Mediated Attenuation of Vagal-Evoked

A FUNCTIONAL STUDY OF NEUROPEPTIDE Y MEDIATED ATTENUATION OF VAGAL-EVOKED BRADYCARDIA MARGARET A. SMITH-WHITE B.Sc. A THESIS SUMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF NEW SOUTH WALES 2003

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ACKNOWLEDGEMENTS I wish to express sincere gratitude to my supervisor, Prof. Erica Potter for invaluable guidance, assistance and advice during the course of this project. I am indebted to the Prince of Wales Medical Research Institute, for allowing me to undertake this research and I thank my colleagues within the institute for providing a stimulating, enjoyable and friendly working environment. I would also like to thank the following people; Dr. Henri Doods and Boehringer Ingelheim Pharma for providing and allowing the use of the Y2 antagonist BIIE0246, Dr. Herbert Herzog (Garvan Institute for Medical Research) for supplying the Y2 and Y4 receptor-knockout mice; Dr. Ray Norton (Walter & Eliza Hall Institute for Medical Research) and Dr. Philip Mack (Peptech Pty Ltd) for their collaboration on Y2 analog design. To my family, I convey my sincere appreciation for their help and moral support at all times, with special thanks to my husband Tony for his endless encouragement throughout this project. Lastly, I wish to thank the National Health and Medical Research Council of Australia for supporting this work. 3 ABSTRACT In the heart, attenuation of cardiac vagal-evoked bradycardia for a prolonged period is observed following strong sympathetic nerve stimulation, such as exercise. This action is attributed to the sympathetic co-transmitter, neuropeptide Y (NPY) released together with classical transmitter noradrenaline (NAd) during stimulation of the nerve. The prolonged inhibition of cardiac vagal activity is thought to mirror the effects of sympathetic activation by extending the excitatory effects of NAd on the heart. This thesis examines the hypothesis that NPY attenuates or inhibits cardiac vagal-evoked bradycardia by activating the Y2 receptor subtype. The aims of this study were twofold. Firstly, to determine the receptor subtype that is responsible for evoking this effect and secondly, to ascertain how residues within NPY interact to induce a conformation acceptable for full inhibitory activity. An initial series of experiments in anaesthetised rats examined the influence that the proline residues in the N-terminal polyproline helix of NPY have on the level and duration of evoked inhibition. This required comparison of generated inhibitory effects by molecules with different N-terminal proline regions, including salmon PP, a chimeric peptide PP/NPY, and N-terminal truncated peptides. Inhibitory effects evoked by intravenous bolus injection of the individual peptides were compared to the actions of NPY. The combined results indicated a correlation between the presence of proline residues in the N-terminal region and potency of inhibition on cardiac vagal activity. As proline residues were removed, the inhibitory effect decreased suggesting that the N-terminal polyproline region was necessary for potent vagal attenuation. Full inhibitory action could be achieved in fragments as long, or 4 longer, than NPY 3-36, whilst shorter C-terminal fragments, such as NPY 24-36, potential products of enzyme degradation, did not evoke potent inhibition. A second series of experiments also in anaesthetised