How does elevated endothelin (a potent vasoconstrictor) cause pulmonary artery constriction in older adults with a history of cardiovascular or respiratory disease, such as pulmonary hypertension, heart failure, or chronic obstructive pulmonary disease (COPD)?

Mechanism of Endothelin-Mediated Pulmonary Artery Constriction

Elevated endothelin-1 (ET-1) causes pulmonary artery constriction through direct binding to ETA receptors on pulmonary artery smooth muscle cells, which activates phospholipase C, increases intracellular calcium, and triggers sustained vasoconstriction—a mechanism that is particularly important in pulmonary arterial hypertension where plasma ET-1 levels correlate directly with disease severity and prognosis. 1

Direct Vasoconstrictor Mechanism

Receptor-Mediated Smooth Muscle Contraction:

• ET-1 binds specifically to ETA-subtype receptors on pulmonary artery smooth muscle cells (PASMCs), initiating a cascade that activates phospholipase C 2
• This activation leads to formation of inositol trisphosphate and diacylglycerol, which activates protein kinase C and increases intracellular calcium concentration 2
• In certain pulmonary vessels, the endothelin receptor couples to voltage-operated calcium channels via G-proteins, providing an additional mechanism for calcium influx 2
• The elevated intracellular calcium directly triggers smooth muscle contraction and sustained vasoconstriction 2

Pathophysiological Context in Disease States

Endothelial Dysfunction and ET-1 Overproduction:

• In pulmonary arterial hypertension, the dysfunctional endothelium produces excessive amounts of vasoconstrictor/mitogenic compounds including endothelin and thromboxane, while simultaneously producing deficient amounts of vasodilators like prostacyclin 1
• Plasma ET-1 levels are markedly elevated in PAH patients (9.07 ± 4.13 pg/mL versus 3.7 ± 0.6 pg/mL in healthy controls) and correlate directly with pulmonary artery pressures and disease severity 3
• Pulmonary clearance of ET-1 is reduced in PAH, further contributing to elevated circulating levels 1

Correlation with Hemodynamic Severity:

• ET-1 levels correlate strongly with pulmonary vascular resistance (r = 0.65, p < 0.01) and the resistance ratio of pulmonary-to-systemic vascular resistance (r = 0.88, p < 0.0001) 3
• In primary pulmonary hypertension specifically, the arterial-to-venous ET-1 ratio exceeds unity (2.21 ± 0.72), indicating net pulmonary production of the peptide 4
• This correlation with severity and prognosis makes ET-1 both a marker and likely mediator of progressive pulmonary vascular disease 1

Proliferative Effects Beyond Acute Vasoconstriction

Vascular Remodeling:

• Beyond acute vasoconstriction, ET-1 stimulates PASMC proliferation, contributing to the chronic structural changes characteristic of pulmonary hypertension 1
• The peptide promotes vascular smooth muscle hypertrophy and hyperplasia, leading to medial thickening and fixed increases in pulmonary vascular resistance 1
• This proliferative effect explains why pulmonary hypertension becomes progressively less reversible over time as structural remodeling advances 1

Disease-Specific Considerations

Heart Failure with Pulmonary Hypertension:

• In chronic heart failure, elevated ET-1 levels correlate specifically with the extent of pulmonary hypertension rather than systemic hemodynamics 3
• Acute ETA receptor blockade causes selective pulmonary vasodilation (decreasing pulmonary artery systolic pressure, pulmonary vascular resistance, and mean pulmonary artery pressure) without affecting systemic vascular resistance or mean arterial pressure 5

COPD-Associated Pulmonary Hypertension:

• In COPD, pulmonary hypertension results from both hypoxic vasoconstriction and organic vascular remodeling, with endothelin playing an increasingly important role in the latter 6
• Endothelin receptor antagonism with bosentan reduced mean pulmonary artery pressure from 37 ± 5 to 31 ± 6 mm Hg and improved pulmonary vascular resistance from 442 ± 192 to 392 ± 180 dynes·cm² over 18 months 6

Mitral Stenosis:

• Decreased pulmonary venous compliance resulting partly from increased pulmonary endothelin-1 spillover contributes to elevated pulmonary venous pressure in mitral stenosis 1
• This mechanism compounds the passive backward transmission of elevated left atrial pressure 1

Clinical Implications

Therapeutic Targeting:

• The central role of ET-1 in pulmonary vasoconstriction and remodeling provides the rationale for endothelin receptor antagonist therapy in PAH 7
• Available endothelin receptor antagonists include bosentan (62.5-125mg twice daily), ambrisentan (5-10mg daily), and macitentan (10mg daily) 7
• These agents should be used in combination with phosphodiesterase-5 inhibitors as first-line therapy for lower or intermediate risk PAH patients 7

Critical Pitfall:

• Do not extrapolate PAH-specific endothelin antagonist therapy to other forms of pulmonary hypertension without appropriate patient selection, as routine use in secondary pulmonary hypertension (except PAH associated with connective tissue disease) is not recommended 7