L5: Exercise, haemorrhage and hypoxia: the cardiovascular responses to specific stresses

The cardiovascular response to exercise: what happens and needs to be regulated

• Increased metabolic demand on muslces

• → requires incrased blood flow (functional hyperaemia)

→ primarily regulated by local mechanism

Changing blood flow in muscles

• blood flow can increase from resting levels

  • 2-3ml-1min-1100g-1→35 (x17 increase)

• → causes a 17 fold DECREASE in ABP

However, the problem is that skeletal muscles makes up 40% of body mass so… (TPR)

• synamic exercise involving multiple muslces would

• PROFOUNDLY influence TPR

What happens in INTENSE exercise

• TPR may drop to 20% of resting value

THEREFORE: why is it important to regulate

• catastropic drop in ABP to 20% of resting value!

THEREFORE: need cardiovascular homeostatic mechanisms

What type of mechanisms are responsible for maintaining ABP and cardiovascular homeostasis

• SYSTEMIC MECHANISMS

(despite this drop in TPR)

The systemic responses can result in…

1. 5 fold INCREASE in cardiac output

   • (3 fold increase in heart rate)

   • (50% increase in stroke volume)

2. May also partially oppose the locally-mediated vasodilatation in muscle

   • such that increase in blood flow through muscles exercised in isolation can exceed the flow through the same muscle during whole-body exercises

Cardiovascular response (LOCAL): Functional hyperaemia→ what is it

• Blood flow to active muscles incrases very rapidly

Functional hyperaemia: distinct phases

1. PHASE 1: blood flow increases very rapidly

   • 2 to 15-20s after initiation of contraction

2. PHASE II: from 20s after initiation of contraction

   • there is a sow increases in blood flow to sustained high levels

Functional hyperaemia: What causes this to happen

Activity in muscle→ wide range of local changes influecing arteriolar diameter:

1. reduced PO2

2. increased PCO2

3. decreased pH

4. increased extracellular K+

5. lactic acid production

6. increased extracellular ADP, AMP and Adenosine

Are some of these more important than others?

PHASE 1: important factors

easy to see which factors affect this coz, most of the rest are slow apart from:

1. K+ ions

• muscle action potential produce immediate and fast increases in extracellular [K+']

  • as much as 10mM

  • depending on activity levels

  • within 5-10s

2. Muscle pump

3. (in some animals but not humans) Neurogenic vasodilatiion

4. Adrenaline? (anticipatory)

PHASE 1: cause 1: effect of rise in intersitial [K+]

1. hyperpolarises arteriolar smooth muscle

2. this closes voltage-gated Ca2+ channels

3. relaxes the muscle

PHASE 1: why doesn’t the etracellular [K+] cause depolarisation?

Due to two effects of raised extracellular [K+] :

1. enchances Na+/K+-ATPase activity

2. enhances activation of inwardly-rectifying K+ channels (KIR) look at AP diagram  

THEREFORE: increased intracellular K+ and increased K+ permeabbiliy

→ hyperpolarisation

PHASE 1: pharmacologic bloackde of either of these routes for K+ entry…

e.g ouabain or barium:

• attenuates vasodilation by approx 50%

PHASE 1: cause 2→ muscle pump

1. muscle contraction accelerate venous return

2. enhances CO

but also

3. may reduce local venous pressures

→ enhancing the pressure gradient through muscle capillaries

PHASE 1: cause 3→ neurogeneic vasodilataion (not in humans)

sympathetic cholinergic nerves directly cause rapid incrase in blood flow to muscle at start of exercise

PHASE 1: cause 4→ Adrenaline

• also cause vasodilatation

but

• not fast enough to contribute to phase 1

but

• may be released as part of an anticitpatory response

PHASE II: why difficult to identify mechanisms

• multiple redundancies mean:

• when one substance is inhibited, the magnitude of hyperaemia can change little

• because other factors then make larger contribution

THEREFORE:

• chnages in some key concentration profoundly influence others

PHASE II: chnages in some key concentration profoundly influence others examples…

1. Reduced Po2 clearly alters skeletal muscle metabolsim

2. resultant metabolic products chaneg

3. therefore, difficult to separate direct responses to Po2 from responses to its downstream influences

PHASE II: some factors of the response have been identified:

1. Raised extracellular K+

2. Adrenaline

3. O2

4. Adenosine and decreased pH

PHASE II: raised extracellular K+

• Similar affect to in PHASE 1

PHASE II: adrenaline

1. actiavtes beta2 receptors

2. on vascular smooth muscle in skeletal muscles

3. by circulating adrenaline

→ VASODILATORY effect

PHASE II: O2→ direct effect of reduced Po2?

