Key Points
- To determine why intravenous administration of big endothelin-1 fails to induce a vasodilator response despite its enzymatic conversion to endothelin-1.
- Measured systemic vascular resistance and hindquarter blood flow in anesthetized rats following intravenous big endothelin-1 challenge.
- Administered the selective ETA-receptor antagonist BQ-123 alongside big endothelin-1 to evaluate whether vasoconstriction masks vasodilation.
- Administered low doses of endothelin-1 (0.03–0.3 nmol/kg) after a high dose of big endothelin-1 (3.0 nmol/kg) to test for endothelial ETB receptor tachyphylaxis.
- Pretreatment with BQ-123 failed to uncover an underlying vasodilator response to big endothelin-1 in the rat hindquarter.
- Low doses of endothelin-1 continued to produce dose-dependent hindquarter vasodilation following big endothelin-1 infusion, ruling out endothelial ETB receptor tachyphylaxis.
- Big endothelin-1 lacks vasodilator action primarily because its intravenous administration results in negligible activation of endothelial ETB receptors.
Structured PICO
PPopulationAnesthetized rats
IInterventionIntravenous administration of big endothelin-1 (bET-1) with BQ-123 (ETA-receptor antagonist) or followed by low doses of ET-1 (0.03-0.3 nmol/kg)
OOutcomeHindquarter vasodilation / vasodilator responsesurrogate
Intravenous administration of big endothelin-1 results in little or no activation of endothelial ETB receptors, explaining its lack of a vasodilator response.