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Interactions Between Potassium Channels and Serotonin in Pulmonary Arterial Hypertension

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Interactions Between Potassium Channels and Serotonin in Pulmonary Arterial Hypertension Interactions between potassium channels and serotonin in pulmonary arterial hypertension This thesis is submitted for the degree of Doctor of Philosophy by Alicia Murray BSc. (Hons) September 2008 Faculty of Biomedical and Life Sciences © Alicia Murray I Abstract Pulmonary arterial hypertension (PAH) is a progressive disease which results from increases in mean pulmonary artery pressure and pulmonary vascular resistance. If untreated it leads to right ventricular failure and death. 5-Hydroxytryptamine (5-HT) has been implicated in the disease process and is thought to promote both vasoconstriction and remodelling of the pulmonary vasculature . The activity of potassium ion (K+) channels plays a major role in influencing pulmonary artery tone by regulating resting membrane potential, intracellular Ca 2+ concentration and contraction of vascular smooth muscle. This study aimed to investigate possible interactions between 5-HT and K + channels in the development of PAH in the mouse. The actions of 5-HT and a range of K+ channel blockers were investigated on isolated intralobar pulmonary arteries (IPA) from wild type (WT) mice and mice over-expressing the serotonin transporter (5HTT), which spontaneously develop PAH. Both 5-HT and linopirdine, a KCNQ K + channel inhibitor, were found to induce contraction of IPA, but were more potent in IPA from WT mice than 5-HTT+ mice. The 5-HT induced vasoconstriction was found to involve influx of Ca 2+ from the extracellular space, Ca 2+ release from the sacroplasmic reticulum and a rho kinase–dependent increase in the sensitivity of the contractile machinery of pulmonary artery smooth muscle cells (PASMC) to intracellular Ca 2+ . Ca 2+ entered the cell via both voltage operated calcium channels (VOCC), activated by membrane depolarisation, and a separate Ca 2+ entry pathway, the latter appearing to contribute more in 5-HTT+ mice. The effects of linopirdine were shown to be due entirely to the entry of Ca 2+ through VOCC in both WT and 5-HTT+ mice IPA. The difference in vasoconstrictor potency between WT and 5HTT+ mice was not seen with any other K + channel blocker, suggesting a selective loss of KCNQ channels and/or VOCC in PAH resulting from 5HTT over expression. KCNQ channel activity was further investigated using the KCNQ channel openers, flupirtine and retigabine. These agents were more potent in dilating IPA from WT mice compared to 5-HTT+ mice, consistent with the loss of expression or activity of KCNQ channels in 5-HTT+ mice. Despite this, orally administered flupirtine was shown to II reverse two indices of established PAH in the 5HTT+ mice; right ventricular pressure and right ventricular hypertrophy. This action of flupirtine was also seen in chronic hypoxic mice, where it prevented the development of PAH. In conclusion, this study provides evidence of an interaction between KCNQ channels and the 5-HT system in the development of PAH. By showing that a KCNQ channel opener can attenuate PAH, both in the developing and established disease situation, this study proposes a new potential therapeutic target in the treatment of PAH. III Acknowledgements There are many people I would like to thank for helping me write this thesis. Firstly, I would like to express my gratitude to my supervisors, Professor Alison Gurney and Professor Mandy MacLean. I truly appreciate your continuous support and guidance in helping me reach this stage. I would also like to thank the British Heart Foundation for funding this project. There are numerous others who have been an enormous help to me during my PhD. Thank-you Shreena, Lynn, Yvonne, Margaret, Ian and Neil. You all have helped me so much, not just by sharing your scientific knowledge with me, but also by being great friends to me over the past few years. I have enjoyed working with you all, it’s been a ball! I’d also like to thank my friends outside of university who have supported me constantly, and have played a big part in reminding me of the outside world, especially over the past year. Finally thank-you to my family, you have helped and encouraged me every step of the way, and I am eternally grateful. Odhran, your love and support has kept me going, thank-you (especially for keeping me grounded during the madness that is ‘writing up’!) IV Contents Abstract I Contents list II List of experimental figures IX List of tables XI Abbreviations XII Chapter 1 Introduction 1 1.1 Anatomy of the pulmonary circulation 2 1.2 Function of the pulmonary circulation 3 Figure 1.1 Diagram of the circulation system. 4 Figure 1.2 Illustration of the structure of a pulmonary artery. 