Sympatholysis Synchronous

Lecture includes voting slides
Session ID = year3exercise
Functional Sympatholysis
Dr Ben Chant
bc15666@Bristol.ac.uk
Lecture includes voting slides
Session ID = year3exercise
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Dr Ben Chant
bc15666@Bristol.ac.uk
Exercise Physiology in
Health and Disease
Seminar 3
Dr Ben Chant Functional

bc15666@bristol.ac.uk
Sympatholysis
Reference:
Berne & Levy, Physiology
Levick, Introduction to Cardiovascular Physiology
Ganong, Review of Medical Physiology
3
Exercise Physiology in
Health and Disease
Seminar 3
Dr Ben Chant Functional

bc15666@bristol.ac.uk
Sympatholysis
Worksheet for today on Blackboard
Fill in as we go along 4
Key References for Functional
Sympatholysis L1
i. Collins DM, McCullough WT & Ellsworth ML. (1998). Conducted vascular
responses: communication across the capillary bed. Microvascular research 56,
43-53.
ii. Van Teeffelen JWGE and Segal SS (2003). Interaction between sympathetic nerve
activation and muscle fibre contraction in resistance vessels of hamster retractor
muscle. J Physiol. 550(Pt 2): 563-74
iii. Burns WR, Cohen KD, Jackson WF. (2004). K+-induced dilation of hamster
cremasteric arterioles involves both the Na+/K+-ATPase and inward-rectifier K+
channels. Microcirculation. 11(3): 279-93.
iv. Hearon CM Jr, Richards JC, Racine ML, Luckasen GJ, Larson DG, Dinenno FA.
(2019). Amplification of endothelium-dependent vasodilatation in contracting
human skeletal muscle: role of KIR channels. J Physiol. 2019;597(5):1321-1335.
v. Hearon CM Jr, Richards JC, Racine ML, Luckasen GJ, Larson DG, Dinenno FA.
Amplification of endothelium-dependent vasodilatation in contracting human
skeletal muscle: role of KIR channels. J Physiol. 2019;597(5):1321-1335. 5
Key References for Functional
Sympatholysis L2
i. Vongpatanasin W, Wang Z, Arbique D, et al. Functional sympatholysis is impaired
in hypertensive humans. J Physiol. 2011;589(Pt 5):1209-1220
ii. Price A, Raheja P, Wang Z, Arbique D, Adams-Huet B, Mitchell JH, Victor RG,
Thomas GD, Vongpatanasin W. Differential effects of nebivolol versus metoprolol
on functional sympatholysis in hypertensive humans. Hypertension. 2013
Jun;61(6):1263-9.
iii. Mizuno M, Iwamoto GA, Vongpatanasin W, Mitchell JH, Smith SA. Exercise
training improves functional sympatholysis in spontaneously hypertensive rats
through a nitric oxide-dependent mechanism. Am J Physiol Heart Circ Physiol.
2014 Jul 15;307(2):H242-51.
iv. Mortensen SP, Nyberg M, Gliemann L, Thaning P, Saltin B, Hellsten Y. Exercise
training modulates functional sympatholysis and α-adrenergic vasoconstrictor
responsiveness in hypertensive and normotensive individuals. J Physiol. 2014 Jul
15;592(14):3063-73.
Functional
Sympatholysis
in Disease
• Essential hypertension
affects ~31% of the adult
population worldwide
(Mills et al. 2016).
• Major cause of
cardiovascular and
cerebrovascular disease
• Associated with elevated
systemic vascular
resistance at rest and a
blunted fall in vascular
resistance during
exercise
MSNA in young normotensive (yNTN), older NTN
• Sympathetic nervous (oNTN), borderline hypertensive (bHTN), untreated HTN
system activity elevated (uHTN), treated but poorly controlled HTN (pcHTN), and
in essential hypertension treated controlled HTN (tHTN) participants.
vs. normotensive
individuals
7
Functional
Sympatholysis
in Disease
• Sympathetic nerve activity

during exercise ↑ in
essential hypertension vs.
normotensive individuals
• In normotensive
individuals, this
sympathetic nerve activity
is normally offset in
metabolically active
skeletal muscle
• Today – we will explore
the data looking at
functional sympatholysis
in essential Isometric handgrip exercise at 30% MVC
hypertension.
Delaney et al. (2010)
8
Functional ***On worksheet***
Sympatholysis
in Disease
TASK – 5/10 minutes
• Sympathetic nerve activity • Do you expect functional
during exercise ↑ in
essential hypertension vs. sympatholysis to be
normotensive individuals ‘normal’ in essential
• In normotensive hypertension?
individuals, this
sympathetic nerve activity • What could the
is normally offset in consequences of
metabolically active impaired functional
skeletal muscle
• Today – we will explore
sympatholysis be?
the data looking at
in essential
hypertension.
9
Functional Sympatholysis in
Disease
noradrenaline
10
Thomas (2015)
Role of Oxidative Stress in hypertension
• Vascular smooth
muscle cell growth
• Impaired
endothelial function
• Reduced
bioavailability of
nitric oxide
15
***On worksheet***
Functional sympatholysis in
hypertension: animal models
q Is there a difference between rest and contraction?
yes did show
q Is there a difference between hypertensive rats (2K1C) and

