The Exercise Pressor Reflex Dr. James P. Fisher Department of - - PowerPoint PPT Presentation

The Exercise Pressor Reflex

Copenhagen, 2019

• Dr. James P. Fisher

Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland

Based on work of Secher, 1977. from Saltin, B. J Physiol 2007;583:819-823

The physiological challenge of exercise

Original blood pressure tracing of one subject with exercise-induced hypotension (idiopathic orthostatic hypotension). Vertical lines are at 10-second intervals.

Patients with autonomic disorders, in which the normal exercise-induced increase in sympathetic nerve activity is markedly attenuated, can experience hypotension potentially leading to reduced physical capacity, fatigue, dizziness and even syncope

Marshall et al., (1961)

Presentation Overview

i. ‘Classic studies’ ii. Group III and IV skeletal muscle afferents iii. EPR and autonomic nervous system iv. EPR in disease states

Fisher et al. Compr Physiol. 2015; 5:1-38

Exercise Pressor Reflex: Classic studies in humans

Alam & Smirk (1937) J Physiol. 89: 372-383 Figure from; Mitchell (2013) Exp Physiol. 98, 867-878.

Rhythmic handgrip exercise (A) Performed under free-flow conditions (B, top) Or with ischemia (C, bottom), which augmented the blood pressure (BP) response

Augmented BP response absent in patient with sensory loss

Mitchell J H (2012) Exp Physiol. 97:14-19

Exercise Pressor Reflex: Classic studies in animals (I)

Coote et al., (1971) J Physiol. 215: 789-804.

• A laminectomy performed (in cat)
• Ventral roots of L7 & S1 sectioned
• Peripheral ends stimulated to contract

the hindlimb muscles

• HR, BP and tension recorded

Pressor response No pressor response after section of dorsal root

Experimental preparation for studying the effect of anaesthetic (lidocaine) block on muscle afferent nerves in the dorsal root

Mitchell J H (2012) Exp Physiol. 97:14-19

Exercise Pressor Reflex: ‘Classic’ studies in animals (II)

McCloskey & Mitchell (1972) J Physiol. 224: 173-186.

Stim Stim Stim

A) B) C)

A & C) control BP response to contraction B) administration of lidocaine at dorsal root to block group III and IV afferents (but not group I and II afferents) abolishes BP response to contraction

Neurophysiological basis for the Exercise Pressor Reflex

Kaufman M (2002) Clin Auton Res. 12 : 429 – 439 Stacey et al. (1969) J Anton. 105: 231-254

Group III (Ad fibres): Located near myotendinous junction Group IV (C fibres): Located near blood vessels Anatomical-functional coupling?

Neurophysiological basis of the exercise pressor reflex

Rapid initial burst

Greaney et al. Auton Neurosci. 2015; 188:51-57

Secondary burst? ≈Response latency

Kaufman M P Exp Physiol 2012;97:51-58

Piezo channels

Muscle metaboreceptors evoke ↑muscle SNA

HR (bpm) 76 88 83 67 63 67 MAP (mmHg) 100 114 127 122 122 107

Mark et al., (1985) Circ Res. 57:461-469. Measurement of muscle sympathetic nerve activity from human peroneal nerve at level of fibular head

A B

Muscle acidosis is linked to increased muscle SNA

• McArdles disease: Genetic myophosphorylase deficiency.
• Therefore, no glycogen degradation in exercising muscle.
• No acidosis, No sympatho-excitation
• But, heart rate still increases (central command?).

Fadel et al., (2003) J Physiol 548: 983-993. Pryor et al., (1990) J Clin Invest. 85:1444-9. Victor et al., (1988) J Clin Invest. 82(4):1301-5.

Muscle metaboreceptors evoke ↑muscle SNA

HR (bpm) 76 88 83 67 63 67 MAP (mmHg) 100 114 127 122 122 107

Mark et al., (1985) Circ Res. 57:461-469. Measurement of muscle sympathetic nerve activity from human peroneal nerve at level of fibular head

A B

Muscle metaboreflex Arterial baroreceptors Peripheral vasculature Heart

BP

Muscle mechanoreflex Central command

Fisher et al. (2010) Physiology News

Why isn’t heart rate elevated with muscle metaboreceptor activation during post-exercise ischaemia?

Green line – Sympathetic Blue line – Parasympathetic

Does parasympathetic blockade unmask a muscle metaboreflex mediated sympathetic tachycardia during PEI?

Time (s)

IHG PEI-M

 Heart Rate

(b min-1) 10 20 30 40 50 60 70

Control Beta-adrenergic blockade Parasympathetic blockade

B)

*

*†

†# *†# †

*†‡

*‡ †‡# †‡

25% MVC

Time (s)

60 120 180 240 300 360 420 480 540 600 660 720

Heart Rate

(b min-1) 40 80 120 160



A) B)

† †# *†# † †‡ *‡ †‡# †‡ Rest IHG PEI-M Recovery

Medulla Oblongata

Modified from: Potts JT. Exp Physiol 2006;91:59–72. Michellini LC, et al. AJP-Heart Circ Physiol 2015;309:H381-92.

