Outline the regulation of blood pressure.
- Pressure = flow x resistance
I. Mean arterial BP = CO x TPR
II. CO = SV x HR - Both short and long term regulation
- Short term regulation – baroreceptor reflex
I. Adjust sympathetic and parasympathetic inputs to the heart to alter cardiac output.
II. Adjust sympathetic input to peripheral resistance vessels to alter TPR
Explain the baroreceptor reflex.
- The baroreceptor reflex works well to control acute changes in BP
- Produces rapid response to changes in BP
- Does not control sustained increases because the threshold for baroreceptor firing resets
Explain the medium and longer term control of blood pressure.
- Complex interaction of neurohumoral responses
- Directed at controlling sodium balance and thus extracellular fluid volume
- Plasma is part of the extracellular fluid compartment
I. Control of extracellular fluid volume controls plasma volume
II. Water follows Na+ therefore controlling total body Na+ levels controls plasma volume
Identify the four parallel neurohumoral pathways control circulating volume and hence BP.
- Renin-angiotensin-aldosterone system
- Sympathetic nervous system
- Antidiuretic hormone (ADH)
- Atrial natriuretic peptide (ANP)
- Renin is released from granular cells of juxtaglomerular apparatus (JGA)
- Decreased circulating volume stimulates renin release:
I. Reduced NaCl delivery to distal tubule
II. Reduced perfusion pressure in the kidney causes the release of renin detected by baroreceptors in afferent arteriole
III. Sympathetic stimulation to JGA increases release of renin
Briefly outline Angiotensen II Receptors.
- Two types of Ang II receptors identified – AT1 and AT2
- Main actions via AT1 receptor
- G-protein coupled receptor
Explain the action of aldosterone on the kidney.
AngII stimulates aldosterone release from the adrenal cortex
Actions of aldosterone:
- Acts on principal cells of collecting ducts
- Stimulates Na+ and therefore water reabsorption
- Activates apical Na+ channel (ENaC, Epithelial Na Channel) and apical K+ channel
- Also, increases basolateral Na+ extrusion via Na/K/ATPase
Outline the actions of ACE and bradykinin
- Angiotensin converting enzyme and bradykinin
- The vasoconstriction effects of AngII are further augmented because ACE is also one of the kininase enzymes which breaks down the vasodilator bradykinin.
Explain the action of inhibitors on ACE
Explain how the sympathetic nervous system control circulating blood volume and hence BP.
- High levels of sympathetic stimulation reduce renal blood flow
I.Vasoconstriction of arterioles
II. Decrease GFR – decrease Na+ excretion
- Activates apical Na/H-exchanger and basolateral Na/K ATPase in PCT
- Stimulates renin release from JGA
I. Leading to increased Ang II levels
II. Leading to increased aldosterone levels – increased Na+ reabsorption
Explain how ADH controls BP.
- Main role is formation of concentrated urine by retaining water to control plasma osmolarity – increases water reabsorption in distal nephron (AQP2)
- ADH release is stimulated by increases in
I. Plasma osmolarity
II. Or severe hypovolaemia
- Also, stimulates Na+ reabsorption
I. Acts on thick ascending limb
II. Stimulates apical Na/K/Cl co-transporter
- Also, called arginine vasopressin - causes vasoconstriction
Outline how natriuretic peptides control BP
- Atrial natriuretic peptide (ANP) promotes Na+ excretion
- Synthesised and stored in atrial myocytes
- Released from atrial cells in response to stretch
- Low pressure volume sensors in the atria
- Reduced effective circulating volume inhibits the release of ANP to support BP
I. Reduced filling of the heart
II. Less stretch
III. Less ANP released
Outline the actions of ANP.
- Causes vasodilation of the afferent arteriole
- Increased blood flow increases GFR
- Also, inhibits Na+ reabsorption along the nephron
- Acts in opposite direction to the other neurohumoral regulators – causes natriuresis (loss of sodium into urine)
- If circulating volume is low ANP release is inhibited – this supports BP
What are prostaglandins?