normotensive rats (sham rats)?
q Tempol scavenges free radicals – what does this data highlight
the importance of?
do free radicals pass the problem of hypertension?
Normotensive Hypertensive
rats rats
16
Zhao et al. (2006)
What is the difference between
rest and contraction?
rats rats
17
***On worksheet***
Is there a difference between
hypertensive rats (2K1C) and
normotensive rats (sham rats)?
rats rats
18
***On worksheet***
Tempol scavenges free radicals –
what does this data highlight the
importance of?
rats rats
19
***On worksheet***
Mechanisms
q ANGII and NADPH oxidase
levels elevated
q Skeletal muscle NO levels
diminished
q Superoxide (O2-) scavenges
NO (forms peroxynitrite)
q Superoxide dismutase
mimetic tempol restored
functional sympatholysis in
hypertensive rats.
20
Zhao et al. (2006)
hypertension: humans
qFunctional sympatholysis measured using:
1. Vascular ultrasound
¦Normally measuring forearm/femoral blood flow
2. Forearm muscle oxygenation levels (near infrared
spectroscopy (NIRS))
Help with techniques:
NIRS is a non-invasive method for monitoring oxygen availability and
utilization by the tissues. In intact skeletal muscle, NIRS allows semi-
quantitative measurements of haemoglobin plus myoglobin
oxygenation (tissue O2 stores) and the haemoglobin volume (Boushel
and Piantadosi, 2000).
21
Vascular ultrasound
Forearm blood flow (FBF, ml min−1) = MBVx𝝿(brachial diameter/2)2×60
FVC (ml min−1(100 mmHg)−1) = (FBF/MAP)×100
Rest Exercise
22
Paper 1
Vongpatanasin et al. (2011)
Participants/Protocol
q Essential hypertension (n=13, age = 47±3, resting blood pressure
(SBP/DBP) = 144±4/87±2 mmHg)
¦ All participants with hypertension withdrawn from medication (t-2 days before experiment)
q Normotensive (n=17, age = 48±2 , resting blood pressure

(SBP/DBP) = 118±3/72±2 mmHg)
q Used both vascular ultrasound (forearm) and NIRS to assess functional
sympatholysis
q MSNA measured using microneurography
MSNA was expressed as burst frequency (bursts min-1)

Total activity (burst frequency x mean burst amplitude) 23
Paper 1
Protocol
30% MVC
amplitude and frequency bigger
24
30% MVC
Paper 1
Protocol – LBNP*
LBNP at −20 mmHg or −30 mmHg was used to unload mainly the
cardiopulmonary baroreceptors and trigger increases in muscle
sympathetic nerve activity (MSNA).
*LBNP – Lower Body Negative Pressure 25
Paper 1
LBNP LBNP

What are the differences between rest
and dynamic HG exercise?
LBNP LBNP 27
Paper 1
+LBNP +LBNP

Are there any differences between HTN
and NTN?
+LBNP +LBNP 29
Paper 1
LBNP LBNP
Rest – similar decreases in muscle oxygenation, FBF, and FVC to LBNP.
HG exercise plus LBNP – decrease in muscle oxygenation, FBF, and FVC

vs. HG exercise plus LBNP in hypertension vs. normotension.

Paper 1
Rest Rest + HG HG +
LBNP LBNP
FBF (ml 114 ± 85 ± 474 ± 477 ±
−1
min ) 15 10* 41* 39*
NTN
FVC 136 ± 103 ± 513 ± 506 ±
(units) 17 12* 50* 44*
FBF (ml 98 ± 17 76 ± 447 ± 384 ±
−1
min ) 11* 56* 50*‡
HTN
FVC 93 ± 15 73 ± 397 ± 343 ±
(units) 11* 49* 41*†‡
FBF, forearm blood flow; FVC, forearm vascular conductance. *P < 0.05 vs. rest; †P <
0.05 vs. normotensive; ‡P < 0.01 vs. handgrip; Normotensive, n= 15; hypertensive, n= 13.
need higher exercise intensity to see true response of normotension and hypertension
31
Paper 1
Rest Rest + HG HG +
LBNP LBNP
SNA (bursts 31±3 39±2* 31±3 41±2*‡
-1
min )
NTN 𝚫 SNA (% 0±0 63±18* 5±7 78±18*‡
total
activity)
SNA (bursts 35±4 43±3* 41±3*† 47±3*‡
-1
min )
HTN 𝚫 SNA (% 0±0 64±19* 54±11*† 133±23*†
total ‡
activity)
FBF, forearm blood flow; FVC, forearm vascular conductance. *P < 0.05 vs. rest; †P <
0.05 vs. normotensive; ‡P < 0.01 vs. handgrip; Normotensive, n= 15; hypertensive, n= 13.
32
Paper 1
Key outcomes
• Functional sympatholysis impaired in untreated

