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

The Exercise Pressor Reflex Dr. James P. Fisher Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland Copenhagen, 2019

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

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’ iii. EPR and autonomic nervous system ii. Group III and IV skeletal muscle afferents iv. EPR in disease states Fisher et al. Compr Physiol. 2015; 5:1-38

Exercise Pressor Reflex: Classic studies in humans 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 Alam & Smirk (1937) J Physiol. 89: 372-383 Figure from; Mitchell (2013) Exp Physiol. 98, 867-878.

Exercise Pressor Reflex: Classic studies in animals (I) Mitchell J H (2012) Exp Physiol. 97:14-19 No pressor response Pressor after section of response dorsal root • A laminectomy performed (in cat) • Ventral roots of L7 & S1 sectioned • Peripheral ends stimulated to contract the hindlimb muscles Coote et al., (1971) J Physiol. 215: 789-804. • HR, BP and tension recorded

Exercise Pressor Reflex: ‘Classic’ studies in animals (II) Mitchell J H (2012) Exp Physiol. 97:14-19 A) Stim B) Stim Experimental preparation for studying the effect of anaesthetic C) (lidocaine) block on muscle afferent nerves in the dorsal root A & C) control BP response to contraction Stim 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 McCloskey & Mitchell (1972) J Physiol. 224: 173-186.

Neurophysiological basis for the Exercise Pressor Reflex Kaufman M (2002) Clin Auton Res. 12 : 429 – 439 Group III (A d fibres ): Located near myotendinous junction Group IV (C fibres): Located near blood vessels Anatomical-functional coupling? Stacey et al. (1969) J Anton. 105: 231-254

Neurophysiological basis of the exercise pressor reflex Rapid initial burst Piezo channels Secondary burst? ≈Response latency Greaney et al. Auton Neurosci. 2015; 188:51-57 Kaufman M P Exp Physiol 2012;97:51-58

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. A B Measurement of muscle sympathetic nerve activity from human peroneal nerve at level of fibular head

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 Fadel et al., (2003) J Physiol 548: 983-993. Pryor et al., (1990) J Clin Invest. 85:1444-9. • But, heart rate still increases (central command?). 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. A B Measurement of muscle sympathetic nerve activity from human peroneal nerve at level of fibular head

Why isn’t heart rate elevated with muscle metaboreceptor activation during post-exercise ischaemia? Central command Peripheral vasculature Muscle BP metaboreflex Muscle mechanoreflex Heart Arterial baroreceptors Green line – Sympathetic Fisher et al. (2010) Physiology News Blue line – Parasympathetic

Does parasympathetic blockade unmask a muscle metaboreflex mediated sympathetic tachycardia during PEI? Time (s) A) 25% MVC B) 160 Rest Recovery 70 IHG PEI-M Control Beta-adrenergic blockade 60 Parasympathetic blockade  Heart Rate 50 Heart Rate 120 (b min -1 ) (b min -1 ) †# 40 †‡# 30 †‡ 80 † 20 *‡ * †‡ 10 *†# * * † 40 0 0 60 120 180 240 300 360 420 480 540 600 660 720 IHG PEI-M Time (s) B) †# †‡# †‡ †  *‡ †‡ *†# †

Slide donated by Lauro Vianna, University of Brasilia RVLM CVLM NTS Medulla Oblongata + – + + Baroreflex + afferents NA/DMV + – + + GABA, gamma- aminobutyric acid EPR . ↑ TPR ↑ Q Modified from: Potts JT. Exp Physiol 2006;91:59 – 72. Michellini LC, et al. AJP-Heart Circ Physiol 2015;309:H381-92.

Placebo (Before Diazepam) 15 0 (mmHg) BP 10 Slide donated by Lauro Vianna, University of Brasilia 0 50 90 HR (bpm) 70 50 1000 MSNA (au) 50 0 0 After Diazepam Administration Responses: Baseline Isometric Handgrip Exercise Post-exercise ischemia 15 Diazepam: 0 (mmHg) BP positive allosteric BP 10 0 modulators of the GABA type A 50 90 receptors HR (bpm) HR (Ex) 70 50 1000 MSNA (au) 50 MSNA 0 0 5 s Baseline Isometric Handgrip Exercise Post-exercise ischemia

Presentation Overview i. ‘Classic studies’ iii. EPR and autonomic nervous system ii. Group III and IV skeletal muscle afferents iv. EPR in disease states Fisher et al. Compr Physiol. 2015; 5:1-38

Exaggerated sympathetic and pressor responses to handgrip in type 2 diabetic patients: role of the muscle metaboreflex (I) Holwerda et al. Am J Physiol Heart Circ Physiol 2016;310:H300-H309

Exaggerated pressor responses to exercise in hypertension eliminated by intrathecal fentanyl • 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 Barbosa et al. 2016. J Physiol. 594.3 pp 715 – 725

Intrathecal fentanyl in human heart failure (HF) increases leg blood flow and oxygen delivery during exercise Amann et al. International Journal of Cardiology 174 (2014) 368 – 375

BP, reported leg pain and dyspnea

SKELETAL MUSCLE Dyspnea (?) AFFERENT SIGNALING Exercise tolerance/ capacity S ympathetic response Hypoperfusion /metabolite accumulation Blood pressure + Impaired functional response ACTIVE MUSCLE sympatholysis & VAS OCON S TRICTOR Impaired vasodilatory TONE 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…

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Blood flow restriction exercise and the brain P ET CO 2 clamp MCAv Finger blood pressure Thigh Cuffs (blood flow restriction) 3 min BFR Exercise (100 bpm) Rest Prodel et al. (2016) AJP – Heart Circ Physiol. 310(9):H1201-9.

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)

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

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