Department of Equine and Small Animal Medicine Faculty of Veterinary Medicine University of Helsinki Finland Interaction of alpha2-adrenoceptor agonists and vatinoxan, a peripherally acting alpha2-adrenoceptor antagonist, in horses SOILE PAKKANEN sss ACADEMIC DISSERTATION To be presented for public examination, with the permission of the Faculty of Veterinary Medicine, University of Helsinki, in the Paatsama hall, Koetilantie 4, Helsinki, March 22th 2019, at 12 noon. Helsinki 2019 Supervised by Professor Outi Vainio, DVM, PhD, DECVPT Docent Marja Raekallio, DVM, PhD Docent Anna Mykkänen, DVM, PhD Faculty of Veterinary Medicine University of Helsinki Finland Reviewed by Professor Rikke Buhl, DVM, PhD Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark Professor Francisco José Teixeira-Neto, DVM, PhD Department of Veterinary Surgery and Anaesthesiology Faculdade de Medicina Veterinária e Zootecnia Universidade Estadual Paulista (UNESP) Botucatu Brazil Opponent Professor Görel Nyman, DVM, PhD, DECVAA Faculty of Veterinary Medicine and Animal Science Swedish University of Agricultural Sciences Uppsala Sweden ISBN 978-951-51-4897-1 (paperback) ISBN 978-951-51-4898-8 (pdf) http://ethesis.helsinki.fi Layout by Maija Savolainen Unigrafia Helsinki 2019 2 3 Supervised by Professor Outi Vainio, DVM, PhD, DECVPT Docent Marja Raekallio, DVM, PhD Docent Anna Mykkänen, DVM, PhD Faculty of Veterinary Medicine University of Helsinki Finland Reviewed by Professor Rikke Buhl, DVM, PhD Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark Professor Francisco José Teixeira-Neto, DVM, PhD Department of Veterinary Surgery and Anaesthesiology Faculdade de Medicina Veterinária e Zootecnia Universidade Estadual Paulista (UNESP) Botucatu Brazil Opponent Professor Görel Nyman, DVM, PhD, DECVAA Faculty of Veterinary Medicine and Animal Science Swedish University of Agricultural Sciences Uppsala Sweden To my Family ISBN 978-951-51-4897-1 (paperback) ISBN 978-951-51-4898-8 (pdf) http://ethesis.helsinki.fi Layout by Maija Savolainen Unigrafia Helsinki 2019 2 3 CONTENTS CONTENTS ............................................................................................................................................. 4 ABSTRACT ............................................................................................................................................ 6 LIST OF ORIGINAL PUBLICATIONS ............................................................................................... 7 ABBREVIATIONS ................................................................................................................................. 8 1. INTRODUCTION .............................................................................................................................. 9 2. REVIEW OF THE LITERATURE .................................................................................................. 10 2.1 Alpha-adrenergic receptors ................................................................................................. 10 2.2 Central α2-adrenoceptors ..................................................................................................... 10 2.3 Peripheral α2-adrenoceptors ................................................................................................. 10 2.4 Central and peripheral imidazoline receptors ...................................................................... 11 2.5 Detomidine and romifidine in horses ................................................................................... 11 2.5.1 Central effects of detomidine and romifidine ......................................................... 11 2.5.1.1 Sedative effect ............................................................................................ 11 2.5.1.2 Antinociceptive effect ................................................................................. 12 2.5.2 Detomidine and romifidine as preanaesthetics before general anaesthesia ........... 13 2.5.3 Pharmacokinetics of detomidine and romifidine .................................................... 13 2.5.4 Cardiovascular and respiratory effects of detomidine and romifidine ................... 15 2.5.5 Gastrointestinal effects of detomidine and romifidine ............................................ 16 2.5.6 Effects of detomidine and romifidine on selected neurohormonal variables and changes related to energy metabolism ................... 16 2.6. Alphα2-adrenoceptor antagonists in horses ......................................................................... 17 2.7 Vatinoxan ............................................................................................................................. 18 2.7.1 Pharmacokinetics of vatinoxan ............................................................................. 18 2.7.2 Cardiovascular effects of vatinoxan ...................................................................... 19 2.7.3 Metabolic effects of vatinoxan ................................................................................ 19 2.7.4 Other effects of vatinoxan ................................................................................ 19 2.8 Simultaneous use of vatinoxan and α2-adrenoceptor agonists ............................................. 19 2.8.1 Vatinoxan and cardiovascular effects of 2α -adrenoceptor agonists .......................19 2.8.2 Effect of vatinoxan on drug plasma concentrations and sedation ........................ 20 2.8.3 Influence of vatinoxan on metabolic and other effects of2 α -adrenoceptor agonists ..........21 3. AIMS OF THE STUDY ..................................................................................................................... 22 4. MATERIALS AND METHODS ....................................................................................................... 23 4.1 Animals ................................................................................................................................ 23 4.2 Instrumentation ..................................................................................................................... 24 4.3 Treatments ............................................................................................................................ 24 4 5 4.4 Study designs ........................................................................................................................ 25 4.5 Clinical assessment of sedation and general anaesthesia ..................................................... 25 4.6 Analyses of drug plasma concentrations ............................................................................. 26 4.7 Pharmacokinetic calculations ............................................................................................... 26 4.8 Cardiorespiratory monitoring .............................................................................................. 26 4.9 Assessment of intestinal borborygmi ................................................................................... 27 4.10 Biochemisrty analyses from serum and plasma .................................................................. 27 4.11 Statistical analyses and power calculations .......................................................................... 28 5. RESULTS ............................................................................................................................................ 29 5.1 Clinical sedation (I, II) ......................................................................................................... 29 5.2 Induction time....................................................................................................................... 29 5.3 Plasma drug concentrations .................................................................................................. 30 5.4 Cardiovascular effects .......................................................................................................... 33 5.4.1 Cardiovascular effects of detomidine, romifidine and MK-467 in conscious horses (I, II) ...................................................................................... 33 5.4.2 Cardiovascular performance in horses under general anaesthesia (III) ............... 34 5.5 Intestinal borborygmi (I,II)................................................................................................... 36 5.6 Effects of romifidine and MK-467 on selected neurohormonal variables and changes related to energy metabolism (IV) .................................................... 37 6. DISCUSSION .................................................................................................................................... 40 6.1 Clinical sedation and plasma drug concentrations ............................................................... 40 6.2 Cardiovascular effects .......................................................................................................... 41 6.2.1 Cardiovascular effects in conscious horses ..............................................................41 6.2.2 Cardiovascular effects in horses under general anesthesia ..................................... 42 6.3 Effects on intestinal borborygmi .......................................................................................... 42 6.4 Effects on selected neurohormonal variables and changes related to energy metabolism ..........................................................................................................