How does endothelin work? (Mechanism and receptors)
Endothelin-1 acts via two specific receptor types: $ET_A$ 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 produces an indirect effect opposite to vasoconstriction.
Role in systemic inflammation and sepsis
A "mediator storm" develops in sepsis and systemic inflammatory response syndrome (SIRS).
- Hyperproduction of mediators: macrophages, monocytes, and endothelial cells produce proinflammatory mediators, including interleukins, TNF, prostaglandins, platelet-activating factor, and endothelins.
- Vascular damage: excessive and prolonged production of proinflammatory mediators leads to a generalized inflammatory response, damage 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 NO and endothelin. The development of pulmonary hypertension in endotoxin shock is explained by the predominance of endothelin secretion or decreased NO production.
Clinical significance and pathologies
Endothelin is involved in the pathogenesis of conditions associated with impaired vascular tone and inflammatory response:
- 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, against a background of arterial hyper- or hypotension leads to the disruption of cerebral perfusion autoregulation.
- Pulmonary arterial hypertension (PAH): endothelin receptor antagonists are used for therapy: bosentan, ambrisentan, and macitentan.
Hemodynamic effects have been described for individual drugs in this group. In the BREATHE-4 study, bosentan reduced mean pulmonary arterial pressure and increased cardiac index. In the PORTICO study, macitentan significantly reduced pulmonary vascular resistance and mean pulmonary arterial pressure, and increased cardiac index by week 12.
Drugs in this group may have limitations due to hepatotoxicity and drug-drug interactions. Endothelin receptor antagonists are not recommended for pregnant patients or those planning pregnancy with PAH due to teratogenic and embryotoxic effects.
Class and exam questions
What happens to endothelin levels in myocardial infarction?
Its level rises sharply. This causes coronary artery constriction and impairs cardiac function.
Which endothelin receptors cause vasoconstriction?
Vasoconstriction is among the effects of $ET_A$ receptor stimulation.
How is endothelin involved in the development of pulmonary hypertension in endotoxin shock?
At high levels of lipopolysaccharide, endothelial cells secrete NO and endothelin. The development of pulmonary hypertension in endotoxin shock is explained by the predominance of endothelin secretion or decreased NO production.
What is the clinical significance of endothelin receptor antagonists in pulmonary hypertension?
For bosentan, a reduction in mean pulmonary arterial pressure and an increase in cardiac index have been described. For macitentan, the PORTICO study showed a significant reduction in pulmonary vascular resistance and mean pulmonary arterial pressure by week 12.
What else to study on this topic
- Nitric oxide (NO) and vascular responses in sepsis
- Systemic inflammatory response syndrome (SIRS)
- Pulmonary arterial hypertension (PAH)
- Vascular smooth muscle cell receptors
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