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Endothelin-1 vasoactive responses in lambs with pulmonary hypertension and increased pulmonary blood flow
J Wong1, V M Reddy, K Hendricks-Munoz
1Department of Pediatrics, University of California, San Francisco 94143-0106, USA.
Insights
Pulmonary hypertension in lambs with increased blood flow causes endothelin-1 (ET-1) to constrict pulmonary vessels, unlike its usual dilating effect. This suggests ET-1 plays a role in the disease
Area of Science:
- Cardiovascular Physiology
- Pediatric Cardiology
- Pharmacology
Background:
- Elevated endothelin-1 (ET-1) concentrations are observed in children with congenital heart diseases leading to pulmonary hypertension.
- The precise role of ET-1 in the pathophysiology of pulmonary hypertension, particularly in cases with increased pulmonary blood flow, remains unclear.
- Understanding ET-1's vasoactive effects is crucial for developing targeted therapies for pediatric pulmonary hypertension.
Purpose of the Study:
- To investigate the vasoactive responses to endothelin-1 (ET-1) in an animal model of pulmonary hypertension with increased pulmonary blood flow.
- To determine ET-1 concentrations in lambs with experimentally induced pulmonary hypertension and increased pulmonary blood flow.
- To elucidate the specific roles of ET-1 receptors (ETa and ETb) in mediating these vasoactive responses.
Main Methods:
- Creation of a surgical vascular shunt between the ascending aorta and main pulmonary artery in fetal sheep to induce increased pulmonary blood flow.
- Induction of pulmonary hypertension post-delivery in experimental lambs and control lambs (using U-46619).
- Administration of ET-1, an ETb-receptor agonist (4AlaET-1), and an ETa-receptor antagonist (BQ-123) to assess pulmonary vascular resistance changes.
- Measurement of systemic arterial concentrations of immunoreactive ET-1.
Main Results:
- In lambs with pulmonary hypertension and increased pulmonary blood flow, ET-1 administration significantly increased pulmonary vascular resistance (29.7 +/- 34.4%).
- The ETa-receptor antagonist BQ-123 decreased pulmonary vascular resistance (-16.0 +/- 5.6%), indicating ETa-receptor mediated vasoconstriction.
- In contrast, in control lambs with pulmonary hypertension induced by U-46619, ET-1 and 4AlaET-1 caused pulmonary vasodilation (decreased resistance).
- Systemic arterial ET-1 concentrations were significantly elevated in lambs with pulmonary hypertension compared to controls (29.2 +/- 9.6 vs. 15.2 +/- 10.7 pg/ml).
Conclusions:
- Pulmonary hypertension combined with increased pulmonary blood flow alters the vasoactive response to ET-1, shifting it from vasodilation to vasoconstriction.
- These altered responses highlight a significant role for ET-1 and its receptors in the pathogenesis of pulmonary hypertension secondary to increased pulmonary blood flow.
- Targeting the ET-1 pathway, particularly ETa receptors, may offer therapeutic potential for this specific type of pulmonary hypertension.
Abstract:
Increased concentrations of endothelin-1 (ET-1) are found in children with congenital heart diseases that produce increased pulmonary blood flow and pulmonary hypertension, but the role of ET-1 in the pathophysiology of pulmonary hypertension is unclear. Therefore, we investigated ET-1-induced vasoactive responses and ET-1 concentrations in an animal model of pulmonary hypertension and increased pulmonary blood flow. Vascular shunts were placed between the ascending aorta and main pulmonary artery in seven late-gestation fetal sheep. Four weeks after spontaneous delivery, ET-1 increased pulmonary vascular resistance by 29.7 +/- 34.4% (P < 0.05), the ETb-receptor agonist [Ala1,3,11,15]ET-1 (4AlaET-1) had no effect, and the ETa-receptor antagonist cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp) (BQ-123) decreased pulmonary vascular resistance by -16.0 +/- 5.6% (P < 0.05). In contrast, in six control lambs with a similar degree of pulmonary hypertension induced by U-46619, ET-1 and 4AlaET-1 decreased pulmonary vascular resistance by 24.8 +/- 17.6, and 20.0 +/- 13.8%, respectively (P < 0.05). In addition, systemic arterial concentrations of immunoreactive ET-1 were elevated in lambs with pulmonary hypertension (29.2 +/- 9.6 vs. 15.2 +/- 10.7 pg/ml, P < 0.05). Pulmonary hypertension and increased pulmonary blood flow alters the response of ET-1 from pulmonary vasodilation to vasoconstriction. These altered responses suggest a role for ET-1 and its receptors in the pathogenesis of pulmonary hypertension secondary to increased pulmonary blood flow.