Pulmonary Vasoconstriction & Inhaled Vasodilators

Compare Nitric Oxide & Prostacyclin in the Pharmacopeia

a) Physiological factors contributing to pulmonary vasoconstriction (60%)

Key principle: pulmonary vascular tone is unusual because alveolar hypoxia causes vasoconstriction. This is the major physiological regulator of pulmonary vasomotor tone and diverts blood away from poorly ventilated lung toward better-ventilated regions.

1. Alveolar hypoxia — hypoxic pulmonary vasoconstriction (HPV)

• Stimulus: reduced regional alveolar PO₂ is the dominant signal; mixed venous PO₂ contributes to a lesser extent.
• Site: predominantly small pulmonary arteries/arterioles adjacent to hypoxic alveoli.
• Acute cellular mechanism (accepted working model):
  • Hypoxia alters oxygen-sensitive redox signalling in pulmonary arterial smooth muscle.
  • Inhibition of O₂-sensitive K⁺ channels reduces K⁺ efflux → membrane depolarisation.
  • Depolarisation opens voltage-gated L-type Ca²⁺ channels; Ca²⁺ release from intracellular stores also contributes.
  • ↑ cytosolic Ca²⁺ → Ca²⁺-calmodulin → myosin light-chain kinase activation → smooth-muscle contraction.
  • RhoA/Rho-kinase signalling increases Ca²⁺ sensitivity and sustains contraction.
• Endothelial modulation: hypoxia favours vasoconstriction through reduced NO/prostacyclin signalling and increased endothelin activity, particularly during more sustained hypoxia.
• Physiological purpose: improves regional V/Q matching. Widespread hypoxia (e.g. high altitude or severe diffuse lung disease) instead produces a global rise in pulmonary vascular tone and pulmonary arterial pressure.

2. Carbon dioxide and pH

• Hypercapnia causes pulmonary vasoconstriction; the effect is less powerful than hypoxia.
• Much of the hypercapnic response is mediated by the accompanying fall in pH, although CO₂ also has effects independent of pH.
• Acidaemia increases pulmonary vascular tone through effects on smooth-muscle ion channels and intracellular Ca²⁺; it also augments HPV.
• Alkalaemia / hypocapnia generally reduce pulmonary vascular tone and attenuate HPV.

3. Autonomic and circulating catecholamines

• Pulmonary vessels receive sympathetic innervation, although resting autonomic control is modest compared with local control.
• α₁-adrenoceptor stimulation: G_q → phospholipase C → IP₃ → ↑ intracellular Ca²⁺ → vasoconstriction.
• Noradrenaline and adrenaline can therefore increase pulmonary vascular tone when α effects predominate.
• β₂-adrenoceptor stimulation opposes this through G_s → ↑ cAMP → vasodilation.

4. Local and neurohumoral vasoconstrictors

Balance of endothelial mediators: constitutive NO and prostacyclin normally oppose constriction. Endothelial dysfunction or reduced NO/PGI₂ activity therefore shifts pulmonary vascular tone toward vasoconstriction.

b) Inhaled pulmonary vasodilators (40%)

Nitric oxide — mechanism of action (part of 25%)

• Diffuses from the alveolus into adjacent pulmonary vascular smooth muscle.
• Binds the haem moiety of soluble guanylyl cyclase → ↑ cGMP → protein kinase G activation → ↓ cytosolic Ca²⁺ and smooth-muscle relaxation.
• Rapidly reacts with haemoglobin after entering blood, so its vasodilator effect is largely confined to the pulmonary circulation.
• Selective delivery to ventilated alveoli redistributes blood flow toward better-ventilated lung and can improve oxygenation.

Nitric oxide — adverse effects (part of 15%)

• Methaemoglobinaemia: oxidation of haemoglobin reduces functional O₂-carrying capacity; monitor methaemoglobin concentration.
• Nitrogen dioxide (NO₂) formation: oxidant airway/alveolar injury, pneumonitis and pulmonary oedema; monitor inspired NO₂.
• Platelet inhibition / bleeding tendency: reduced platelet activation/aggregation; thrombocytopenia is also reported.
• Systemic hypotension may occur, particularly at higher exposure or with other vasodilators.
• Rebound pulmonary hypertension and hypoxaemia with abrupt withdrawal → wean gradually.

Prostacyclin — mechanism of action (part of 25%)

• Prostacyclin (PGI₂) / epoprostenol binds the IP receptor on vascular smooth muscle.
• IP is a G_s-coupled receptor → activates adenylyl cyclase → ↑ cAMP → protein kinase A → reduced intracellular Ca²⁺ and reduced myosin light-chain kinase activity → vasodilation.
• Also inhibits platelet activation and aggregation through increased platelet cAMP.
• When nebulised/inhaled, the effect is concentrated in ventilated regions, promoting V/Q matching and reducing pulmonary vascular tone.

Prostacyclin — adverse effects (part of 15%)

• Systemic hypotension from spill-over systemic vasodilation.
• Platelet inhibition and bleeding, especially with thrombocytopenia or concurrent anticoagulation.
• Flushing, headache, nausea, diarrhoea and jaw discomfort.
• Airway irritation / cough; bronchospasm is uncommon but possible with inhaled delivery.
• Rebound pulmonary hypertension can occur if a short-acting prostacyclin infusion/nebulisation is abruptly interrupted.

Exam focus

• Do not turn part (a) into a generic list of determinants of PVR: the stem asks specifically about pulmonary vasoconstriction and its mechanisms.
• Give the most detail to hypoxic pulmonary vasoconstriction, then CO₂/pH and neurohumoral mediators.
• For each inhaled vasodilator, link the receptor/second-messenger pathway to smooth-muscle relaxation, and link each major adverse effect to its mechanism where possible.