hypertensive humans
• But, this was only during HG + LBNP, not handgrip
alone.
Points to consider
• 30% MVC – was this high enough?

• What effect could anti-HTN medications have
• Could responses be different in the legs vs. the arms
33
Paper 1
Ibesartan = AT1 receptor antagonist

n=7
LBNP LBNP LBNP
Does Ibesartan improve functional sympatholysis?

it works-significantly different from other groups
34
Does Ibesartan improve functional sympatholysis?
n=7
35
LBNP LBNP LBNP
Paper 1

n=7
LBNP LBNP LBNP
Discuss: Any plausible mechanisms?

36
Paper 1

n=7
AT1 receptor antagonist restored functional

sympatholysis in a small group of hypertensive
participants (n=7).
No normotensive control group
37
Paper 2
Price et al. (2013)
Protocol
q Essential hypertension (n=21, age = 54±3, resting blood
pressure (SBP/DBP) = 141±3/86±2 mmHg)
q No control group
q Used both vascular ultrasound (forearm) and NIRS to

assess functional sympatholysis
q MSNA measured using microneurography
q Subjects performed rhythmic handgrip (20/min); 30%

MVC for 6 min.
38
Paper 2
Price et al. (2013)
Protocol
q Nebivolol vs. Metoprolol
q Both selective 𝛽-adrenoreceptor 1 (𝛽1) antagonists
¦ Nebivolol –also has antioxidant effects (decreases ROS) and NO
potentiating effects.
¦ Meteroprolol - a selective 𝛽-adrenoreceptor 1 antagonist.
q Limitation of 𝛽-adrenoreceptor 1 antagonist

¦ Known to limit cardiovascular exercise performance at both
moderate and high intensity exercise (-ve effect on cardiac
outputMAX).
39
Paper 2
Price et al. (2013)
Protocol
q Nebivolol vs. Metoprolol
q Both selective 𝛽-adrenoreceptor 1 antagonists
¦ Nebivolol – a selective 𝛽-adrenoreceptor 1 antagonist, but also
has antioxidant effects (decreases ROS) and NO potentiating
effects.
¦ Meteroprolol - a selective 𝛽-adrenoreceptor 1 antagonist.
q Based on everything we know so far, what do you

think they found? (2 mins)
40
Based on everything we know, so
far, what do you think they found?
A. Both drugs (nebivolol
and metoprolol)
improved functional
sympatholysis
B. Nothing!
C. Nebivolol improved
functional
sympatholysis
D. Metoprolol improved
functional
sympatholysis
41
Paper 2
Protocol
Price et al. (2013)
Vs.
42
Paper 2
Price et al. (2013)
Key questions:
Which drug is more

effective at improving
functional
sympatholysis?
What are the potential

mechanisms?
43
Paper 2
Price et al. (2013)
Key take home:

Nebivolol improves
functional
sympatholysis in
response to
rhythmic handgrip
exercise plus LBNP.
Suggests a key role
for NO.
44
Paper 1 and 2 Vongpatanasin et al. (2011) and
Price et al. (2013)
Key point:
Neither nebivolol or
ibesartan normalised the
elevated SNA during HG
exercise in HTN
Despite improving
SNA higher in HTN
vs. NTN during
rhythmic handgrip
Why might this be?
exercise
these drugs are changing response to that level of SNA
Pressor and sympathoexcitatory responses to rhythmic handgrip alone in

normotensive and hypertensive subjects
*P < 0.05 vs. normotensive; †P < 0.05 vs. min 0 (rest).
Why might this be?
Key point:
Neither nebivolol or
ibesartan normalised the
elevated SNA during HG
exercise in HTN
Despite improving
Why might this be?
46
Paper 3
q So, what about exercise training?
capable of improving functional sympatholysis
mechanism: change the number of receptors (free nerve endings) on the endothelium and muscle
WHYUT
SHRUT
SHRET
3 months of voluntary
wheel running only in
the SHRUT
Lumbar nerve stimulation (Hz)

Mitchell et al. (2014b) ‘Sympathetic nerve activation’ Mechanisms?47
Paper 3
WHYUT
SHRUT
SHRET
the SHRUT
‘Sympathetic nerve stimulation’
*P < 0.05, compared with WKYUT. †P < 0.05, compared with SHRUT.
Describe the graph to the person sat next to you?
Mitchell et al. (2014b)

Mechanisms?48
Paper 3
WHYUT
SHRUT
SHRET
the SHRUT
‘Sympathetic nerve stimulation’
*P < 0.05, compared with WKYUT. †P < 0.05, compared with SHRUT.
What effect does exercise training have on functional

sympatholysis?