• unlikey that there is a direct effect of reduced pO2 on muscle arterioles

because…

• although pO2 falls in muscle capillaries in exercise

• it as not been shown to fall in the vicinity og arterioles

PHASE II: O2→ effect of increased offloading of O2 from haemoglobin

RESULT:

1. release of ATP and NO from RBCs

2. low O2 ALSO→ enhances activity of ectonucleotideases

   • → produce vasodilatory adenosine from ATP

i.e can get an idea as to how these factors are interconnected in phase 2

PHASE II: Adenosine and decreased pH

• Adenosine ALSO accumulates arounf active muscle fibres

  • source may be ATP released by active muscle

  • acted on by extracellular ectonucleotides

→ THIS RELEASE of ATP is at least partly via CFTR channels

• in response to reduced intracellular pH

• linking pH changes to vasodilatation

(reduced pH→ CFTR channel response→ ATP release→ acted on extraceullar ectonucleotideases→ adenosine accumulates→ vasodilatation)

PHASE II: how does adenosine work

Strong vasodilator

1. acting on A2A receptors

2. increase cAMP levels in smooth muscle

3. activates protein kinase A (PKA)

4. opens Katp channels

5. hyperpolarises cell (by same mechanism as K+ accumulation)

6. may therefore act synergistically with increased K+

PHASE II: lactic acid?

• not been shwon to have direct effect 

• that is distinct from its effect on pH

Summary of functional hyperaemia

• complex and not completely understood

CLEAR EFFECTS

1. exercising muscles receive a bloody supply closely matched to its metabolic demans

2. increase in blood flow results largely or wholly from local vasodilatory influences

BUT NOW, the systemic control procresses must prevent the resultatn reduction in TPR from having dire consequences

Systemic circulatory control in exercise: dealing with the consequences of functional hyperaemia: problem being face

• TPR drops

• as little as 20% of its resting value in intense exercise

→ this is mean the ABP will change (which we want to keep constant)

What needs to be done to solve this problem

• increase CO

• to maintain ABP

How is this acheived: (seen in L4 + one more)

1. sympathetic venoconstriction→ increase MSFP

2. recuced cardiac vagal stimulation→ increase HR

3. increase cardiac sympathetic stimulation→ increase HR and myocardial contracility

4. Muscle pump action of contracting muscles on nearby veins

   • pushes blood towards heart due to presence of venous valvves

4. Effect of ‘muscle pump’ action

1. blood pushed towrads heart

2. reduced resistance to venous return RVR

3. increasing VR at given MSFP

   • MSFP may increase 3-fold yet VR and CO may ncrease 6-fold

→ THEREFORE: muscle pump activity must be halving RvR

NET RESULT: causes mean ABP to rise slightly in exercise

What produces:

1. incrased sympathetic acticty

2. reduced cardiac vagal activity?

Cardiac centre in medulla→ from three inputs

How is cardiac centra in medulla well positioned to coordinate response to circulatory changes in exercise:

Receives input from

1. higher brain  centres involved in ‘decising’ to exercise

2. muscle and join sensors that respond to movements

3. arterial baro- and chemoreceptors

but which is most important?

How to figure out which factor is most important

1. separate cental command to exercise from actual occurrence of exercise

2. use curare to block neuromuscular junction

What does this demonstrate

• increase in heart rate during exercise can occur without any actual exercise occuring

• such centrally-mediated cardiovascular responses correlate with the perceived effor of exercise

Indeeed, it is possible to record increased heaert rate even before exercise begins

hen what is the role of barpreceptors in exercise?

• unknown centrally-commanded mechanism:

  • to reset

  • possibly in part due to joint and position sensors competing with baroreceptors inputs to the nucleus tractus solitarious

What is the effective result of this?

• baroreceptors then maintain the stability of blood pressure

• around a slightly raised set point

Limiting factors in exercise: The highest cardiac outputs are seen in exercise→ there for does cardiac output…

• limit maximum performance

or

• is maximum performance limited by some other factor?

What are the other factors that may limit maximum performance?

1. ability of muscles to perform work

2. rate of O2 uptake in the lungs

How do we know what actual factor is limiting?

• depends on a person’s level of fitness…

Fitness level: Normal lungs

• O2 uptake is not limiting

  • → shown by measuring perfoance at normal and raised levels of Po2:

    • raised inhaled Po2 does not significantly improve performance

Fitness level: reasonably fit

• ability of muscles to perform work is not limiting by comparing power output 

  • when pedalling an exercise bike with one vs two legs

• Power output with 2 legs is less than double power output with just one leg

What does this suggest

• during 2 legged cycling:

• muscles are not able to produce their maximum power output
  

Explanantion of what is happening here (From the lecture)

• with diagram

• I think it was saying

• each leg in the double cycling→ gets less blood→ has to work faster→ must have increased resistance→ vasoconstri ion to maintain ABP→

Fitness level: less fit people

• may not have sufficient muscle aerobic capacity to produce this effect

• may instead be limited by their unfit muscles

Together this suggests…

• circulation provides the ultimate limitation on whole-body power output during exercise

Note: this limitation exists despite…

• mean blood pressure being sustained even in mos intensive exercise

THEREFORE

• it is not possible to exerise so hard that ABP drops

This suggests that

• there is a central regulation of activity levels according to circulatory requirments

aka:

• one component of feeling of fatigue must relate 

  • althouhg ideirectly

• to circulatory capacity

Exercise in disease states:

• ability of relative circulatory inadequacy to regulate activity levels

and

• produce the feeling of fatigue has important consequences in disease 

  • sates involving reduced maximum cardiac output

This particulalrly includes:

• heartfailture for which fatigue may be a prominent feature

Heamorrhage: what happens

1. Blood loss

2. decrease MSFP

3. decrease VR and CO

4. decrease ABP

Heamorrhage: (rapid) response

1. Reduced blood volume (feedback)→ vasoconstrictory (among other things)

2. pain/emotional state (feed foward)

rapid response in seconds

main aim is to→ increase MSFP, HR and TPR

1. Feedback → Reduced blood volume baroreceptors

1. Arterial baroreceptors (carotid sinus and aortic arch) and low-pressure baroreceptors (terminal great veins and atris)→ detect changes

2. Medulla:

   • reduced cardioinhibitory

   • increase vasomotor

3. increases sympathetic

4. increases vagal tone

5. renal effects

6. increase MSFP, increase HR and increase TPR

   • helping direct blood to where you want it

1. Feedback→ reduced blood volume→ microvasculature changes

1. reverse stress relaxation→ smooth muscle contracts when stretch is reduced

2. decrease downstream capillary pressure

3. autotransfusion (fluid from tissue into cap) (0.5-1L)

   • mobilisation of tissue fluid 

   • due to reduced capillary pressures shift the balance of starling filtration-reabsorption forces

   • towards reabsorption of fluid

4. increase MSFP

1. Feedback→ hormonal effects

• catecholamines

• agiostensin II

• ADH

are released, effect:

VASOCONSTRICTORY effects especially in high concentrations

2. Feed forward→ pain response

1. higher brain centres (cortex and hypothalamus)

2. stimulates areas as a response to pain or fear

3. increases HR itself

Haemorrahage: less rapid response

1. 24-48 hours: plasma protesins replaced by synthesis in liver

2. 5-7 days: increasd RBC production→ restore those lost

Haemorrghage: less rapid response (stimulates by)

• release of erythropoietin from the kidneys

• in response to reduced oxygen delivery

Hypoxia: two reasons for this happening

1. Lack of O2 due to stop breaking→ (diving)

2. Lack of O2 due to reduced concnetraion in inhaled air

Hyposixa: two reasons have two different responses

note: chronic lung disease may combine aspects of both stresses

1. conservation of O2→ conserve for brain (if not getting anything else)

2. Increased blood flow to tissues→ still get some O2 so just incrase cardiac ouput to compensate (O2 delivery = flow x concentration) so need to increase flow

Hypoxia response: 1. why need a different mechanism for conservation of O2

1. direct effect of recuded Po2

2. produces metabolic vasodilation in tissues

HOWEVER: in diving this is not ideal→ it would allow other tissues other than the brain to use O2 faster→ want to conserve O2 for the brain!

Hypoxia response: 1. Reduced Po2 is detected by

• carotid and aortic bodies

  • and in central chemoreceptors and integrated in the medulla

Hypoxia response: 1. this causes a reflex response…

1. slowed heart rate→ mediated by cardiac vagal reflex

2. systemic vasoconstriction> mediated by sympathetic nervous system

This is called: diving reflex  or the primary chemoreceptor response

Hypoxia response: 1. what is the overall effect of this response

1. reduces cardiac work to a minimum

2. sympathetic drive overwhelms the metabolic vasodilatation

   • to divert the available blood to those tissues 

     • with little sympathetic vasoconstrictor innervation

     • → the brain and heart

Hypoxia response: 1. In diving animals (seals)

• response is very well developed

→ but also observed in humans especially in cold-water immersion

• Where the heart rate can drop to as low as 20-30 beats per minute

Hypoxia response 2: how can the body generate a different response at altitude from that during diving??

• reduced Po2 must surely activate the same pathways

• whether there is low oxygen concentration vs when there is reduction total oxygen amount

Answer: secondary chemoreceptor response

Hypoxia response: 2. Secondary chemoreceptor response

1. when reduced Po2 produces an increased rate and depth of breathing

   • → as it normally does if breathing is not restricted

2. pulmonary stretch receptors send afferent impulses via vagus nerve

3. to the medulla

4. stimulate vasomotor centre

5. → venoconstriction

6. increase MSFP

7. increase CO

8. inhibits cardio-inhibitory centre

9. increases HR

10. causes pattern of vasodilataion/constriction that favors vital tissues

NET RESULT: rise in cardiac output→ allow tissue oxygen needs to be met, despite reduced blood oxygen concentrations

Hypoxia: animal models have shown…

• animal models of obstructive sleep apnoae

• → suggest that chronic hypoxia may lead to chronic hypertension by this mechanism