rats examined the structure of N-acetyl [Leu28, 31] NPY 24-36, a potent agonist of the inhibitory action on vagal-evoked bradycardia. This shortened C-terminal analog of NPY has therapeutic value as a drug to treat parasympathetic hyperactivity. The results show that structural components within N-acetyl [Leu28, 31] NPY 24-36 necessary for potent activity are (i) its amphipathicity, resulting from the helical arrangement of hydrophilic and hydrophobic residues (ii) side chains of arginine residues 25, 33 and 35 and (iii) a stabilised -helix extending from residues 24-32. Leucine residues initially substituted into the NPY 24-36 fragment to produce N-acetyl [Leu28, 31] NPY 24-36 resulted in an increase in potency, as did strengthening the region between residues 28-32 by lactamisation. It is plausible therefore to suggest that the leucine residues within N-acetyl [Leu28, 31] NPY 24-36 stabilise the analog in the same way that the N-terminal proline region does in the whole molecule. It is likely that by stabilising the C-terminal amphipathic portion in both NPY and N-acetyl [Leu28, 31] NPY 24-36 the structure necessary for the correct presentation of the extension residues is achieved. As the NPY mediated inhibitory action on cardiac vagal activity is proposed as Y2 receptor evoked, a specific Y2 receptor antagonist was used to test the selectivity of N-acetyl [Leu28, 31] NPY 24-36 for this receptor. The antagonist, BIIE0246 significantly reduced the inhibitory effect produced by N-acetyl [Leu28, 31] NPY 24-36 supporting the proposal that N-acetyl [Leu28, 31] NPY 24-36 acted specifically at Y2 receptors to inhibit vagal-evoked bradycardia. This antagonist also significantly reduced the inhibitory effect on vagal activity evoked by stimulation of 5 the cardiac sympathetic nerve. Additional experiments in Y2 receptor-knockout mice showed intravenous injection of both NPY and N-acetyl [Leu28, 31] NPY 24-36 failed to attenuate vagal-evoked bradycardia. Resting heart rate was however increased in these mice with the effect considered to be centrally mediated as neither NPY nor Nacetyl [Leu28, 31] NPY 24-36 reduced resting hear rate when injected intravenously. As the cloned form of Y2 receptor was targeted for deletion in Y2 receptor-knockout mice, the absence of inhibitory activity on the cardiac vagus in these mice suggests that the same form of Y2 receptor found centrally is also present at the heart. It is therefore plausible to suggest the Y2 receptor may also produce an inhibitory action in regions of the brain able to affect cardiac sympathetic outflow to the heart. The conclusions reached from the pharmacological and anatomical evidence strongly support the hypothesis that NPY released during stimulation of the sympathetic nerve, acts via Y2 receptors on the vagus nerve, to attenuate vagalevoked bradycardia. 6 PUBLICATIONS ARISING FROM WORK DESCRIBED IN THIS THESIS 1. Smith-White, M.A., Wallace, D. & Potter, E.K. (1998) Sympathetic-parasympathetic interactions at the heart in the anaesthetised rat. Journal of the Autonomic Nervous System 75, 171-175 2. Smith-White, M., Moriarty, M.J & Potter, E.K. (1998) A comparison of actions of (NPY) agonists and antagonists at NPY Y1 and Y2 receptors in anaesthetised rats. Neuropeptides 32(2), 109-118 3. Smith-White, M.A. & Potter, E.K. (1999) Structure-activity analysis of N-acetyl [Leu28, 31] NPY 24-36: a potent neuropeptide Y Y2 receptor agonist. Neuropeptides 33(6) 526-533 4. Smith-White, M.A., Hardy, T.A., Brock, J.A. & Potter, E.K. (2001) Effects of a selective neuropeptide Y Y2 receptor antagonist, BIIE0246, on Y2 receptors at peripheral neuroeffector junctions. British Journal of Pharmacology, 132 861 – 868. 