DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM UNIVERSITATIS HELSINKIENSIS 91/2015

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1 DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM UNIVERSITATIS HELSINKIENSIS 91/2015 FLAVIA RESTITUTTI Central, Cardiovascular and Metabolic Effects of Dexmedetomidine Associated with the Selective Peripheral Alpha2-adrenoceptor Antagonist MK-467 in Dogs DEPARTMENT OF EQUINE AND SMALL MEDICINE FACULTY OF VETERINARY MEDICINE DOCTORAL PROGRAMME IN CLINICAL VETERINARY MEDICINE UNIVERSITY OF HELSINKI

2 Central, cardiovascular and metabolic effects of dexmedetomidine associated with the selective peripheral alpha 2 -adrenoceptor antagonist MK-467 in dogs ACADEMIC DISSERTATION

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5 Contents

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8 Abstract

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10 List of original publications

11 Abbreviations

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13 1 Introduction

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15 2 Review of the literature 2.1 α-adrenergic receptors α 2 -adrenoceptors

16 Subtypes and physiological effects

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19 2.2 α 2 -adrenoceptor agonists used in veterinary medicine Xylazine Romifidine

20 2.2.3 Detomidine

21 2.2.4 Medetomidine Dexmedetomidine Central effects

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23 Cardiovascular effects

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25 Effects on glucose, insulin and free fatty acids

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27 Other effects

28 2.3 Use of anticholinergics with α 2 -adrenoceptor agonists

29 2.4 α 2 -adrenoceptor antagonists Atipamezole

30 2.4.2 MK-467

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34 2.5 Contrast-enhanced ultrasound

35 3 Aims of the study

36 4 Materials and methods 4.1 Animals 4.2 Instrumentation

37 4.3 Study design 4.4 Treatments, drugs and dosages

38 4.5 Clinical assessment of sedation and hypnosis (I)

39 4.6 Cardiorespiratory monitoring (II)

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42 4.7 CEUS (III)

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44 4.8 Iohexol test (III) 4.9 Plasma glucose, insulin, NEFA, cortisol (IV) and lactate measurements (II, IV)

45 4.10 Statistical analysis

46 5 Results 5.1 Clinical sedation and bispectral index (I)

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49 5.2 Cardiovascular effects (II, III)

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53 5.3 Plasma glucose and insulin 5.4 Plasma lactate (II, IV) 5.5 Plasma NEFA (lv)

54 5.6 Plasma cortisol (IV)

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56 6 Discussion 6.1 Central effects (I) Sedation score

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58 6.1.2 Bispectral index

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60 6.2 Cardiovascular effects (II, III) Haemodynamic parameters

61 6.2.2 Blood flow in abdominal organs (III)

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64 6.2.3 Lactate (II, IV)

65 6.3 Glucose and insulin (IV)

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67 6.4 Effects on NEFA (IV)

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69 6.5 Methodological considerations and limitations of the studies

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71 7 Conclusions

72 Acknowledgements

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74 References

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102 Recent Publications in this Series 71/2015 Johanna Lotsari-Salomaa Epigenetic Characteristics of Lynch Syndrome-Associated and Sporadic Tumorigenesis 72/2015 Tea Pemovska Individualized Chemical Systems Medicine of Acute and Chronic Myeloid Leukemia 73/2015 Simona Bramante Oncolytic Adenovirus Coding for GM-CSF in Treatment of Cancer 74/2015 Alhadi Almangush Histopathological Predictors of Early Stage Oral Tongue Cancer 75/2015 Otto Manninen Imaging Studies in the Mouse Model of Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type, EPM1 76/2015 Mordekhay Medvedovsky Methodological and Clinical Aspects of Ictal and Interictal MEG 77/2015 Marika Melamies Studies on Canine Lower Respiratory Tract with Special Reference to Inhaled Corticosteroids 78/2015 Elina Välimäki Activation of Inflammasome and Protein Secretion by Endogenous Danger and Microbe-Derived Signals in Human Macrophages 79/2015 Terhi Keltanen Postmortem Biochemistry - Analysis of Metabolic Imbalance 80/2015 Mari Savolainen The Effects of Prolyl Oligopeptidase Inhibition in α-synuclein Based Mouse Models of Parkinson s Disease 81/2015 Teemu Luostarinen Studies on Hemodynamics and Coagulation in Neuroanesthesia 82/2015 Olaya Llano Novel Molecular Mechanisms of Dendritic Spine Development 83/2015 Abdirisak Ahmed Haji Omar Oral and Cutaneous Squamous Cell Carcinomas: Differences in Tumor and Tumor Microenvironment 84/2015 Katja Airaksinen Modifications of Cortical Activity by Deep Brain Stimulation in Advanced Parkinson s Disease: an MEG Study 85/2015 And Demir Clinical Use of Urinary Gonadotropin Determinations in Children and Adolescents 86/2015 Raisa Haavikko Synthesis of Betulin Derivatives with New Bioactivities 87/2015 Hongxin Chen Heterobasidion annosum sensu stricto Pathogenesis: Bioinformatic and Functional Study of Cerato-Platanin Family Proteins 88/2015 Kristiina Rajamäki Role of the Inflammasome Pathway in Atherosclerosis 89/2015 Pirkko Kriikku Toxicological Abuse Profile of New Recreational Drugs in Driving-Under- The-Influence and Post-Mortem Cases in Finland 90/2015 Eeva Mustonen Red Clover Isoflavonoids in Feed, Plasma and Milk of Ruminants Helsinki 2015 ISSN ISBN