- Act as vasodilators
- More important clinically than physiologically
- Locally acting prostaglandins (mainly PGE2) enhance glomerular filtration and reduce Na+ reabsorption
- May have important protective function
- Act as a buffer to excessive vasoconstriction produced by SNS and RAAS
- Important when levels of Ang II are high
What are the roles of Dopamine?
- Dopamine is formed locally in the kidney from circulating L-DOPA
- Dopamine receptors are present on renal blood vessels and cells of PCT & TAL
- DA causes vasodilation and increases renal blood flow
- DA reduces reabsorption of NaCl – Inhibits NH exchanger and Na/K ATPase in principal cells of PCT and TAL
What is hypertension and what causes it?
- Hypertension: the sustained increase in blood pressure.
- In around 95% of cases the cause is unknown – ‘essential’ or primary hypertension
- Where the cause can be defined it is referred to as secondary hypertension. Examples
I. Renovascular disease
II. Chronic renal disease
IV. Cushing’s syndrome
- With secondary hypertension – important to treat the primary cause
What are the stages of hypertension?
Outline Primary hypertension.
- Aka Essential hypertension
- No definable cause
I. Genetic factors – high BP tends to run in families
II. Environmental factors
III. Pathogenesis unclear
IV. Recent research suggests dysfunction of DA receptors
- Sustained elevation of BP
I. Diastolic pressure > 90mmHg
II. or Systolic pressure > 140mmHg
Outline the causes of Secondary Hypertension.
- Only accounts for a small percentage of cases
- Identifiable pathological cause
- Can treat the primary cause
Explain Secondary hypertension: Renovascular disease.
- Occlusion of the renal artery (renal artery stenosis) causes a fall in perfusion pressure in that kidney
- Decreased perfusion pressure leads to increased renin production
- Activation of the renin-angiotensin-aldosterone system
- Vasoconstriction and Na+ retention at other kidney
Explain Secondary hypertension: Renal parenchyma disease
- Earlier stage may be a loss of vasodilator substances
- In later stage Na+ and water retention due to inadequate glomerular filtration – volume-dependent hypertension
Explain Secondary Hypertension: adrenal causes
- Conn's syndrome
I. Aldosterone secreting adenoma
II. Hypertension and hypokalaemia
- Cushing's syndrome
I. Excess secretion of glucocorticoid cortisol
II. At high concentration acts on aldosterone receptors - Na+ and water retention
- Tumour of the adrenal medulla
II. Secretes catacholamines (noradrenaline and adrenaline)
Explain the complications of hypertension.
- Hypertension – the silent killer
- Although hypertension may be asymptomatic, it can have unseen damaging effects on – heart and vasculature – potentially leading to heart failure, MI, stroke, renal failure and retinopathy
Outline the general treatment of hypertension.
- For secondary hypertension – treat primary cause
- Most cases no identifiable primary cause
- You can work out possible targets for treating hypertension from the following equations
I. BP = CO x TPR
II. BP = SV x HR x TPR
Outline the treatment of hypertension: non-pharmalogical approaches.
- Reduced Na+ intake
- Reduced alcohol intake
- Lifestyle changes above can have limited effect
- Failure to implement lifestyle changes could limit the effectiveness of antihypertensive therapy
Outline the treatment of hypertension: targeting RAAS
- ACE inhibitors – prevent production of Ang II from Ang I
- Ang II receptor antagonists (AII antagonists)
- Ang II is a powerful vasoconstrictor, has direct actions on the kidney and promotes the release of aldosterone, thus leading to NaCl and H2O retention.
- Blocking production or action of Ang II has diuretic and vasodilator effects
Explain the treatment of hypertension with vasodilators.
