D2. Cardiorespiratory exercise- detailed

Question 1

Headings pneumonic

Answer 1

FCRNPCBLC

Question 2

Headings (list)

Answer 2

Introduction

Feed-forward control - central command of respiration

Cardiovascular function

Redundancy in the response to central command

Neural circuitry in central command

Peripheral feedback in exercise

Chemoreceptors

Baroreflex

Local vascular changes

Cardiovascular responses to training

Question 3

Introduction subheadings (list)

Answer 3

Exercise

Arterial pressure

Central command

Question 4

(Intro) Exercise

Answer 4

● Skeletal muscle oxygen demand can increase 40-fold during exercise, from 75ml/min to 3000ml/min.

● Exercise is a form of physical activity that involves voluntary contraction of skeletal muscles, leading to an increased metabolic rate which needs to be supported by cardiorespiratory changes.

● Exercise in which skeletal muscle contraction causes principally a change in length with little change in tension is termed dynamic or isotonic, and that in which the contraction causes principally a change in tension with little change in length is termed static or isometric.

● In light static exercise the heart rate and blood pressure increase much more than during dynamic exercise at the same oxygen uptake level.

Question 5

(Intro) Arterial pressure

Answer 5

● Cardiac output increases during exercise, whereas total peripheral resistance decreases due to vasodilation in skeletal and coronary vascular beds.

● Therefore, there is only a mild increase in mean arterial pressure during exercise.

● The changes which occur in arterial pH, PO2 and PCO2 values during exercise are usually small.

● Arterial PO2 often rises slightly because of hyperventilation although it may eventually fall at high work rates.

Question 6

(Intro) Central command

Answer 6

● The central nervous system is important in increasing both CV and respiratory response both prior to, and at the very beginning of exercise.

● Once exercise has begun, there is peripheral feedback from chemoreceptors and the exercise pressor reflex, that maintains the equilibrium established during exercise.

● The relative importance of central command and exercise pressor reflex components in determining responses to exercise is dependent upon the type of exercise (static or dynamic), the intensity of exercise, the time after onset of exercise (immediate, steady state, exhaustion, etc.) and the effectiveness of blood flow in meeting the metabolic needs of the contracting muscles.

● Figure 1

Question 7

Feed-forward control- central command of respiration subheadings (list)

Answer 7

Krogh & Lindhart 1913

Central-command mechanism

Question 8

(Feed-forward) Krogh & Lindhart 1913

Answer 8

● Central command of cardiorespiratory homeostasis is largely responsible for the initial response to exercise.

● This can often occur prior to exercise due to anticipation, and is typically most prominent, before feedback mechanisms begin to function.

● Krogh & Lindhart in collaboration with Miss Florence Buchanan 1913 performed a seminal study defining the contribution of central command to the control of ventilation and cardiac output.

● The authors used six subjects, three of which were trained to sudden exertions. The authors observed immediate and rapid increases in ventilation and pulse rate on the start of bicycle ergometer exercise.

Question 9

(Feed-forward) Central-command mechanism

Answer 9

● Feed-forward control of the respiratory system can be initiated in the hypothalamic locomotor regions, which then feeds on to brainstem respiratory control neurons.

● The sympathetic nervous system, via circulating catecholamines from the adrenal medulla, which act on beta 2 adrenoreceptors, causing bronchodilation, leading to increased ventilation.

● Figure 2

Question 10

Cardiovascular function subheadings (list)

Answer 10

Sympathetic activation

Donald 1968

Vinogradova 2002

D’Souza 2014 and HCN

Question 11

(Cardiovascular) Sympathetic activation

Answer 11

● The cardiovascular (CV) changes during exercise are largely mediated by the autonomic nervous system.

● Specifically, sympathetic activation, as is seen in the diagram above, is responsible for the increase in cardiac output.

● Catecholamines act on beta 1 adrenergic receptors in the heart having positive chronotropic and inotropic effects, on the pacemaker cells in the sinoatrial node and ventricular myocytes respectively.

● This increase in cardiac contractility is augmented by the increased venous return in exercise, in line with the Starling effect, caused by peripheral muscular contraction, leading to further increases in cardiac output.

