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Sílvia Vilares Conde Sílvia Vilares Conde FUNCTIONAL SIGNIFICANCE OF ADENOSINE IN CAROTID BODY CHEMOSENSORY ACTIVITY IN CONTROL AND CHRONICALLY HYPOXIC ANIMALS Lisboa, 2007 a Dissertation presented to obtain the PhD degree in “Ciências da Vida – Especialidade Farmacologia” at the Faculdade de Ciências Médicas, Universidade Nova de Lisboa and Biotecnología: Aplicaciones Biomédicas at the Facultad de Medicina, Universidad de Valladolid Supervised by Profs. Constancio Gonzalez, Emília Monteiro and Ana Obeso. b Realizado com o apoio da Fundação para a Ciência e Tecnologia, SFRH/BD/14178/2003 financiada pelo POCI 2010 no âmbito da Formação avançada para a Ciência, Medida IV.3. c To my mum and dad d This work: Originated the following publications: - Conde S.V., Obeso A., Vicario I., Rigual R., Rocher A. and Gonzalez C. (2006), Caffeine inhibition of rat carotid body chemoreceptors is mediated by A2A and A2B adenosine receptors, J. Neurochem., 98, 616-628. (Chapter 3) - Conde S.V. and Monteiro E.C. (2006), Activation of nicotinic ACh receptors with α4 subunits induces adenosine release at the rat carotid body, Br. J. Pharmacol., 147, 783-789. (Chapter 2) - Conde S.V. and Monteiro E.C. (2004), Hypoxia induces adenosine release from the rat carotid body, J. Neurochem., 89 (5), 1148-1156. (Chapter 1) - Conde S.V. and Monteiro E.C. (2003), Adenosine-acetylcholine interactions at the rat carotid body, In: “Chemoreception: From cellular signalling to functional plasticity”, JM Pequinot et al. (Eds), Klumer Academic Press London, 305-311. (Chapter 2) Won the following awards: - 1st Prize “De Castro-Heymans–Neil Award” awarded by ISAC (International Society for Arterial Chemoreception) to the best work presented by a Young Researcher each triennial ISAC Meeting, 2002 - Pfizer Honor Young Researcher Prize awarded by the Portuguese Society of Medical Sciences, 2002 e Functional significance of adenosine in carotid body chemoreception PhD thesis, Silvia Vilares Conde INDEX Page List of Figures and Tables………………………………………………………... VII Acknowledgements ………………………………………………………………… XII Abbreviations used…………………………………………………………………. XIV Glossary………………………………………………………………………………. XVII Abstract ………………………………………………………………………………. XX Resumo……………………………………………………………………………….. XXI Resumen……………………………………………………………………………… XXVI 1. GENERAL INTRODUCTION 1 1.1. The carotid body: morphology 4 1.2. Chemotransduction mechanisms at the carotid body: coupling stimulation and secretion 5 1.3. Function and control of the carotid body in resting conditions and in hypoxia 8 1.4. Function and control of the carotid body in hypercapnia and acidosis…… 11 1.5. Neurotransmission in the carotid body: role of adenosine, dopamine, ACh and ATP 13 1.5.1. Adenosine……………………………………………………………….. 13 1.5.1.1. Metabolic pathways of adenosine formation and release……… 14 1.5.1.2. Adenosine receptors……………………………………………….. 15 1.5.1.3. Physiological role of adenosine………………………………….. 17 1.5.1.4. Adenosine in chemoreception in the carotid body ……………... 18 1.5.2. Dopamine……………………………………………………………….. 20 1.5.2.1. Catecholamines synthesis and metabolism…………………….. 20 1.5.2.2. Dopamine receptors……………………………………………….. 22 1.5.2.3. Dopamine effects on chemoreception and ventilation…………. 23 1.5.3. ATP………………………………………………………………………. 26 1.5.3.1. Role of ATP in chemoreception in the carotid body……………. 27 1.5.4. Acetylcholine…………………………………………………………….. 28 1.5.4.1. Acetylcholine receptors……………………………………………. 29 1.5.4.2. Effects of ACh on carotid body chemoreception………………... 31 1.6. Effects of chronic hypoxia 33 1.6.1. Morphological changes in the carotid body induced by chronic sustained hypoxia……………………………………………………………. 35 I Functional significance of adenosine in carotid body chemoreception PhD thesis, Silvia Vilares Conde 1.6.2. Neurochemical changes in the carotid body in response to chronic sustained hypoxia…………………………………………………... 36 1.6.3. Chemoreceptor function blunting after prolonged hypoxia………………………………………………………………………... 39 1.7. Caffeine 40 1.7.1. Effects of acute caffeine treatment on ventilation…………………. 41 1.7.2. Chronic treatment with caffeine……………………………………... 42 2. GENERAL AND SPECIFIC AIMS 45 3. CHAPTER 1 – STUDY OF THE EFFECT OF HYPOXIA ON THE RELEASE OF ADENOSINE FROM THE RAT CAROTID BODY 46 3.1 Introduction and aim 46 3.2. Material and methods 46 3.2.1. Tissue preparation and experimental conditions………………….. 46 3.2.2. Characterization of the content and release of adenosine in rat carotid bodies………………………………………………………………… 47 3.2.3. Characterization of the release of adenosine from SCG and arterial tissue ………………………………………………………………… 47 3.2.4. Effect of adenosine transporter inhibitors………………………….. 48 3.2.5. Metabolic pathways of adenosine production at the rat carotid body …………………………………………………………………………... 