructive lung disease: a double-blind, two-week study. Int. J. Clin. Pharmacol. Ther. Toxicol. 1980, 18:21-25.
5. Basu A., Krady J.K., Levison S.W. Interleukin-1: a master regulator of neuroinflammation. J. Neurosci. Res. 2004, 78:151-156.
6. Beishuizen A., Thijs L.G. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J. Endotoxin Res. 2003, 9:3-24.
7. Ben Menachem-Zidon O., Avital A., Ben-Menahem Y., Goshen I., Kreisel T., Shmueli E.M., Segal M., Ben Hur T., Yirmiya R. Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling. Brain Behav. Immun. 2011, 25:1008-1016.
8. Benveniste E.N., Huneycutt B.S., Shrikant P., Ballestas M.E. Second messenger systems in the regulation of cytokines and adhesion molecules in the central nervous system. Brain Behav. Immun. 1995, 9:304-314.
9. Bessis N., Guery L., Mantovani A., Vecchi A., Sims J.E., Fradelizi D., Boissier M.C. The type II decoy receptor of IL-1 inhibits murine collagen-induced arthritis. Eur. J. Immunol. 2000, 30:867-875.
10. Blandino P., Barnum C.J., Deak T. The involvement of norepinephrine and microglia in hypothalamic and splenic IL-1beta responses to stress. J. Neuroimmunol. 2006, 173:87-95.
11. Blandino P., Barnum C.J., Solomon L.G., Larish Y., Lankow B.S., Deak T. Gene expression changes in the hypothalamus provide evidence for regionally-selective changes in IL-1 and microglial markers after acute stress. Brain Behav. Immun. 2009, 23:958-968.
12. Blatteis C.M., Li S., Li Z., Feleder C., Perlik V. Cytokines, PGE2 and endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediat. 2005, 76:1-18.
13. Bluthe R.M., Michaud B., Kelley K.W., Dantzer R. Vagotomy attenuates behavioural effects of interleukin-1 injected peripherally but not centrally. NeuroReport 1996, 7:1485-1488.
14. Boner A.L., Vallone G., Brighenti C., Schiassi M., Miglioranzi P., Richelli C. Comparison of the protective effect and duration of action of orally administered clenbuterol and salbutamol on exercise-induced asthma in children. Pediatr. Pulmonol. 1988, 4:197-200.
15. Boyle N.T., Connor T.J. MDMA ("Ecstasy") suppresses the innate IFN-gamma response in vivo: a critical role for the anti-inflammatory cytokine IL-10. Eur. J. Pharmacol. 2007, 572:228-238.
16. Brodde O.E., Bruck H., Leineweber K. Cardiac adrenoceptors: physiological and pathophysiological relevance. J. Pharmacol. Sci. 2006, 100:323-337.
17. Burniston J.G., Tan L.B., Goldspink D.F. beta2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J. Appl. Physiol. 1985, 98:1379-1386.
18. Cao C., Matsumura K., Yamagata K., Watanabe Y. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response. Brain Res. 1995, 697:187-196.
19. Carter D.B., Deibel M.R., Dunn C.J., Tomich C.S., Laborde A.L., Slightom J.L., Berger A.E., Bienkowski M.J., Sun F.F., McEwan R.N., et al. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 1990, 344:633-638.
20. Civantos Calzada B., Aleixandre de Artinano A. Alpha-adrenoceptor subtypes. Pharmacol. Res. 2001, 44:195-208.
21. Clinton S.M., Sucharski I.L., Finlay J.M. Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex. Psychopharmacology 2006, 183:404-412.
22. Colotta F., Dower S.K., Sims J.E., Mantovani A. The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1. Immunol. Today 1994, 15:562-566.
23. Connor T.J., Song C., Leonard B.E., Merali Z., Anisman H. An assessment of the effects of central interleukin-1beta, -2, -6, and tumor necrosis factor-alpha administration on some behavioural, neurochemical, endocrine and immune parameters in the rat. Neuroscience 1998, 84:923-933.