- L-type Ca channel blockers
I. Reduce Ca2+ entry to vascular smooth muscle cells
II. Relaxation of vascular smooth muscle
- In principle, could also use α1 receptor blockers
I. Reduce sympathetic tone (relaxation of vascular smooth muscle)
II. Can cause postural hypotension
Explain the treatment of hypertension with diuretics.
- Thiazide diuretics – reduce circulating volume
- Inhibit Na/Cl co-transporter on apical membrane of cells in distal tubule
- Other diuretics e.g. aldosterone antagonists (spironolactone) will also lower BP – not first line choice
Explain the treatment of hypertension using beta blockers.
- Less commonly used to treat hypertension
- Blocking β1 receptors in the heart will reduce effects of sympathetic output – reduce heart rate and contractility
- Not used in hypertension alone
- Would only be used if there are other indications such as previous MI
Identify some diseases attributable to hypertension (clue: all vascular).
- Heart failure
- Cerebral haemorrhage
- Chronic kidney failure
- Hypertensive encephalopathy
- Peripheral vascular disease
- Aortic aneurysm
- Myocardial infarction
- Coronary heart disease
Explain the effects of hypertension.
- Increased afterload leads to:
i. LVF - heart failure
II. Increased myocardial oxygen demand - Myocardial ischaemia & Myocardial infarction
- Arterial damage leads to:
I. Artherosclerosis - Myocardial ischaemia & MI, cerebrovascular disease (stroke), aneurysm, nephrosclerosis & renal failure, retinopathy
II. Weakened vessels - cerebrovascular disease (stroke), aneurysm, nephrosclerosis & renal failure, retinopathy
What are the target organs of clinical cardiovascular disease?
Should be assessed by clinical history and physical examination:
Outline Haemodynamic shock.
- Acute condition of inadequate blood flow throughout the body
- A catastrophic fall in arterial blood pressure leads to circulatory shock
Mean arterial BP = CO x TPR
- Shock can be due to fall in CO
- Or fall in TPR beyond capacity of the heart to cope
Identify and define three different types of shock.
- Cardiogenic shock (pump failure) – ventricle cannot empty properly
- Mechanical shock (obstructive) – ventricle cannot fill properly
- Hypovolaemic shock – reduced blood volume leads to poor venous return
NB. Hypovolaemic shock can also result from severe burns and severe diarrhoea/vomiting and loss of Na+
Describe the characteristics of hypovolaemic shock
- Reduced blood volume
- Most commonly due to haemorrhage
- < 20% blood loss unlikely to cause shock
- 20-30% some signs of shock response
- 30-40% substantial decrease in mean aBP and serious shock response
- Severity of shock is related to amount and speed of blood loss
Explain what happens during a haemorrhage.
- Venous pressure falls
- Cardiac output falls (Starling’s Law)
- Arterial pressure falls
- Detected by baroreceptors
Explain what happens during the compensatory response.
- Increased sympathetic stimulation
- Increased force of contraction
- Peripheral vasoconstriction
- Also, get some ‘internal transfusion’
- Increased peripheral resistance reduces the capillary hydrostatic pressure
- Net movement of fluid into capillaries
Explain how peripheral vasoconstriction (shutdown) impairs tissue perfusion.
- Tissue damage due to hypoxia
- Release of chemical mediators – vasodilators
- TPR falls
- Blood pressure falls dramatically
- Vital organs can no longer be perfused
- Multi system failure
- Longer term responses to restore blood volume
- Renin-angiotensin-aldosterone system
- Anti-diuretic hormone
- 20% blood volume loss – Restoration of body fluid volumes in about 3 days, if salt and water intake are adequate
- Patient has tachycardia, weak pulse, pale skin, cold, clammy extremities
What is pump failure and what are its potential causes?
- Acute failure of the heart to maintain cardiac output – pump failure
- Potential causes:
I. Following myocardial infarction – damage to left ventricle
II. Due to serious arrhythmias
III. Acute worsening of heart failure
Describe the characteristics of cardiogenic shock.