Mechanisms?49
Paper 3
Mechanisms? L-NAME systemic NOS inhibition (both eNOS and nNOS)
qL-NAME attenuated the improvements in

functional sympatholysis in the SHRET (Mitchell et
al. 2014b).
Before L-NAME
After L-NAME
§P < 0.05, compared with before L-NAME administration. 50

Paper 3
Mechanisms?
qL-NAME attenuated the improvements in
functional sympatholysis in the SHRET (Mitchell et
al. 2014b).
qSimilar results found in normotensive rats
(Jendzjowsky et al. 2013)
qExercise increases…
¦Bioavailability of NO (eNOS, nNOS)
¦Endothelial function
51
Paper 4
Mortensen et al. (2014)
Protocol
qEssential hypertension (n=8, age = 47±2, resting
blood pressure (SBP/DBP) = 162±4/102±4 mmHg)
¦ Participants withdrawn from HTN medication before study (2 weeks)
qNormotensive (n=8, age = 46±1 , resting blood

pressure (SBP/DBP) = 135±4/81±2 mmHg)
qFunctional sympatholysis assessed in the femoral

artery pre and post 8 weeks aerobic exercise
training (80% HRMAX and <60% HRMAX)
52
Paper 4
Protocol
30 minutes rest Femoral artery Infusion of:

tyramine
ATP
ATP + tyramine
Exercise protocol: Measurement of
femoral blood flow
One-legged knee extensor using ultrasound
exercise (10, 20, 30 W)
One-legged knee extensor
exercise (10, 20, 30 W) +
tyramine 53
Paper 4
Pre-training Post-training
Figure 2. § Different from normotensive individuals, P < 0.05; #different from control
exercise, P < 0.05; ¤different from before training, P < 0.05.
Functional Sympatholysis in
Disease
noradrenaline
55
Point to consider…
qWhat are the implications of an impaired

functional sympatholysis in skeletal muscle in
hypertension?
qNext up.. The Exercise Pressor Reflex – how does

this link to functional sympatholysis?
56
TASK
57

Sympatholysis Synchronous

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Lecture includes voting slides

Dr Ben Chant Functional

Dr Ben Chant Functional

• Sympathetic nerve activity

q Is there a difference between hypertensive rats (2K1C) and

q Normotensive (n=17, age = 48±2 , resting blood pressure

MSNA was expressed as burst frequency (bursts min-1)

*LBNP – Lower Body Negative Pressure 26

*LBNP – Lower Body Negative Pressure 28

Rest – similar decreases in muscle oxygenation, FBF, and FVC to LBNP.

HG exercise plus LBNP – decrease in muscle oxygenation, FBF, and FVC

*LBNP – Lower Body Negative Pressure 30

• Functional sympatholysis impaired in untreated

• 30% MVC – was this high enough?

Ibesartan = AT1 receptor antagonist

LBNP LBNP LBNP

Does Ibesartan improve functional sympatholysis?

Ibesartan = AT1 receptor antagonist

LBNP LBNP LBNP

Discuss: Any plausible mechanisms?

Ibesartan = AT1 receptor antagonist

AT1 receptor antagonist restored functional

q Used both vascular ultrasound (forearm) and NIRS to

q Subjects performed rhythmic handgrip (20/min); 30%

q Limitation of 𝛽-adrenoreceptor 1 antagonist

q Based on everything we know so far, what do you

Which drug is more

What are the potential

Key take home:

Pressor and sympathoexcitatory responses to rhythmic handgrip alone in

Why might this be?

Lumbar nerve stimulation (Hz)

Describe the graph to the person sat next to you?

Mitchell et al. (2014b)

What effect does exercise training have on functional

Mitchell et al. (2014b)

qL-NAME attenuated the improvements in

§P < 0.05, compared with before L-NAME administration. 50

qNormotensive (n=8, age = 46±1 , resting blood

qFunctional sympatholysis assessed in the femoral

30 minutes rest Femoral artery Infusion of:

qWhat are the implications of an impaired

qNext up.. The Exercise Pressor Reflex – how does

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