24. Connor T.J., Starr N., O'Sullivan J.B., Harkin A. Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-gamma?. Neurosci. Lett. 2008, 441:29-34.
25. Culmsee C., Semkova I., Krieglstein J. NGF mediates the neuroprotective effect of the beta2-adrenoceptor agonist clenbuterol in vitro and in vivo: evidence from an NGF-antisense study. Neurochem. Int. 1999, 35:47-57.
26. Culmsee C., Stumm R.K., Schafer M.K., Weihe E., Krieglstein J. Clenbuterol induces growth factor mRNA, activates astrocytes, and protects rat brain tissue against ischemic damage. Eur. J. Pharmacol. 1999, 379:33-45.
27. Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann. N.Y. Acad. Sci. 2001, 933:222-234.
28. Dantzer R., O'Connor J.C., Freund G.G., Johnson R.W., Kelley K.W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 2008, 9:46-56.
29. Daubert G.P., Mabasa V.H., Leung V.W., Aaron C. Acute clenbuterol overdose resulting in supraventricular tachycardia and atrial fibrillation. J. Med. Toxicol. 2007, 3:56-60.
30. Day J.S., O'Neill E., Cawley C., Aretz N.K., Kilroy D., Gibney S.M., Harkin A., Connor T.J. Noradrenaline acting on astrocytic beta(2)-adrenoceptors induces neurite outgrowth in primary cortical neurons. Neuropharmacology 2014, 77:234-248.
31. Dinarello C.A. Biologic basis for interleukin-1 in disease. Blood 1996, 87:2095-2147.
32. Feinstein D.L., Heneka M.T., Gavrilyuk V., Dello Russo C., Weinberg G., Galea E. Noradrenergic regulation of inflammatory gene expression in brain. Neurochem. Int. 2002, 41:357-365.
33. Geyer M.A., Frampton S.F. Peripheral mediation of effects of clenbuterol on locomotor and investigatory behavior in rats. Pharmacol. Biochem. Behav. 1988, 30:417-420.
34. Gleeson L.C., Ryan K.J., Griffin E.W., Connor T.J., Harkin A. The beta2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity. Brain Behav. Immun. 2010, 24:1354-1361.
35. Goldschmidt P.L., Frances H., Simon P. Stimulation of beta-adrenergic receptors and spontaneous motor activity in mice. Pharmacol. Biochem. Behav. 1984, 21:177-180.
36. Goshen I., Kreisel T., Ounallah-Saad H., Renbaum P., Zalzstein Y., Ben-Hur T., Levy-Lahad E., Yirmiya R. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 2007, 32:1106-1115.
37. Goshen I., Kreisel T., Ben-Menachem-Zidon O., Licht T., Weidenfeld J., Ben-Hur T., Yirmiya R. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol. Psychiatry 2008, 13:717-728.
38. Griffin W.S., Liu L., Li Y., Mrak R.E., Barger S.W. Interleukin-1 mediates Alzheimer and Lewy body pathologies. J. Neuroinflammation 2006, 3:5.
39. Harkin A., Houlihan D.D., Kelly J.P. Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine. J. Psychopharmacol. 2002, 16:115-123.
40. Harkin A., O'Donnell J.M., Kelly J.P. A study of VitalView for behavioural and physiological monitoring in laboratory rats. Physiol. Behav. 2002, 77:65-77.
41. Hart B.L. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 1988, 12:123-137.
42. Hein L. Adrenoceptors and signal transduction in neurons. Cell Tissue Res. 2006, 326:541-551.
43. Hertz L., Chen Y., Gibbs M.E., Zang P., Peng L. Astrocytic adrenoceptors: a major drug target in neurological and psychiatric disorders?. Curr. Drug Targets CNS Neurol. Disord. 2004, 3:239-267.
44. Hicks K.K., Seifen E., Stimers J.R., Kennedy R.H. Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control. J. Auton. Nerv. Syst. 1998, 69:21-30.
