Endothelin-1 vasoactive responses in lambs with pulmonary
hypertension and increased pulmonary blood flow.
Wong, Jackson, V. Mohan Reddy, Karen Hendricks-Munoz, John R.
Liddicoat, Rene Gerrets, Jeffrey R. Fineman.
Departments of Pediatrics and Cardiothoracic Surgery, University of
California San Francisco, San Francisco, CA 94143-0106 and the
Department of Pediatrics, New York University, New York, New York
10016
APStracts 2:0256H, 1995.
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 7 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 Ala 1, 3, 11, 15 ET-1 (4 Ala ET-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 6 control lambs with a similar degree
of pulmonary hypertension induced by U46619, ET-1 and 4 Ala ET-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 pg/ml 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.
Received 22 February 1995; accepted in final form 1 June 1995.
APS Manuscript Number H165-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 July 1995.