5 1.3 Physiology of the pulmonary circulation 6 1.3.1 Regulation of pulmonary blood flow 7 1.3.1.1 Passive factors regulating the control of pulmonary blood flow 7 1.3.1.2 Active regulation of pulmonary blood flow 8 1.3.1.3 Endothelial cell control of pulmonary blood flow 11 1.3.1.4 Hypoxic control of pulmonary blood flow 13 1.4 Pulmonary artery smooth muscle contraction 14 Figure 1.3 Mechanism of SMC contraction 15 Table 1.1 Revised Clinical Classification of Pulmonary Hypertension 16 1.5 Pulmonary arterial hypertension 17 1.5.1 Genetic Basis of pulmonary arterial hypertension 17 1.5.3 Epidemiology of pulmonary arterial hypertension 18 Table 1.2 NYHA/ WHO Classification of functional status of patients with pulmonary hypertension. 20 1.5.4 Pathobiology of pulmonary arterial hypertension 21 1.5.4.1 Vasoconstriction 21 1.5.4.2 Remodelling 22 Figure 1.4 Diagrams of pulmonary arteries in the lung 23 V Figure 1.5 Images of remodelling of small muscular pulmonary artery 24 Figure 1.6 Image of a plexiform lesion 25 1.6 The 5-Hydroxytryptamine (5-HT) hypothesis of PAH 26 1.6.1 5-HT pharmacology 28 1.6.1.1 5-HT transporter 29 Figure 1.7 5-HT synthesis and metabolism 30 1.6.1.2 5-HT receptors and expression in pulmonary arteries 31 Figure 1.8 Signalling cascades of the 5-HT G-protein coupled receptors. 33 1.6.2 5-HT and PAH 34 1.6.2.1 5-HT and pulmonary vasoconstriction 34 1.6.2.2 5-HT and pulmonary vascular remodelling 35 Figure 1.9 Diagram showing the effects of 5-HT on a PASMC. 36 Figure 1.10 Proposed 5-HTT in the development of pulmonary vasoconstriction and vascular medial hypertrophy. 37 1.6.4 The role of PASMC membrane potential in 5-HT uptake 38 1.7 K+ and membrane potential of PASMCs 38 1.7.1 K+ channels – general features 39 1.7.1.1 Families of K+ channels 40 1.7.1.1.1 Two transmembrane domain (2TM) potassium channels 40 1.7.1.1.2 Four transmembrane domain (4TM) potassium channels 41 Figure 1.11 Diagram showing the α-subunits of each family of K+ channel. 42 Figure 1.12 Phylogenetic tree of K + channels. 43 1.7.1.1.3 Six transmembrane domain (6TM) potassium channels 44 1.7.2 K+ channels found in PASMCs 46 1.7.2.1 KV & KCNQ channels 47 + 1.7.2.2 Calcium activated K channels (K Ca ) 48 + 1.7.2.3 K channels inhibited by intracellular ATP, (K ATP ) 48 + 1.7.2.4 Two-pore domain K channels (K 2P ) 49 1.8 K+ channels and PAH 49 1.8.2 5-HT and K + channels in PAH 50 1.9 Study Aims 50 VI Chapter 2 Materials and methods 51 2.1 Animal models 52 2.1.1 The 5-HTT+ mouse model of pulmonary hypertension 52 2.1.2 Hypoxic Mouse model 52 2.1.2.1 Maintenance of animals 52 2.1.2.2 Hypobaric chamber design and components 53 2.1.3 Hemodynamic measurements 53 2.1.4 Determination of heart weights 54 2.2 In-vitro pharmacological studies 54 2.2.1 Wire myography 54 2.2.2 Equipment 54 2.2.3 Tissue preparation - Dissection of intralobar pulmonary arteries (IPAs) 55 Figure 2.1 Picture of hypobaric chamber used to generate hypoxic mice. 56 Figure 2.2 Picture of wire myograph used to measure vessel constriction. 56 Figure 2.3 Diagram showing location of main intralobar pulmonary artery which was used in myography experiments. 57 Figure 2.4 Diagram showing the artery mounting procedure . 58 2.2.4 Myograph mounting procedure 59 2.2.5 Transmural pressure applied to vessels and normalisation 59 2.2.6 Protocol for myography experiments 61 2.2.7 Data Analysis of pharmacological studies 61 2.2.7.1 Measurement of agonist potency 62 2.2.7.2 Statistical analysis of pharmacological studies 62 2.3 Flupirtine dosing study 62 2.3.1 Dosing protocol 63 2.4 Membrane potential measurement 64 2.4.1 Isolation of PASMCs 64 2.4.2 Electrophysiology 65 2.4.2.1 Patch-clamp protocols 65 2.4.2.2 Pipettes & Pipette solution 67 VII 2.4.2.4 Sources of error 67 2.4.2.5 Data analysis of current clamp studies 68 Figure 2.6 Diagram showing the Whole Cell Patch Clamp technique. 69 2.5 Drugs and solutions 70 Table 2.1 PSS solutions. 70 Table 2.2 Internal pipette solution. 70 Table 2.3 Drugs & reagents. 71 Table 2.4 List of solvents used to dissolve drugs. 72 Chapter 3 Characterisation of K + channels mediating resting tone in PASMCs and the effects of K+ channel blockers on 5-HT induced contraction 73 Introduction 74 Table 3.1 Pharmacology of Potassium channel blockers. 79 Results 80 Discussion 91 Conclusion 96 Chapter 4 Mechanisms of action underlying vasoconstriction induced by 5-HT and linopirdine 97 Introduction 98 Methods 100 Results 102 Discussion 118 Conclusion 122 Chapter 5 Effects of the KCNQ channel openers, flupirtine and retigabine, on pulmonary arteries in PAH 123 Introduction 124 Methods 126 VIII Results 126 Discussion 134 Conclusion 136 Chapter 6 General discussion 137 General discussion 138 IX List of experimental figures Chapter 3 Figure 3.1 Effect of 50 mM KCl in WT control and 5-HTT+ mice IPAs.
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