Question 12

(Cardiovascular) Donald 1968

Answer 12

● This was demonstrated by Donald et al. in 1968 who showed the importance of the sympathetic nervous system in initiating the cardiovascular system’s responses to exercise.

● Using 9 greyhounds, 6 with normal hearts, and 3 denervated hearts, the dogs ran around the race course with their heart rate being recorded.

● Those with denervated hearts had a slower onset and magnitude of heart rate increase.

● In order to determine that the sympathetic nervous system was mediating these effects, experimenters added propranolol, a non-specific beta blocker.

Question 13

(Cardiovascular) Vinogradova 2002

Answer 13

● Method; Used confocal imaging and fluo-3AM to measure CaT in isolated rabbit SANCs

● Results; Demonstrated that 0.1micromol/L isoproterenol induces 3-fold increase in no of Ca release events during diastolic depolarisation [CRDDs] per cycle, a shift to higher CRDD amplitudes and increase in spatial width

● This resulted in acceleration of diastolic depolarisation rate and increased SANC firing rate

● However, application of ryanodine = able to abolish effect of beta-AR stimulation

Question 14

(Cardiovascular) D’Souza 2014 and HCN

Answer 14

● Exercise dysregulates the coupled clock

● D’Souza et al in 2014 evaluated this possibility by first demonstrating that exercise in rats by training with uphill running was sufficient to generate bradycardia

● The authors concluded this was attributable to electrophysiological remodelling of SAN cells as the bradycardia persisted in the presence of autonomic nervous blockade with propranolol and atropine in vivo.

● The authors then patch-clamped isolated rat cells from trained and untrained animals in the whole cell configuration.

Question 15

Redundancy in the response to central command subheadings (list)

Answer 15

Denervated dogs can still exercise

Boulton 2016

Amman 2011 and peripheral feedback

Question 16

(Redundancy) Denervated dogs can still exercise

Answer 16

● However, denervated heart dogs were still able to exercise effectively. This is similar to cardiac transplant patients who are still able to exercise.

● However, the heart rate of these patients during exercise remains relatively constant, but the stroke volume increases.

● This suggests there may be some redundancy in the response to central command.

● There is debate as to whether peripheral feedback or central command is more important in cardiovascular control during exercise.

Question 17

(Redundancy) Boulton 2016

Answer 17

● Boulton et al in 2016 attempted to investigate this by measuring muscle sympathetic nerve activity with microneurography in the left peroneal nerve.

● The authors compared MSNA activity after electrically stimulated contractions or isometric dorsiflexion, using the presumption that electrically stimulated contractions would not activate central command.

● The authors thus showed that MSNA was significantly elevated with pre-contraction levels, whereas electrically-evoked contractions did not.

● The authors therefore concluded that central command was most important in MSNA activity which controls muscle perfusion.

Question 18

(Redundancy) Amman 2011 and peripheral feedback

Answer 18

● Central command is also subject to regulation from peripheral feedback.

● Therefore, the prolonged effects of the central command during exercise undergo some form of regulation.

● Amman et al in 2011 examined this modulatory affect by using intrathecal fentanyl to block Group III/IV afferent muscle fibres.

● The authors were able to estimate central motor drive using an electromyogram. The authors then observed that fentanyl increased central motor command, but depressed cardiovascular functioning as determined by arterial pressure and heartrate measurement.

Question 19

Neural circuitry in central command subheadings (list)

Answer 19

Thornton 2002

Eldridge 1981- deep brain structures

Koba 2022 and DBS

Periaqueductal grey

Question 20

(Neural) Thornton 2002

Answer 20

● Given the importance of central command in the cardiovascular and respiratory response to exercise there is an understandable interest in deciphering the brain regions involved.

● In an attempt to uncouple ‘central command’ from movement feedback, Thornton et al. in 2002 used hypnotic suggestion of exercise during concurrent positron emission tomography scanning.

● Three cognitive conditions were used, involving the imagination of: (i) free-wheeling downhill on a bicycle; (ii) cycling up a hill; and (iii) volitional hyperventilation with the CO2 clamped to match the breathing observed in (ii).
significant activation was seen in the supplementary motor area (SMA) and premotor area (PMA).

