Thapsigargin stimulates increased no activity in hypoxic
hypertensive rat lungs and pulmonary arteries.
Muramatsu, Masashi, Robert C. Tyler, David M. Rodman, and Ivan F.
McMurtry.
CVP Research Laboratory, Department of Medicine, University of
Colorado Health Sciences Center, Denver, Colorado 80262 USA
APStracts 2:0525A, 1995.
This study addressed the controversy of whether endothelium-derived
nitric oxide (NO) activity is increased or decreased in the
hypertensive pulmonary vasculature of chronically-hypoxic rats.
Thapsigargin, a receptor-independent Ca++ agonist and stimulator of
endothelial NO production, was used to compare NO-mediated
vasodilation in perfused lungs and conduit pulmonary artery rings
isolated from adult male rats either kept at Denver's altitude of
5,280 ft (control pulmonary normotensive rats) or exposed for 4-5 wk
to the simulated altitude of 17,000 ft (chronically-hypoxic pulmonary
hypertensive rats). Under baseline conditions, thapsigargin (10-9-10
-7 M) caused vasodilation in hypertensive lungs and vasoconstriction
in normotensive lungs. Whereas the sustained vasodilation in
hypertensive lungs was reversed to vasoconstriction by the inhibitor
of NO synthase, nitro-L-arginine (10-4 M, L-NNA), a transient
vasodilation to thapsigargin in acutely-vasoconstricted normotensive
lungs was potentiated. As measured by a chemiluminescence assay, the
recirculated perfusate of hypertensive lungs accumulated considerably
higher levels of NO-containing compounds (NOx) than did normotensive
lungs, and thapsigargin-induced stimulation of NOx accumulation was
greater in hypertensive than in normotensive lungs. Similarly, low
concentrations of thapsigargin (10-10-10-9 M) caused greater
endothelium-dependent L-NNA-reversible relaxation of hypertensive
than of normotensive pulmonary artery rings. The increased
sensitivity of hypertensive arteries to thapsigargin-induced
relaxation was eliminated in nominally Ca++-free medium and was not
mimicked by ryanodine, a releaser of intracellular Ca++. These
results with thapsigargin, which acts on endothelial cells to
stimulate Ca++ influx and a sustained rise in intracellular [Ca++],
support the idea that pulmonary vascular endothelium-derived NO
activity is increased rather than decreased in chronic hypoxia
-induced pulmonary hypertension in rats.
Received 4 May 1995; accepted in final form 22 November 1995.
APS Manuscript Number A471-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 8 December 95