Baroreflex afferents NTS NA/DMV CVLM RVLM

+ + + + + + + – –

EPR

↑TPR ↑Q

.

Slide donated by Lauro Vianna, University of Brasilia

GABA, gamma- aminobutyric acid

Baseline Isometric Handgrip Exercise Post-exercise ischemia

Placebo (Before Diazepam)

90 50 50 1000 70 50 15 10

Baseline Isometric Handgrip Exercise Post-exercise ischemia

5 s

MSNA (au) HR (bpm) BP (mmHg)

90 50 50 1000 70 50 15 10

MSNA (au) HR (bpm) BP (mmHg)

After Diazepam Administration Slide donated by Lauro Vianna, University of Brasilia

Diazepam: positive allosteric modulators of the GABA type A receptors

Responses: BP HR (Ex) MSNA

Presentation Overview

i. ‘Classic studies’ ii. Group III and IV skeletal muscle afferents iii. EPR and autonomic nervous system iv. EPR in disease states

Fisher et al. Compr Physiol. 2015; 5:1-38

Holwerda et al. Am J Physiol Heart Circ Physiol 2016;310:H300-H309

Exaggerated sympathetic and pressor responses to handgrip in type 2 diabetic patients: role of the muscle metaboreflex (I)

Exaggerated pressor responses to exercise in hypertension eliminated by intrathecal fentanyl

Barbosa et al. 2016. J Physiol. 594.3 pp 715–725

• Fentanyl, a μ-opioid receptor agonist, attenuates the central projection of opioid-sensitive group III

and IV muscle afferents

• NT: Normotensive controls. HT CTRL: Hypertensive control. HT FENT: Hypertensive with fentanyl.
• Leg cycling at 40W

Amann et al. International Journal of Cardiology 174 (2014) 368–375

Intrathecal fentanyl in human heart failure (HF) increases leg blood flow and oxygen delivery during exercise

BP, reported leg pain and dyspnea

ACTIVE MUSCLE VAS OCON S TRICTOR TONE Exercise tolerance/ capacity

Blood pressure response

Hypoperfusion /metabolite accumulation S ympathetic response

+ Impaired functional sympatholysis & Impaired vasodilatory signaling

Dyspnea (?)

SKELETAL MUSCLE AFFERENT SIGNALING

Vianna & Fisher (2019) Current Opinion in Physiology. In press.

Exercise with blood flow restriction… “could precipitate adverse cardiovascular or cerebrovascular events (e.g., cardiac arrhythmia, myocardial infarction, stroke and sudden cardiac death)”

Key points

• The exercise pressor reflex powerfully increases

SNA.

• The exercise pressor reflex is heightened in

several disease states (e.g., T2DM, HTN, HF).

• This has potential implications for cardiac

electrical stability, skeletal muscle and brain blood flow, blood pressure and exercise tolerance/performance.

• Lots of “whys” remains…

Thank you for listening!!

Blood flow restriction exercise and the brain

Finger blood pressure MCAv PETCO2 clamp Thigh Cuffs (blood flow restriction) Prodel et al. (2016) AJP – Heart Circ Physiol. 310(9):H1201-9.

Rest Exercise (100 bpm) BFR

3 min

Clinical perspective: Skeletal muscle afferents and cardiac autonomic control during exercise

• Sudden cardiac death due to ventricular tachy-arrhythmias is the leading cause of

death in industrially developed countries

• Subnormal cardiac parasympathetic tone and baroreflex sensitivity, and elevated

cardiac sympathetic drive may allow for the formation of malignant ventricular arrhythmias

• Implications for patient populations with exaggerated muscle afferent drive during

exercise (e.g. CHF, COPD, hypertension).

• Improved cardiac parasympathetic tone and baroreflex sensitivity via exercise training

(treadmill running) reduces risk of VF in dog model of sudden cardiac death Billman, (2006)

Br J Sports Med. 2014 Aug;48(15):1134-5.

• USA Triathlon (USAT) Fatality Incidents Study reviewed data

from 2003 to 2011. Of the 38 deaths, 30 occurred during the swim.

• ‘Autonomic Conflict’ (AC) occurs when both divisions of the

autonomic nervous system are co-activated resulting in cardiac arrhythmias and, possibly, death.

Original record showing the neural and cardiovascular responses to trigeminal nerve stimulation in one participant.

Fisher et al. Am J Physiol Heart Circ Physiol 2015;308:H367-H375

Percentage change from rest in mean arterial pressure (A), heart rate (B), femoral vascular conductance (C), heart rate variability (RMSSD; D), and MSNA (E and F) during TGS, post-exercise ischemia (PEI), and combined PEI + TGS.

Fisher et al. Am J Physiol Heart Circ Physiol 2015;308:H367-H375