- Heart fills, but fails to pump effectively
- Central venous pressure (CVP) may be normal or raised
- Dramatic drop in arterial BP
- Tissues poorly perfused
I. Coronary arteries may be poorly perfused – exacerbates problem
II. Kidneys may be poorly perfused – reduced urine production (oliguria)
When would one start to consider cardiac arrest?
- Unresponsiveness associated with lack of pulse
- Heart has stopped or has ceased to pump effectively
- Asystole (loss of electrical and mechanical activity)
- Pulseless Electrical Activity (PEA)
- Ventricular fibrillation (uncoordinated electrical activity)
I. Most common form of cardiac arrest
II. Often following MI / electrolyte imbalance
III. Or some arrhythmias (eg long QT and Torsades de Pointes)
How does one manage cardiac arrest?
- Basic life support – chest compression and external ventilation
- Advanced life support
II. Electric current delivered to the heart
III. Depolarises all the cells – puts them into refractory period
IV. Allows coordinated electrical activity to restart
I. Enhances myocardial function
II. Increases peripheral resistance
Describe the characteristics of mechanical shock in terms of cardiac tamponade.
- Cardiac tamponade
I. Blood or fluid build-up in pericardial space
II. Restricts filling of the heart
III. Limits end diastolic volume
IV. Affects left and right sides of heart
- High central venous pressure
- Low arterial blood pressure
- Heart attempts to beat – continued electrical activity
Describe the characteristics of mechanical shock in terms of pulmonary embolism.
- Massive pulmonary embolism (PE)
- Embolus occludes a large pulmonary artery
I. Pulmonary artery pressure is high
II. Right ventricle cannot empty
III. Central venous pressure high
IV. Reduced return of blood to left heart
V. Limits filling of left heart
VI. Left atrial pressure is low
VII. Arterial blood pressure low
IX. Also: chest pain, dyspnoea
How might an embolus reach the lungs?
- Typically, due to deep vein thrombosis
- Portion of thrombus breaks off
- Travels in venous system to right side of the heart
- Pumped out via pulmonary artery to lungs
- The effect of this will depend on the size of the embolus
Describe the characteristics of distributive shock.
- Low resistance shock (normovolaemic)
- Profound peripheral vasodilation -
I. Decrease in TPR
II. Blood volume constant, but volume of the circulation has increased
Describe the characteristics of anaphylactic shock.
- Severe allergic reaction (anaphylaxis)
I. Release of histamine from mast cells – other mediators
II. Powerful vasodilator effect – fall in TPR
III. Dramatic drop in arterial pressure - Increased sympathetic response - CO increased but can’t overcome vasodilation
IV. Impaired perfusion of vital organs
V. Mediators also cause bronchoconstriction and laryngeal oedema – difficulty breathing
- Patient will have
I. Difficulty breathing
III. Rapid heart rate
IV. Red, warm extremities
- Acutely life threatening
- Adrenaline – Vasoconstriction via action at α1 adrenoceptors
Describe the characteristics of septic (toxic) shock.
- Sepsis – serious life-threatening response to infection, can lead to septic shock
- Endotoxins released by circulating bacteria
I. Profound inflammatory response (excessive)
II. Causes profound vasodilation
III. Dramatic fall in TPR
IV. Fall in arterial pressure
V. Impaired perfusion of vital organs
VI. Also - capillaries become leaky (reduced blood volume)
VII. Increased coagulation and localised hypo-prefusion
- Persisting hypotension requiring treatment to maintain blood pressure despite fluid resuscitation.
- Decreased arterial pressure
I. Detected by baroreceptors
II. Increased sympathetic output
III. Vasoconstrictor effect overridden by mediators of vasodilation
IV. Heart rate and stroke volume increased
- Patient has
II. Warm, red extremities initially BUT later stages of sepsis – vasoconstriction – localised hypo-perfusion
Describe the general feature of management of the various types of shock.