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Endothelin-1 is elevated in monocrotaline pulmonary hypertension
H F Frasch1, C Marshall, B E Marshall
1Center for Anesthesia Research, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, 19104-4283, USA.
The American Journal of Physiology
|February 10, 1999
Summary
In monocrotaline-induced pulmonary hypertension, inhibiting nitric oxide synthase (NOS) causes vasoconstriction. This is mediated by endothelin-1 (ET-1) acting on ETA receptors, a process reversed by ETA antagonists.
Area of Science:
- Cardiovascular Research
- Pulmonary Medicine
- Pharmacology
Background:
- Pulmonary hypertension involves complex vascular remodeling and altered signaling pathways.
- Nitric oxide synthase (NOS) and endothelin-1 (ET-1) play critical roles in regulating pulmonary vascular tone.
- The interplay between NOS inhibition and ET-1 in established pulmonary hypertension requires further elucidation.
Purpose of the Study:
- To investigate the pulmonary vasoconstrictor response to NOS inhibition in a rat model of monocrotaline (MCT)-induced pulmonary hypertension.
- To determine the role of endothelin-1 (ET-1) and its receptors (ETA and ETB) in mediating this vasoconstriction.
- To assess the impact of NOS inhibition on hypoxic pulmonary vasoconstriction in the context of MCT-induced pulmonary hypertension.
Main Methods:
- Isolated, perfused rat lungs were studied 3 weeks after MCT or saline injection.
- Pulmonary arterial pressure responses to NOS inhibition (L-NMMA) and ANG II were measured.
- The effects of ETA (BQ-123) and ETB (BQ-788) receptor antagonists on L-NMMA-induced responses were evaluated.
- ET-1 concentrations in lung perfusate were measured.
Main Results:
- MCT-injected rats exhibited pulmonary hypertension and heightened vasoconstriction to ANG II and L-NMMA.
- The pressor response to NOS inhibition correlated with the severity of pulmonary hypertension.
- Pretreatment or reversal with an ETA antagonist, but not an ETB antagonist, prevented or reversed L-NMMA-induced constriction.
- Elevated ET-1 levels were found in MCT-injected lungs, but not altered by NOS inhibition.
Conclusions:
- Elevated endogenous ET-1 acting via ETA receptors contributes to pulmonary vasoconstriction in MCT-induced pulmonary hypertension.
- This ET-1 mediated constriction is normally masked by endogenous nitric oxide (NO) production.
- NOS inhibition exacerbates hypoxic pulmonary vasoconstriction, particularly in established pulmonary hypertension.