A FUNCTIONAL STUDY OF NEUROPEPTIDE Y MEDIATED ATTENUATION OF VAGAL-EVOKED BRADYCARDIA

Короткий опис

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
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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.
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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).
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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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