Describe the physiological factors that affect pulmonary arterial pressure (65% of marks). Write short notes on the use of inhaled nitric oxide as a pulmonary vasodilator (35% of marks).

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College Answer

Pressure in a system is generated by the interaction between flow and resistance. A structured 
approach to defining and describing the many factors that influence fluid flow and resistance 
was required to score well. Poiseuille’s law describes the determinants of resistance to laminar 
fluid flow and provides a useful answer structure. It is also necessary to describe factors that 
determine flow. This includes factors that determine venous return, as well right and left heart 
output. 
A standard structured answer to the pharmacology of nitric oxide enabled concise and high 
scoring answering of this question.

Discussion

Though this question appears to have asked for factors which influence pulmonary arterial pressure, judging by the college answer what they really wanted was a discussion of pressure in general hydrodynamic terms. "A structured approach to defining and describing the many factors that influence fluid flow and resistance was required to score well", the examiners said. Poiseuille’s law was brought up. It is therefore somewhat weird that specifically pulmonary pressure was asked about in the question, as this might have misled the trainees and sent them into a pointless discussion of hypoxic pulmonary vasoconstriction and suchlike. What follows, therefore, is an effort to explore the factors which affect the pressure of any fluid travelling any vessel, but with an attempt to flavour the discussion with factors which are uniquely pulmonary.

Thus:

  • Pressure is the product of flow and resistance.
  • Flow in the pulmonary circulation is equal to flow in the systemic circulation, i.e. it is the cardiac output, and is therefore determined by:
    • Heart rate
    • Afterload (specifically RV afterload)
    • Ventricular stroke volume, which is in turn determined by
      • Preload
      • Cardiac contractility
      • Ventricular compliance
  • Resistance in the pulmonary circulation is determined by:
    • Proportions of laminar and turbulent flow
    • For turbulent flow, resistance cannot be determined by standard equations, only to say that it increases non-linearly as flow increases
    • Most flow in healthy pulmonary arteries is laminar
    • For laminar flow, resistance is described by the Hagen-Poiseuille equation:
      Poiseuille equation
      where:
      • Δp is the pressure difference between the arterial and venous circulation;
      • L is the length of the vessel,
      • μ is the dynamic viscosity of the blood,
      • Q is the volumetric flow rate (cardiac output),
      • R is the radius of the vessels
    • Of these, the easily regulated variable is vessel radius, which is affected by:
      • Blood flow 
      • Lung volume
      • Hypoxic pulmonary vasoconstriction
      • Humoural and hormonal mediators (eg. eicosanoids)
      • Drugs (eg. nitric oxide and sildenafil)

Now, as to nitric oxide:

Name Nitric oxide
Class Inhaled pulmonary vasodilator
Chemistry A free radical with the formula NO
Routes of administration Administered as par tof inspired gas mixture, usually as an admixture fraction measured in tens of ppm, via a proprietary system (INOMax)
Absorption Absorbs rapidly into the systemic 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

References

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