Viva F5(ii)

What are the main physiological factors that affect pulmonary vascular resistance?
  • These are:
    • Pulmonary blood flow
    • Lung volume
    • Oxygenation (i.e. hypoxic pulmonary vasoconstriction)
    • Metabolic and endocrine factors eg catecholamines, hypercapnia, acidaemia
    • Autonomic nervous system tone
    • Blood viscosity
How does pulmonary blood flow affect pulmonary vascular resistance?
  • Increased blood flow results in decreases pulmonary vascular resistance in order for pulmonary arterial pressure to remain stable.
  • This is due to: 
    • Distension of pulmonary capillaries (mainly), and
    • Recruitment of previously collapsed or narrowed capillaries

relationship of pulmonary vascular resistance and pulmonary blood flow 2.0

  • Capillaries with a small diameter due to low pressure would also have a higher resistance to flow

  • As blood flow and pressure increase, these previously narrowed vessels increase in diameter and start to participate again in the pulmonary circulation, i.e. they are recruited.

How does lung volume affect pulmonary vascular resistance?
  • Pulmonary vascular resistance is lowest at FRC
  • At low lung volumes, it increases due to the compression of larger vessels
  • At high lung volumes, it increases due to the compression of small vessels

relationship of lung volume and pulmonary vascular resistance

  • Large vessels collapse at smaller volumes and small vessels collapse at large volumes 
  • At RV, large vessels have higher resistance because:
    • They are usually held open by the effects of alveolar septal stretch and parenchymal traction
    • The weight of the lung also presses on them
    • Their cross section is formed by this
    • Also there is hypoxic pulmonary vasoconstriction due to loss of lung volume
    • The increase the pulmonary vascular resistance is not large: the large vessels do not contribute very much to the total pulmonary vascular resistance (40% of the resistance happens at the level of the capillaries).
  • At TLC, small vessels have higher resistance:
    • The capillaries within alveolar septa are squished between hyperexpanded alveoli.
    • The elastic bands of connective tissue which make up the structural scaffold of the alveolar walls are stretched tight, constraining these capillaries and forcing them into a certain shape.
  • At FRC, the pulmonary vascular resistance is at its minimum. 
    • The forces which compress the little alveolar wall capillaries and the forces which collapse the larger vessels exert the least influence at this lung volume. 
How does atelectasis affect pulmonary vascular resistance?
What is hypoxic pulmonary vasoconstriction?
  • Oxygen sensing by some mechanism, nobody is completely sure what:
    • Direct effect on potassium channels, or maybe
    • Mitochondrial reactive oxygen species production, or perhaps
    • Changes in cellular energy state, or maybe
    • activation of a hitherto undiscovered hypoxia-induceable factor
  • Regulation of the response by pulmonary endothelial cells, by means of several intermediate modulators:
    • Nitric oxide, which is counter-regulatory (i.e. it promotes vasodilation)
    • Prostacycline, which also promotes vasodilation
    • Endothelin-1, which is a vasoconstrictor acting via G-protein coupled receptors on vascular smooth muscle
  • Effector (vasoconstrictor) response by membrane depolarization after sodium ion influx, leading to an increase in calcium concentration and therefore smooth muscle contraction. 
  • Determined by the total regional oxygenation.  Not only alveolar but also mixed pulmonary arterial oxygen content matters
  • The specific thing which controls HPV is (probably) oxygen tension, not content
  • HPV is produced by an increase in the resistance of small distal pulmonary arteries, vessels approximately 100 μm in diameter.
  • Hypoxic pulmonary vasoconstriction is a biphasic process. There is an initial rapid vasoconstriction, and a chronic slower vasoconstriction
For extra nerd credit, what factors affect hypoxic pulmonary vasoconstriction?
  • It is more vigorous in neonatal/foetal life, and it may be dampened by ageing
  • It appears to be attenuated by hypothermia
  • It is decreased by iron, and iron infusions can decrease the pulmonary response to hypoxia; in return, desferrioxamine can increase pulmonary hypoxic vasoconstriction.
  • It is reduced in the presence of infection, be it systemic sepsis or localised lobar pneumonia
What endogenous metabolic and endocrine factors affect pulmonary vascular resistance?
  • Vasoactive mediators:
    • Catecholamines increase PVR
    • Arachidonic acid metabolites (eg. thromboxane A2) increase PVR
    • Histamine (acting on H1 receptors) usually increases PVR
    • Substance P
    • Neurokinin A
    • Adenosine usually decreases  PVR
  • Metabolic factors:
    • Hypercapnia 
      • but only slightly: with a relatively high inspired fraction of CO2 (12-15%, or about 115 mmHg) there was only a modest increase in pulmonary pressure, from 15 mmHg to about 22.5 mmHg
    • Acidaemia: 
      • a lower pH has the effect of sensitising pulmonary arteries, making them more reactive to hypoxia.
      • PVR essentially doubles when comparing hypoxia (FiO2 of 10%) at a pH of 7.42 vs. hypoxia at a pH of 7.19. 
      • Alkalaemia, in turn, has the opposite effect; hypoxic pulmonary vasoconstriction tends to be suppressed
    • Hypothermia 
      • seems to increase pulmonary pressures
How does the autonomic nervous system affect pulmonary vascular resistance?
  • Pulmonary arteries have both α1 and β2 receptors.
  • They are innervated by both the sympathetic nerve fibres arising from the thoracic spine and by the vagus nerve (M3 receptors)
  • The density of these receptors favours α1 neurotransmission, and they seem to be distributed mainly around the larger pulmonary arteries.
  • Activation of these receptors has its greatest significance as a trophic stimulus, promoting the hypertrophy of pulmonary vascular smooth muscle and thereby contributing to pulmonary hypertension
What drugs are you aware of that might affect pulmonary vascular resistance?

