How Does Endothelin Work? (Mechanism and Receptors)
Endothelin-1 acts through two specific receptor subtypes: $ET_A$ and $ET_B$.
- Endothelin receptors are located predominantly on vascular smooth muscle cells and, to a lesser extent, on fibroblasts.
- Stimulation of $ET_A$ receptors causes vasoconstriction, proliferation of vascular smooth muscle cells, and activation of extracellular matrix protein synthesis by fibroblasts.
- Stimulation of $ET_B$ receptors, located on endothelial cells, mediates opposing effects, such as vasodilation (via NO and prostacyclin release).
Role in Systemic Inflammation and Sepsis
During sepsis and systemic inflammatory response syndrome (SIRS), a "cytokine/mediator storm" occurs.
- Hyperproduction of Mediators: Macrophages, monocytes, and endothelial cells secrete proinflammatory mediators, including interleukins, TNF, prostaglandins, platelet-activating factor, and endothelins.
- Vascular Injury: Excessive and prolonged production of proinflammatory mediators leads to a generalized inflammatory reaction, injury to the microcirculatory endothelium, increased capillary permeability, systemic vasodilation, hypotension, hypovolemia, and tissue ischemia.
- Pulmonary Hypertension in Endotoxin Shock: In the presence of high lipopolysaccharide levels, endothelial cells secrete both nitric oxide (NO) and endothelin. The development of pulmonary hypertension in endotoxin shock is attributed to an imbalance favoring endothelin secretion or reduced NO production.
Clinical Significance and Pathologies
Endothelin is implicated in the pathogenesis of conditions characterized by vascular tone dysregulation and inflammatory responses:
- Myocardial Infarction: Endothelin levels rise sharply, causing coronary artery constriction and impairing cardiac function.
- Meningococcal Infection: The release of vasoactive substances, including endothelins and NO, coupled with arterial hypo- or hypertension, leads to a disruption of cerebral perfusion autoregulation.
- Pulmonary Arterial Hypertension (PAH): Endothelin receptor antagonists (ERAs) such as bosentan, ambrisentan, and macitentan are used in therapy.
Specific hemodynamic effects have been demonstrated for these agents. In the BREATHE-4 trial, bosentan reduced mean pulmonary arterial pressure and increased cardiac index. In the PORTICO trial, macitentan significantly decreased pulmonary vascular resistance and mean pulmonary arterial pressure while increasing cardiac index by week 12.
These agents carry potential limitations due to hepatotoxicity and drug-drug interactions. ERAs are contraindicated in pregnant patients or those planning pregnancy with PAH due to teratogenic and embryotoxic effects.