45. Hida W., Sakurai M., Ichinose M., Shindoh C., Chonan T., Kikuchi Y., Inoue H., Takishima T. Effect of clenbuterol on peripheral airway obstruction in bronchial asthma. Curr. Med. Res. Opin. 1985, 9:616-625.
46. Hoey A.J., Matthews M.L., Badran T.W., Pegg G.G., Sillence M.N. Cardiovascular effects of clenbuterol are beta 2-adrenoceptor-mediated in steers. J. Anim. Sci. 1995, 73:1754-1765.
47. Hofman F.M., Hinton D.R., Johnson K., Merrill J.E. Tumor necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 1989, 170:607-612.
48. Hueston C.M., Deak T. The inflamed axis: the interaction between stress, hormones, and the expression of inflammatory-related genes within key structures comprising the hypothalamic-pituitary-adrenal axis. Physiol. Behav. 2014, 124:77-91.
49. Johnson J.D., O'Connor K.A., Watkins L.R., Maier S.F. The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses. Neuroscience 2004, 127:569-577.
50. Johnson J.D., Campisi J., Sharkey C.M., Kennedy S.L., Nickerson M., Greenwood B.N., Fleshner M. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 2005, 135:1295-1307.
51. Junker V., Becker A., Huhne R., Zembatov M., Ravati A., Culmsee C., Krieglstein J. Stimulation of beta-adrenoceptors activates astrocytes and provides neuroprotection. Eur. J. Pharmacol. 2002, 446:25-36.
52. Kamburoff P.L., Prime F.J., Schmidt O.P. The bronchodilator effect of NAB 365. Br. J. Clin. Pharmacol. 1977, 4:67-71.
53. Kent S., Bluthe R.M., Dantzer R., Hardwick A.J., Kelley K.W., Rothwell N.J., Vannice J.L. Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc. Natl. Acad. Sci. U.S.A. 1992, 89:9117-9120.
54. Kent S., Rodriguez F., Kelley K.W., Dantzer R. Reduction in food and water intake induced by microinjection of interleukin-1 beta in the ventromedial hypothalamus of the rat. Physiol. Behav. 1994, 56:1031-1036.
55. Konsman J.P., Veeneman J., Combe C., Poole S., Luheshi G.N., Dantzer R. Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide. Eur. J. Neurosci. 2008, 28:2499-2510.
56. Koo J.W., Duman R.S. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:751-756.
57. Liang W., Mills S. Profile of ligand binding to the porcine beta2-adrenergic receptor. J. Anim. Sci. 2001, 79:877-883.
58. Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001, 25:402-408.
59. Lynch A.M., Lynch M.A. The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur. J. Neurosci. 2002, 15:1779-1788.
60. Marien M.R., Colpaert F.C., Rosenquist A.C. Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res. Brain Res. Rev. 2004, 45:38-78.
61. Mason J.L., Suzuki K., Chaplin D.D., Matsushima G.K. Interleukin-1beta promotes repair of the CNS. J. Neurosci. 2001, 21:7046-7052.
62. Mazzanti G., Di Sotto A., Daniele C., Battinelli L., Brambilla G., Fiori M., Loizzo S., Loizzo A. A pharmacodynamic study on clenbuterol-induced toxicity: beta1- and beta2-adrenoceptors involvement in guinea-pig tachycardia in an in vitro model. Food Chem. Toxicol. 2007, 45:1694-1699.
63. McNamee E.N., Griffin E.W., Ryan K.M., Ryan K.J., Heffernan S., Harkin A., Connor T.J. Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex. Neuropharmacology 2010, 59:37-48.
64. McNamee E.N., Ryan K.M., Griffin E.W., Gonzalez-Reyes R.E., Ryan K.J., Harkin A., Connor T.J. Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration. Brain Behav. Immun. 2010, 24:660-671.
65. McNamee E.N., Ryan K.M., Kilroy D., Connor T.J. Noradrenaline induces IL-1ra and IL-1 type II receptor expression in primary glial cells and protects against IL-1beta-induced neurotoxicity. Eur. J. Pharmacol. 2010, 626:219-228.