Pulmonary vasodilators and vasoconstrictors
Vasodilators Vasoconstrictors
  • Nitric oxide
  • Milrinone
  • Levosimendan
  • Sildenafil
  • Vasopressin
  • Bosantan / ambrisantan
  • Prostacycline and its analogs
  • Calcium channel blockers
  • ACE-inhibitors
  • Adenosine
  • Adrenaline
  • Noradrenaline
  • Methylene blue
Outline the pharmacology of inhaled nitric oxide
Name Nitric oxide
Class Inhaled pulmonary vasodilator
Chemistry A free radical with the formula NO
Routes of administration Administered as part of inspired gas mixture, usually as an admixture fraction measured in tens of ppm, via a proprietary system (INOMax)
Absorption Absorbs rapidly into the pulmonary circulation via the lungs
Solubility As it dissociates in water, nitric oxide produces nitric acid (HNO3) which has a pKa of -1.3
Distribution VOD is impossible to measure, but is potentially very large. NO reacts with oxygen and water to produce nitrogen dioxide and nitrites, which then bind to haemoglobin and produce either nitrosylhaemoglobin or methaemoglobin, i.e. it can be described as "highly protein bound".
Target receptor Soluble guanylyl cyclase (which is induced by NO)
Mechanism of action Inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain smooth muscle contraction
Metabolism One way or another, nitric oxide ends up as methaemoglobin and nitrate. Either it reacts with lung water, becoming nitrite (which reacts with oxyhemoglobin and generates methaemoglobin and nitrate) or it combines directly with oxyhaemoglobin, with the same results. If it encounters hypoxic blood, it can combine with deoxyhaemoglobin to create nitrosyl-haemoglobin, which then rapidly becomes methaemoglobin when it contacts oxygen.
Elimination Nitrates are eliminated mainly in urine whereas methaemoglobin is metabolised in several hours into
haemoglobin by endogenic reductases. The nitrates excreted in urine represent over 70% of the inhaled NO
dose.
Time course of action Onset of effect is seen within seconds
Clinical effects Apart from pulmonary vasodilation, there is methemoglobinaemia, hypotension (maybe some of it does leak into the systemic circulation, or maybe this the effect of depressed LV function, rebound hypoxia after abrupt withdrawal, thrombocytopenia (in as many as 10% of patients) and increased susceptibility to pulmonary infections probably due to NO2 formation and associated lung injury.
Single best reference for further information TGA (AusPAR) product information
Outline the pharmacology of inhaled prostacycline
Name Epoprostenol
Class Inhaled pulmonary vasodilator
Chemistry Synthetic analogue of the naturally occurring eicosanoid prostacyclin (prostaglandin I2 or PGI2)
Routes of administration Can be intravenous, but usually nebulised as a part of a solution with a glycine buffer, using a continuous ultrasonic nebuliser
Absorption Absorbs rapidly into the pulmonary circulation via the lungs
Solubility Natural pKa is 4.4; requires a diluent which contains glycine and sodium hydroxide. The pH of the reconstituted drug mixture has a pH of around 12, because the drug tends to spontaneously hydrolyse in aqueous solution at a normal pH
Distribution 0.357L/kg
Target receptor Activates G protein-coupled PGE receptors on platelets and endothelial cells, which activates adenlyl cyclase and increases cAMP
Mechanism of action Increased cyclic AMP leads to decreased platelet activation and activates PKA, which phosphorylates and inhibits myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation
Metabolism Degrades spontaneously as well as enzymatically into about sixteen major and minor metabolites
Elimination Half-life is about six minutes
Time course of action Platelet inhibition effects last up to 2 hrs; smooth muscle vasodilation is very shortlived (comparable with half-life)
Clinical effects Vasodilation (pulmonary as well as systemic); inhibition of platelet aggregation; facial flushing, tachycardia, bronchodilation, inhibition of gastric acid secretion, and decreased gastric
emptying
Single best reference for further information Flolan PI by GlaxoSmithCline

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