Endothelins are powerful vasoactive peptides with major roles in blood pressure regulation, vascular tone, and pathology. Removal of certain rare tumours (e.g. malignant hemangioendothelioma) can reduce endothelin secretion and lower BP.

🧬 About Endothelins

Produced by the vascular endothelium.
Endothelin-1 (ET-1): 21-amino acid peptide derived from a 39-aa precursor (Big ET-1).
Three isoforms: ET-1, ET-2, ET-3 → ET-1 is the most studied and physiologically relevant.

⚡ Actions of Endothelin-1

One of the most potent endogenous vasoconstrictors known.
Binds smooth muscle receptors → ↑ intracellular calcium → powerful, sustained vasoconstriction.
Also involved in vascular remodelling, fibrosis, and hypertrophy.

📈 Stimuli for Endothelin Release

Hypoxia and adrenaline (epinephrine).
Cortisol and angiotensin II.
Shear stress (↑ flow), insulin, ciclosporin.

📉 Inhibitors of Endothelin Release

Nitric oxide (NO), atrial natriuretic peptide (ANP).
Prostacyclin (PGI₂) and Prostaglandin E₂ (PGE₂).
These act as vasodilators → balancing endothelin-induced constriction.

🔑 Endothelin Receptors

Both ET_A and ET_B are Gq-protein coupled → activate IP₃ → ↑ Ca²⁺ release → smooth muscle contraction.
ET_A receptor:
- Located mainly on vascular smooth muscle.
- Responsible for vasoconstriction under physiological conditions.
ET_B receptor:
- On both endothelial cells & smooth muscle.
- On endothelium → stimulates NO release → vasodilation, anti-apoptotic effects.
- On smooth muscle → can also mediate vasoconstriction.

💊 Clinical Relevance

Pulmonary Arterial Hypertension (PAH): Endothelin levels ↑; drugs such as bosentan and ambrisentan (endothelin receptor antagonists) improve outcomes.
Cardiovascular disease: Endothelin contributes to hypertension, atherosclerosis, and heart failure (due to vasoconstriction + remodelling).
Oncology: Rare vascular tumours may secrete endothelins → hypertension, reversed by tumour removal.

📌 Exam Pearls

ET-1 is the strongest endogenous vasoconstrictor (stronger than angiotensin II).
Think “balance”: ET-1 vasoconstriction vs NO/PGI₂ vasodilation.
ET receptor antagonists are a mainstay in PAH management.
Endothelin dysregulation = hypertension, vascular injury, fibrosis.

📊 Endothelin Receptor Comparison

Feature	ET_A Receptor	ET_B Receptor
Main Location	Vascular smooth muscle	Endothelial cells & vascular smooth muscle
Coupling	Gq-protein → IP₃ → ↑Ca²⁺	Gq-protein → IP₃ → ↑Ca²⁺
Primary Effect	Vasoconstriction (↑ BP, ↑ vascular tone)	Dual action: – Endothelium → NO release → vasodilation – Smooth muscle → vasoconstriction
Physiological Role	Maintains baseline vascular tone	Balances ET_A-mediated constriction by promoting vasodilation & endothelial health
Pathology	Hypertension, vascular remodelling, heart failure	Endothelial dysfunction (↓ NO release) worsens vascular disease
Drug Target	Endothelin receptor antagonists (e.g. bosentan, ambrisentan) block both ET_A and ET_B, used in pulmonary arterial hypertension (PAH).

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Endothelins