66. Mori K., Ozaki E., Zhang B., Yang L., Yokoyama A., Takeda I., Maeda N., Sakanaka M., Tanaka J. Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors. Neuropharmacology 2002, 43:1026-1034.
67. O'Donnell J.M. Reduced locomotor activity of rats mediated by peripheral beta adrenergic receptors. Res. Commun. Chem. Pathol. Pharmacol. 1993, 82:375-378.
68. O'Sullivan J.B., Ryan K.M., Curtin N.M., Harkin A., Connor T.J. Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration. Int. J. Neuropsychopharmacol. 2009, 12:687-699.
69. Papiris S., Galavotti V., Sturani C. Effects of beta-agonists on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease. Respiration 1986, 49:101-108.
70. Parnet P., Amindari S., Wu C., Brunke-Reese D., Goujon E., Weyhenmeyer J.A., Dantzer R., Kelley K.W. Expression of type I and type II interleukin-1 receptors in mouse brain. Brain Res. Mol. Brain Res. 1994, 27:63-70.
71. Patrizio M. Tumor necrosis factor reduces cAMP production in rat microglia. Glia 2004, 48:241-249.
72. Pinteaux E., Parker L.C., Rothwell N.J., Luheshi G.N. Expression of interleukin-1 receptors and their role in interleukin-1 actions in murine microglial cells. J. Neurochem. 2002, 83:754-763.
73. Pinteaux E., Rothwell N.J., Boutin H. Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia 2006, 53:551-556.
74. Pinteaux E., Trotter P., Simi A. Cell-specific and concentration-dependent actions of interleukin-1 in acute brain inflammation. Cytokine 2009, 45:1-7.
75. Plata-Salaman C.R., Oomura Y., Kai Y. Tumor necrosis factor and interleukin-1 beta: suppression of food intake by direct action in the central nervous system. Brain Res. 1988, 448:106-114.
76. Porter M.H., Hrupka B.J., Langhans W., Schwartz G.J. Vagal and splanchnic afferents are not necessary for the anorexia produced by peripheral IL-1beta, LPS, and MDP. Am. J. Physiol. 1998, 275:R384-R389.
77. Ramos B.P., Colgan L.A., Nou E., Arnsten A.F. Beta2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals. Neurobiol. Aging 2008, 29:1060-1069.
78. Ryan K.J., Griffin E.W., Connor T.J. Complementary anti-inflammatory actions of the beta-adrenoceptor agonist clenbuterol and the glucocorticoid dexamethasone in rat brain. J. Neuroimmunol. 2011, 232:209-216.
79. Ryan K.J., Griffin E., Yssel J.D., Ryan K.M., McNamee E.N., Harkin A., Connor T.J. Stimulation of central beta2-adrenoceptors suppresses NFkappaB activity in rat brain: a role for IkappaB. Neurochem. Int. 2013, 63:368-378.
80. Scheller J., Rose-John S. Interleukin-6 and its receptor: from bench to bedside. Med. Microbiol. Immunol. 2006, 195:173-183.
81. Semkova I., Schilling M., Henrich-Noack P., Rami A., Krieglstein J. Clenbuterol protects mouse cerebral cortex and rat hippocampus from ischemic damage and attenuates glutamate neurotoxicity in cultured hippocampal neurons by induction of NGF. Brain Res. 1996, 717:44-54.
82. Seu E., Lang A., Rivera R.J., Jentsch J.D. Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys. Psychopharmacology (Berl) 2009, 202:505-519.
83. Shaftel S.S., Kyrkanides S., Olschowka J.A., Miller J.N., Johnson R.E., O'Banion M.K. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest. 2007, 117:1595-1604.
84. Shirato K., Tanihata J., Motohashi N., Tachiyashiki K., Tomoda A., Imaizumi K. Beta2-agonist clenbuterol induced changes in the distribution of white blood cells in rats. J. Pharmacol. Sci. 2007, 104:146-152.
