Circulation, Vol 89, 2498-2502, Copyright © 1994 by American Heart Association
M Husain, C Adrie, F Ichinose, M Kavosi and WM Zapol
BACKGROUND: This study was designed to demonstrate the development of
biochemical tolerance to organic nitrates by measuring levels of exhaled
gaseous nitric oxide (NO) in lambs given intravenous (IV) nitroglycerin or
sodium nitroprusside. METHODS AND RESULTS: IV injections of nitroglycerin
or sodium nitroprusside produced dose- dependent and sustained increases in
the exhaled levels of nitric oxide measured by chemiluminescence in awake
lambs with tracheostomies. After a 6-hour IV infusion of 25
micrograms.kg-1.min-1 nitroglycerin, peak exhaled NO levels were
significantly reduced (-53.6 +/- 4.9%, mean +/- SEM, P < .001) and
systemic hypotensive responses were attenuated (- 52.6 +/- 5.9%, P <
.001) after an IV challenge of nitroglycerin but not sodium nitroprusside.
After a subsequent 12-hour nitroglycerin-free period, there was complete
recovery of NO excretion in exhaled breath and a return to baseline of
systemic hypotensive changes on administration of IV nitroglycerin boluses.
For IV sodium nitroprusside challenges, pulmonary NO excretion and systemic
hypotensive responses remained constant throughout the study. Challenges
with IV nitroglycerin but not sodium nitroprusside during a 12-hour
nitroglycerin-free period resulted in delayed biochemical recovery with
various exhaled NO levels and systemic hypotensive responses to challenges
with IV nitroglycerin. CONCLUSIONS: Measurements of exhaled NO provide in
vivo, noninvasive evidence for the development of biochemical tolerance to
nitroglycerin. There was reduced NO release into exhaled gas from the
pulmonary vasculature concomitant with evidence of tolerance to
nitroglycerin vasodilation in the systemic circulation.
ARTICLES
Exhaled nitric oxide as a marker for organic nitrate tolerance
Department of Anaesthesia, Harvard Medical School, Massachusetts General Hospital, Boston 02114.
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