● In addition, the thalamus, bilateral cerebellum and right dorsal lateral prefrontal cortex (DLPFC Brodmann area 9) were also activated.

Question 21

(Neural) Eldridge 1981- deep brain structures

Answer 21

● There is also interest in the deep brain structures that mediate the cardiovascular responses to exercise.

● Eldridge et al. in 1981 advanced the findings from studies in humans, via experiments in cats.

● Preparations included anesthetized cats with intact brains, unanesthetized with decortication at the level of the hypothalamus, and unanesthetized with decerebration at level of the mesencephalon.

● Spontaneous actual locomotion and attempts to move (fictive locomotion; motor electrical activity in peripheral nerves after pharmacological-induced paralysis) occurred in all preparations, except the mesencephalic cats.

Question 22

(Neural) Koba 2022 and DBS

Answer 22

● Later work in Parkinsonian patients receiving Deep brain stimulation has shown that high frequency stimulation of the STN thus blocking inhibitory neurons increased heart rate and systolic blood pressure.

● Koba et al. (2022) used optogenetics in rats to study a monosynaptic pathway from the mesencephalic locomotor region (MLR) to the rostral ventrolateral medulla (RVLM).

● Voluntary running increased Fos expression in this circuit, indicating neural activation.

● Exciting the pathway optogenetically raised heart rate and blood pressure, mimicking exercise responses.

Question 23

(Neural) Periaqueductal grey

Answer 23

● The periaqueductal grey is a midbrain region that has a well-established role in the modulation of pain and sympathetic nervous system outflow.

● The neural architectural of the PAG is very heterogeneous where it is divided into four distinct longitudinal columns.

● The PAG, in particular the lPAG and aspects of the dlPAG, appears to be a key communicating circuit for ‘central command’.

● Moreover, the PAG also fulfils many requirements of a command centre.

Question 24

Peripheral feedback in exercise subheadings (list)

Answer 24

Alam & Smirk 1937

Exercise-pressor reflex

McCloskey & Mitchell 1983

Afferent signals and cardiovascular adjustment

Question 25

(Peripheral feedback) Alam & Smirk 1937

Answer 25

● Alam & Smirk in 1937 first provided evidence for a peripheral feedback system now termed the exercise pressor reflex. ● The authors measured blood pressure in the arm of subjects who had sphygmomanometer cuffs around their thighs to occlude blood flow. ● The authors then asked the subjects to exercise, observing an increase in both systolic and diastolic blood pressure. ● After exercise cessation the blood pressure increase was maintained until such time as the circulation was restored by deflation of the sphygmomanometer cuffs.

Question 26

(Peripheral feedback) Exercise-pressor reflex

Answer 26

● The EPR represents a negative feedback mechanism located in the skeletal muscle, which is sensitive to mechanical and metabolic stimuli during muscle work. ● Nerve fibers which are activated by metabolites accumulation (i.e., the “metaboreceptors”), they are thought to be sensitive to several substances such as lactic acid, potassium, bradykinin, arachidonic acid products, ATP, diprotonated phosphate, and adenosine.

Question 27

(Peripheral feedback) McCloskey & Mitchell 1983

Answer 27

● McCloskey & Mitchell in 1983 were able to advance our understanding of the reflex cardiovascular responses from muscle. ● The authors used anaesthetised and decerebrate cats, stimulating isometric exercise by electrical excitation of the ventral root nerve fibres. ● The authors performed similar occlusion experiments to Alam & Smirk, and showed this response was mimicked by injection of isotonic injection of KCl or dorsal root sectioning. ● To investigate the nerve fibres involved the authors used direct local anaesthetic block of the dorsal roots to determine the nerve fibres involved.

Question 28

(Peripheral feedback) Afferent signals and cardiovascular adjustment

Answer 28

● Afferent signals from group III/IV fibers are known to project to several brain stem nuclei including the NTS (thought to be the primary centre for EPR signal processing), which in turn promotes a reflex decrease in parasympathetic activity to the heart and an increase in sympathetic outflow to the heart and blood vessels. ● It is now also thought that the PAG may act as an important coordinator of muscle afferent impulses. ● The typical hemodynamic response to metaboreflex activation is an increase in arterial blood pressure. ● This cardiovascular adjustment is thought to be primarily achieved by increasing SVR because of peripheral sympathetic vasoconstriction.