85. Sims J.E., March C.J., Cosman D., Widmer M.B., MacDonald H.R., McMahan C.J., Grubin C.E., Wignall J.M., Jackson J.L., Call S.M., et al. CDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 1988, 241:585-589.
86. Smith D.J. The pharmacokinetics, metabolism, and tissue residues of beta-adrenergic agonists in livestock. J. Anim. Sci. 1998, 76:173-194.
87. Spulber S., Bartfai T., Schultzberg M. IL-1/IL-1ra balance in the brain revisited - evidence from transgenic mouse models. Brain Behav. Immun. 2009, 23:573-579.
88. Swiergiel A.H., Dunn A.J. Lack of evidence for a role of serotonin in interleukin-1-induced hypophagia. Pharmacol. Biochem. Behav. 2000, 65:531-537.
89. Swiergiel A.H., Dunn A.J. Effects of interleukin-1beta and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacol. Biochem. Behav. 2007, 86:651-659.
90. Tanabe K., Nishimura K., Dohi S., Kozawa O. Mechanisms of interleukin-1beta-induced GDNF release from rat glioma cells. Brain Res. 2009, 1274:11-20.
91. Tanaka K.F., Kashima H., Suzuki H., Ono K., Sawada M. Existence of functional beta1- and beta2-adrenergic receptors on microglia. J. Neurosci. Res. 2002, 70:232-237.
92. Teng Y.D., Choi H., Huang W., Onario R.C., Frontera W.R., Snyder E.Y., Sabharwal S. Therapeutic effects of clenbuterol in a murine model of amyotrophic lateral sclerosis. Neurosci. Lett. 2006, 397:155-158.
93. Tizard I. Sickness behavior, its mechanisms and significance. Anim. Health Res. Rev. 2008, 9:87-99.
94. Tomozawa Y., Yabuuchi K., Inoue T., Satoh M. Participation of cAMP and cAMP-dependent protein kinase in beta-adrenoceptor-mediated interleukin-1 beta mRNA induction in cultured microglia. Neurosci. Res. 1995, 22:399-409.
95. Tracey K.J. The inflammatory reflex. Nature 2002, 420:853-859.
96. Turner P.V., Brabb T., Pekow C., Vasbinder M.A. Administration of substances to laboratory animals: routes of administration and factors to consider. J. Am. Assoc. Lab. Anim. Sci. 2011, 50:600-613.
97. Wallukat G. The beta-adrenergic receptors. Herz 2002, 27:683-690.
98. Wheatley D. Clenbuterol ("Spiropent"): a long-acting bronchodilator. Curr. Med. Res. Opin. 1982, 8:113-119.
99. Wieczorek M., Dunn A.J. Relationships among the behavioral, noradrenergic, and pituitary-adrenal responses to interleukin-1 and the effects of indomethacin. Brain Behav. Immun. 2006, 20:477-487.
100. Xiang Y., Kobilka B. The PDZ-binding motif of the beta2-adrenoceptor is essential for physiologic signaling and trafficking in cardiac myocytes. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:10776-10781.
101. Zalko D., Debrauwer L., Bories G., Tulliez J. Metabolism of clenbuterol in rats. Drug Metab. Dispos. 1998, 26:891-899.
102. Zhang Q., Xiang J., Wang X., Liu H., Hu B., Feng M., Fu Q. Beta(2)-adrenoceptor agonist clenbuterol reduces infarct size and myocardial apoptosis after myocardial ischaemia/reperfusion in anaesthetized rats. Br. J. Pharmacol. 2010, 160:1561-1572.
103. Zhou Z.Z., Jones S.B. Involvement of central vs. peripheral mechanisms in mediating sympathoadrenal activation in endotoxic rats. Am. J. Physiol. 1993, 265:R683-R688.
104. Zhu Y., Prehn J.H., Culmsee C., Krieglstein J. The beta2-adrenoceptor agonist clenbuterol modulates Bcl-2, Bcl-xl and Bax protein expression following transient forebrain ischemia. Neuroscience 1999, 90:1255-1263.