48 3.2.6. Nucleotide extraction ………………………………………………… 48 3.2.7. HPLC analysis ……………………………………………………….. 49 3.2.8. Drugs………………………………………………………………….. 50 3.2.9. Data analysis………………………………………………………….. 50 3.3. Results 51 3.3.1. Adenosine quantification ……………………………………………. 51 3.3.2. Adenosine content and release from carotid body during hypoxia 52 3.3.3. Adenosine released by SCG and arterial tissue…………………... 53 3.3.4. Effect of adenosine transport inhibitors……………………………. 55 3.3.5. Metabolic pathways of adenosine production at the rat carotid body…………………………………………………………………………… 55 3.4. Discussion 56 4. CHAPTER 2 – EFFECT OF ACTIVATION OF NICOTINIC ACH RECEPTORS WITH α4 SUBUNITS ON ADENOSINE RELEASE AT THE RAT CAROTID BODY 61 4.1 Introduction and aim 61 II Functional significance of adenosine in carotid body chemoreception PhD thesis, Silvia Vilares Conde 4.2. Material and methods 61 4.2.1. Animals and surgical procedures…………………………………… 61 4.2.2. Effect of ACh nicotinic receptor agonists on adenosine released from carotid body…………………………………………………………….. 62 4.2.3. Effect of ACh nicotinic receptor antagonists on adenosine released from carotid body………………………………………………….. 62 4.2.4. Pharmacological demonstration of the involvement of neuronal nicotinic acetylcholine receptors……………………………………………. 63 4.2.5. Effect of extracellular ATP catabolism inhibitor on the release of adenosine evoked by nicotine……………………………………………… 63 4.2.6. Nucleotide extraction and HPLC analysis…………………………. 63 4.2.7. Drugs and chemicals………………………………………………… 63 4.2.8. Data analysis………………………………………………………….. 64 4.3. Results 64 4.3.1. Demonstration of the involvement of neuronal nicotinic acetylcholine receptors and characterization of nicotinic receptors that modulates the release of adenosine from rat carotid body ……………... 64 4.3.2. Effect of inhibition of ATP catabolism on the release of adenosine evoked by nicotine on carotid body…………………………… 68 4.4. Discussion 69 5. CHAPTER 3 – ACUTE EFFECTS OF CAFFEINE ON RAT CAROTID BODY CHEMORECEPTOR FUNCTION 73 5.1. Introduction and aim 73 5.2. Material and methods 73 5.2.1. Animals and surgical procedures…………………………………… 73 5.2.2. Labelling of catecholamines stores: release of 3H- CA……………………………………………………………………………… 74 5.2.3. Recording of carotid sinus nerve activity…………………………... 75 5.2.4. Carotid body cell dissociation and culture, and immunocytochemistry……………………………………………………….. 76 5.2.5. Drugs and chemicals………………………………………………… 77 5.2.6. Data analysis…………………………………………………………. 78 5.3. Results 78 5.3.1. Effect of caffeine on the basal release of 3H-CA…………………. 78 5.3.2. Effect of caffeine on the release of 3H-CA induced by hypoxia and high external K+…………………………………………………………. 80 III Functional significance of adenosine in carotid body chemoreception PhD thesis, Silvia Vilares Conde 5.3.3. Pharmacological characterisation of adenosine receptors involved in the inhibitory effect of caffeine on the release of 3H-CA from the carotid body………………………………………………………………. 82 5.3.4. Immunocytochemical demonstration of A2B adenosine receptors in chemoreceptor cells………………………………………………………. 86 5.3.5. Actions of caffeine on the carotid sinus nerve activity: a mixed A2A and A2B receptors mediated effect…………………………………….. 87 5.4. Discussion 90 6. CHAPTER 4 – ADENOSINE MODULATES THE RELEASE OF CATECHOLAMINES FROM RAT CAROTID BODY CHEMORECEPTORS THROUGH AN INTERACTION BETWEEN D2 DOPAMINE RECEPTORS AND A2B ADENOSINE RECEPTORS 95 6.1. Introduction and aim 95 6.2. Material and methods 95 6.2.1. Animals and surgical procedures…………………………………… 95 6.2.2. Labelling of catecholamines stores: release of 3H- CA……………………………………………………………………………… 96 6.2.3. Drugs and chemicals………………………………………………… 96 6.2.4. Data analysis………………………………………………………….. 96 6.3. Results 97 3 6.3.1. Effect of NECA, an A2 agonist on the release of H-CA from rat carotid body………………………………………………………………….. 97 6.3.2. Reversion of the inhibitory effect of caffeine on the 3H-CA by a D2 antagonist, sulpiride……………………………………………………… 98 3 6.3.3. Effect of D2 antagonists on the release of H-CA release by rat carotid body and its potentiation with NECA……………………………… 99 6.3.4. Inhibitory effect of the D2 agonist, propylnorapomorphine, on the release of 3H-CA from carotid body and its reversion by NECA………... 102 6.3.5. Effect of ionomycin on the release of 3H-CA by carotid body modified by norapropylapomorphine and NECA…………………………. 104 6.4. Discussion 105 7 – CHAPTER 5 – EFFECT OF CHRONIC CAFFEINE INTAKE ON THE CAROTID BODY CHEMOSENSORY ACTIVITY IN CONTROL AND CHRONIC HYPOXIC RATS 112 7.1. Introduction and aim 112 7.2. Materials and methods 112 IV Functional significance of adenosine in carotid body chemoreception PhD thesis, Silvia Vilares Conde 7.2.1. Chronic caffeine intake in control and chronic hypoxic animals…. 112 7.2.2. Measurement of tissue catecholamines content…………………
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