Question 29

Chemoreceptors subheadings (list)

Answer 29

Central vs peripheral Wasserman 1975 PaCO2

Question 30

(Chemoreceptors) Central vs peripheral

Answer 30

● Both central and peripheral chemoreceptors are important in increasing the respiratory drive during exercise. ● These two chemoreceptors are traditionally thought to be sensitive, either directly or indirectly to plasma carbon dioxide content. ● Recent experimental approaches have changed the understating of the carotid chemoreflex contribution to the autonomic responses during exercise in normoxia and normocapnia. ● Recent data suggest that carotid chemoreceptors are sensitized during exercise and so mediate about one-third of the increase in sympathetic activity during exercise in healthy humans.

Question 31

(Chemoreceptors) Wasserman 1975

Answer 31

● The significance of the chemoreceptor response during exercise was highlighted by Wasserman et al in 1975. ● Subjects in this experiment had previously been treated for asthma using carotid body denervation thus eliminating part of the peripheral chemoreceptor response. ● The denervated patients had reduced hyperpnoea in exercise above the anaerobic threshold (where lactic acid in the blood begins to rise rapidly), indicating that the chemoreceptor reflex is key in increasing ventilation during intense exercise. ● However, the researchers used a control group of patients without underlying asthma, so it is difficult to interpret whether or not the changes in ventilation increase are due to the asthma or the absence of chemoreceptor functioning.

Question 32

(Chemoreceptors) PaCO2

Answer 32

● There has been some debate as to what is the trigger for the activation of chemoreceptors, given that the mean PaCO2 remains roughly constant. ● However, there has been suggestions that given PaCO2 fluctuates, this may activate the chemoreceptors. ● Alternatively, other soluble factors such as H+, K+ and lactic acid have been proposed.

Question 33

Baroreflex subheadings (list)

Answer 33

Resetting through muscle afferents or central command Potts 2003 Controlling muscle vasodilation and cardiac chronotropism

Question 34

(Baroreflex) Resetting through muscle afferents or central command

Answer 34

● As mean and pulsatile pressure increase, baroreceptors should respond to increase parasympathetic and decrease sympathetic outflows, a pattern designed to counter the rise in arterial pressure. ● However, during exercise the baroceptor needs to be reset to permit rises in arterial pressure. ● This baroreflex resetting is thought to occur through either muscle afferents or central command.

Question 35

(Baroreflex) Potts 2003

Answer 35

● Potts et al in 2003 proposed one mechanism of this arterial baroreceptor resetting by using an arterially perfused decerebrate rat. ● The authors used electrically evoked forelimb contraction and measured the baroreceptor responsiveness. ● The authors measured this responsiveness by assessing the heart rate changes to transient increases in arterial perfusion pressure and rate. ● The authors were thus able to show that evoking forelimb contraction activated forelimb skeletal afferent muscle fibres, which in turn significantly reduced baroreflex responsiveness.

Question 36

(Baroreflex) Controlling muscle vasodilation and cardiac chronotropism

Answer 36

● Resetting of the arterial baroreflex may occur from stimulation of skeletal muscle afferents and/or activation of central command. ● The baroreflexes during exercise therefore oppose any mismatch between vascular resistance and CO by controlling muscle vasodilatation and cardiac chronotropism in order to avoid any excessive variation in blood pressure.

Question 37

Local vascular changes subheadings (list)

Answer 37

Metabolic substances Groucher 1990 Zhao 2020

Question 38

(Local) Metabolic substances

Answer 38

● The metabolic control of skeletal muscle arterioles is important to match perfusion to skeletal muscle metabolism. ● During enhanced metabolic demand, and depending on the actual conditions, tissue cells release several substances that apparently act as vasodilatory mediators, including increased pCO2, lactate, K+, adenosine, H+, inorganic phosphate and reactive oxygen species. ● Adenosine is mainly generated from AMP that is released from the skeletal muscle fibres and dephosphorylated by ecto 5′nucleotidase bound to the sarcolemma. ● This adenosine is a potent vasodilator in both the coronary and skeletal muscle vasculature by acting on extraluminal A2A receptors on the vascular smooth muscle.