5. Smith-White, M.A., Herzog, H. & Potter, E.K. (2002) Role of neuropeptide Y Y2 receptors in modulation of cardiac parasympathetic neurotransmission. Regulatory Peptides, 103 105- 111 6. Smith-White, M.A., Herzog, H. & Potter, E.K. (2002) Cardiac function in neuropeptide Y Y4 receptor knockout mice. Regulatory Peptides, 110 47-54 7. Yao S, Smith-White MA, Potter EK, Norton RS, (2002). Stabilisation of the helical structure of Y2 selective analogues of neuropeptide y by lactam bridges. Journal of Medicinal Chemistry 45:2310-2318. 8. Smith-White, M.A., Iismaa, T & Potter, E.K. (2003) Galanin and NPY reduce cholinergic transmission in the heart of the anaesthetised mouse. (submitted to British journal of Pharmacology, accepted awaiting publication). 7 TABLE OF CONTENTS PAGE ACKNOWLEDGEMENTS 2 ABSTRACT 3 PUBLICATIONS 6 ABBREVIATIONS 9 CHAPTER 1 – INTRODUCTION AND LITERATURE REVIEW 10 AUTONOMIC REGULATION OF THE HEART BEAT 11 NEUROPEPTIDE Y FAMILY OF PEPTIDES 28 NEUROPEPTIDE Y MOLECULE 34 NEUROPEPTIDE Y RECEPTORS 42 Y2 RECEPTOR 54 Y2 RECEPTOR MODELLING 61 CHAPTER 2 - METHODS AND PROTOCOLS 68 CHAPTER 3 - THE RAT AND MOUSE CARDIOVASCULAR SYSTEM AS MODELS 78 FOR THE STUDY OF INHIBITION OF VAGAL-EVOKED BRADYCARDIA CHAPTER 4 –EXAMINING THE CONTRIBUTION THE N-TERMINAL POLYPROLINE 93 REGION WITHIN NPY HAS ON THE LEVEL OF INHIBITION OF VAGALEVOKED BRADYCARDIA CHAPTER 5 – STRUCTURE- ACTIVITY ANALYSIS OF 110 N-acetyl [Leu 28, 31] NPY 24-36: A POTENT INHIBITOR OF VAGAL-EVOKED BRADYCARDIA 8 CHAPTER 6 – EFFECTS OF SELECTIVE Y2 RECEPTOR ANTAGONIST, BIIE0246 142 ON THE INHIBITION OF VAGAL-EVOKED BRADYCARDIA THAT FOLLOWS SYMPATHETIC STIMULATION CHAPTER 7 - EFFECTS OF NPY AND N-acetyl [Leu 28, 31] NPY 24-36 IN NEUROPEPTIDE Y Y2 RECEPTOR KNOCKOUT MICE 153 CHAPTER 8 - EFFECTS OF Y4 RECEPTOR DELETION ON Y2 MEDIATED INHIBITION OF VAGAL-EVOKED BRADYCARDIA 164 CHAPTER 9 - GENERAL DISCUSSION 177 REFERENCES 183 APPENDIX 240 9 Abbreviations ACh, acetylcholine; NAd, noradrenaline, NPY, neuropeptide Y, dmnX, dorsal motor nucleus of the vagus; nTs, nucleus of the tractus solitarius; NA, nucleus ambiguus; SA, sinoatrial; PVN, paraventricular nucleus; AV, atrioventricular; PYY, peptide YY; PP, pancreatic polypeptide; PYX-1 (Ac-[3-(2,6- dichlorobenzyl)Tyr27, D-Thr32]NPY-(27-36) amide) and PYX-2 (Ac-[3-(2,6- dichlorobenzyl)Tyr27, 36,DThr32] NPY-(27-36) amide); PP-56 (D-myo-inositol 1,2,6-triphosphate; -trinositol); 1229U91 also known as GR231118 ([2’,4],[2’,4]homodimer of Ile-Glu-Pro-Dpr-Tyr- Arg-Leu-Arg-Tyr-CONH2); BIBP3226 ((R)-N2 –(diphenylacetyl)-N-[(4- hydroxyphenol) methyl] argininamide); SR120819A (1-[2-[2-(2-naphthylsulfamoyl)-3-phenylpropionamido]-3-[-4- (dimethylaminomethyl)-c-cyclohexylmethyl] amidino]phenyl]propioyl]- pyrrolidine(R,R)sterioisomer); CGP 71683A (trans-naphtalene-1-sulphonic acid [4- [(4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl]-amide hydrochloride); BIIE0246, ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-yl]- 1-piperazinyl]-2-oxo-ethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo- 1,2-diphenyl-3-H-1,2,4-triazol-4-y]ethyl]-argininamid.

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