Endothelin blockade augments pulmonary vasodilation in the ovine
fetus.
Ivy, D. Dunbar, John P. Kinsella, Steven H. Abman.
Divisions of Cardiology, Neonatology, Pulmonary Medicine and
Critical Care Department of Pediatrics, University of Colorado School
of Medicine & The Children's Hospital, Denver, CO
APStracts 3:0424A, 1996.
The physiologic role of endothelin-1 (ET-1) in regulation of vascular
tone in the perinatal lung is controversial. Recent studies suggest
that ET-1 contributes to high basal pulmonary vascular resistance in
the normal fetus, but its role in the modulation of pulmonary
vascular tone remains uncertain. We hypothesized that high ET-1
activity opposes the vasodilator response to some physiologic
stimuli, such as increased pressure. To test the hypothesis that ET-1
modulates fetal pulmonary vascular responses to acute and prolonged
physiologic stimuli, we performed a series of experiments in the
late-gestation ovine fetus. We studied the hemodynamic effects of two
ET-1 antagonists, BQ 123 (a selective ETA receptor antagonist) and
phosphoramidon (a nonselective ET-1 converting enzyme inhibitor),
during mechanical increases in pressure due to partial ductus
arteriosus compression in chronically-prepared, late-gestation fetal
lambs. In control studies, partial ductus arteriosus compression
decreased the ratio of pulmonary artery pressure to pulmonary artery
flow in the left lung 34 +/- 6 % from baseline. Intrapulmonary
infusions of BQ 123 ( 0.5 [mu]g/min for 10 min; 0.025 [mu]g/min for 2
h) or phosphoramidon (1.0 mg/min for 10 min) augmented the peak
vasodilator response during ductus arteriosus compression (52 +/- 3
and 49 +/- 6 % from baseline, respectively, p<0.05 vs
control). In addition, unlike the transient vasodilator response to
ductus arteriosus compression in control studies, ET blockade with BQ
123 or phosphoramidon prolonged the increase in flow caused by ductus
arteriosus compression. In summary, ETA receptor blockade and ET-1
converting enzyme inhibition augment and prolong fetal pulmonary
vasodilation during partial compression of the ductus arteriosus. We
conclude that ET-1 activity modulates acute and prolonged responses
of the fetal pulmonary circulation to changes in vascular pressure.
We speculate that ET-1 contributes to regulation and maintenance of
high pulmonary vascular resistance in the normal ovine fetal lung.
Received 23 February 1996; accepted in final form 8 August 1996.
APS Manuscript Number A179-6.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 7 October 1996