Question 39

(Local) Groucher 1990

Answer 39

● In a seminal study in 1990, Groucher et al used the adenosine receptor antagonist, 8-phenyltheophylline, which had lower phosphodiesterase interactions than its predecessors. ● The authors exposed the right gracilis muscle in anaesthetised cats and stimulated contraction with electrical impulses to the obturator nerve. ● The authors measured blood flow with an electromagnetic flow probe and measured the blood flow for 30 minutes following exercise. ● It was shown that gracilis muscle blood flow increased during exercise. However, this increase in blood flow was decreased over 40%, suggesting adenosine is a significant in metabolic regulation of vascular tone.

Question 40

(Local) Zhao 2020

Answer 40

● Another adenosine-based molecule, ATP, is also important in metabolic regulation of vascular tone. ● Zhao et al in 2020 showed the importance of ATP-sensitive potassium channels in cardiac myocytes. ● The authors used a mouse papillary muscle preparation where the small septal artery was cannulated and pressurised. ● The authors showed that pinacidil application to this preparation induced vasodilation in the artery through opening of KATP channels.

Question 41

(Local) Catecholamines

Answer 41

● Furthermore, the sympathetic nervous system helps to redistribute blood flow during exercise. ● Circulating catecholamines promote vasoconstriction in mesenteric and gastric resistance arteries. ● However, adrenaline is capable of dilating coronary blood flow to promote blood flow. Metabo-regulation of skeletal blood vessels is particularly important as well.

Question 42

Cardiovascular responses to training subheadings (list)

Answer 42

White 1998 and vascularisation of cardiac muscle Diameter of resistance vessels Serneri 2001 and hypertrophy

Question 43

(CVS responses to training) White 1998 and vascularisation of cardiac muscle

Answer 43

● There have been many studies showing there is angiogenesis in skeletal muscle cells, increasing delivery of oxygen to these tissues, although there have been studies, notably by White et al in 1998. ● Researchers trained minipigs for 1, 3, 8 and 16 weeks, compared them with controls, and observed the capillary and arteriolar densities and diameters. ● Capillaries had increased in density at the end of week 3 in the coronary vasculature, and from then there was increased arteriolar formation by week 16. ● Increased blood flow to the cardiac muscle allows more efficient pumping of the heart, leading to greater cardiac output and further muscular contraction.

Question 44

(CVS responses to training) Diameter of resistance vessels

Answer 44

● Training can lead to long-term adaptations that facilitate increased exercise intensity. ● One such change is the increased diameter of resistance vessels within tissues that require oxygen during exercise. ● There may also be an increase in vasodilation potential during exercise in response to continued training in some individuals.

Question 45

(CVS responses to training) Serneri 2001 and hypertrophy

Answer 45

● Power and strength training, such as power lifting, results in pressure overload and concentric physiological hypertrophy endurance training, such as swimming or running, results in volume overload and eccentric physiological hypertrophy. ● Work by Serneri et al in 2001 led to the hypothesis that insulin-like growth factor 1 (IGF1) signalling was involved in physiological hypertrophy. ● Researchers compared the aortic-coronary sinus gradient for IGF-1 in soccer players and sedentary controls, using radioimmunoassay for IGF-1. ● There was no gradient observed in sedentary controls, but in trained athletes, there was a positive IGF-1 gradient, with more growth factor present in the coronary sinus.

Question 46

Conclusion

Answer 46

● Exercise necessitates cardiovascular and ventilatory adaptations to facilitate increased blood flow and supply sufficient oxygen to skeletal muscles. ● These changes are either mediated by feedforward central command which promotes sympathetic outflow, increasing heart rate and stroke volume. ● Furthermore, there is activation of the motor outflow to respiratory muscles. ● Alternatively, feedback control from the muscle pressor reflex or chemoreceptors which feedback to midbrain regions and also increase sympathetic outflow.