Effects of hypoxia and vascular tone on endothelium-dependent and
independent responses in developing lungs.
Gordon, John B., Fernando R. Martinez, Denise C. O'donnell, and Mary
L. Tod.
Departments of Pediatrics, Medicine and Physiology, University of
Maryland School of Medicine, Baltimore,, Maryland, 21201
APStracts 2:0200A, 1995.
The endothelium-derived relaxing factor identified as nitric oxide
(EDNO) is a potent modulator of raised pulmonary vasomotor tone in
mature animals. However, its role during newborn development is
uncertain, for both increases and decreases in EDNO activity have
been described. We hypothesized that factors other than maturational
changes in endothelial synthesis of and/or vascular smooth muscle
responsiveness to EDNO contribute to these discordant results. In
this study, we assessed the influence of baseline vasomotor tone and
oxygen tension on pulmonary artery dose-responses to the endothelium
-dependent and -independent vasodilators, acetylcholine (Ach) and
sodium nitroprusside (SNP), respectively, in indomethacin-treated,
lungs of 2 day and 1 month old lambs. During 4% O2 ventilation
(maximal hypoxic stimulus), responses to both dilators decreased with
age suggesting that the modulating effect of EDNO was greater in
younger lungs. However, baseline pulmonary vascular resistance (PVR)
was higher in 2 day old lungs during 4% O2 ventilation. When baseline
PVR were matched during hypoxia or infusion of a thromboxane mimetic
under normoxic conditions, developmental differences in Ach-induced
vasodilation were minimal. Hypoxia itself had no effect on responses
to Ach in 2 day old lungs. Thus, differences in baseline PVR, rather
than maturational changes in nitric oxide synthase activity, seemed
responsible for the age-dependent decrease in Ach-induced
vasodilation during 4% O2 ventilation. In contrast, SNP caused
greater vasodilation in 2 day than 1 month old lungs regardless of
baseline PVR. These data and previous studies suggest that while
responsiveness to EDNO decreases as basal EDNO synthesis increases
after birth, the modulating effects of EDNO in young newborns may be
enhanced by high PVR. The mechanism by which increased vasomotor tone
enhances EDNO synthesis remains to be elucidated.
Received 24 August 1994; accepted in final form 5 May 1995.
APS Manuscript Number A891-4.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 26 May 1995.