Nebulized sildenafil is a selective pulmonary vasodilator in lambs
with acute pulmonary hypertension
Fumito Ichinose, MD; Juan Erana-Garcia, MD; Jonathan Hromi, BA; Yehuda Raveh, MD; Rosemary Jones, PhD;
Lori Krim, PhD; Martin W. H. Clark, BsC; Jeffrey D. Winkler, PhD; Kenneth D. Bloch, MD; Warren M. Zapol, MD
P
ulmonary artery hypertension
is an important feature of
acute and chronic lung disease
of various etiologies. Systemic
vasodilator therapy with intravenous
agents is limited by a lack of pulmonary
selectivity and can cause both pulmonary
and systemic vasodilation with poten-
tially catastrophic arterial hypotension.
Furthermore, systemic administration of
vasodilators may worsen arterial oxygen-
ation by increasing blood flow to poorly
ventilated lung regions, resulting in in-
creased right-to-left intrapulmonary
shunting.
In contrast to systemically adminis-
tered vasodilators, inhaling low concen-
trations of nitric oxide (NO) gas has been
shown to cause selective pulmonary va-
sodilation (1) as the result of rapid inac-
tivation of NO by hemoglobin binding on
entry into the intravascular space (2). Be-
cause the vasodilating effects of NO are
largely mediated via cyclic guanosine
monophosphate (cGMP) -dependent
mechanisms, we hypothesized that inhi-
bition of the cGMP-selective phosphodi-
esterase type 5 would augment the vaso-
dilating effects of inhaled NO by
increasing cGMP levels in vascular
smooth muscle cells. We reported that an
intravenous infusion of zaprinast mark-
edly prolonged the pulmonary vasodila-
tion induced by inhaled NO (3). Recently,
we further demonstrated that enteral ad-
ministration of sildenafil, the novel and
highly-selective phosphodiesterase type 5
inhibitor that is now clinically available
under the trade name of Viagra (Pfizer,
New York, NY) (4, 5), caused pulmonary
vasodilation in awake lambs with
U46619-induced pulmonary hypertension
(6). Although aerosolized zaprinast
caused selective pulmonary vasodilation
and augmented the pulmonary vasodilat-
ing effects of inhaled NO (7), intravenous
administration of zaprinast caused vaso-
dilation of poorly ventilated lung regions
and impaired the beneficial effects of in-
haled NO on systemic oxygenation in a
sheep model of acute lung injury (8).
From the Department of Anesthesia and Critical
Care (Drs. Ichinose, Erana-Garcia, Raveh, Jones, and
Zapol and Mr. Hromi) and the Cardiovascular Research
Center and Cardiology Division of the Department of
Medicine (Dr. Bloch), Massachusetts General Hospital,
Harvard Medical School, Boston, MA; the Department
of Chemistry, the University of Pennsylvania (Drs.
Winkler and Krim), Philadelphia, PA; and Pfizer Central
Research (Mr. Clark), Sandwich, UK.
Address requests for reprints to: Fumito Ichinose,
MD, Department of Anesthesia and Critical Care, Car-
diovascular Research Center, Massachusetts General
Hospital, Boston, MA 02114. E-mail: ichinose@
etherdome.mgh.harvard.edu
Supported, in part, by National Institutes of Health
grant HL42397. Dr. Bloch is an Established Investiga-
tor of the American Heart Association.
The Massachusetts General Hospital has been
granted patents on the inhalation of nitric oxide and
phosphodiesterase inhibitors, and the authors have a
right to receive royalties.
Copyright © 2001 by Lippincott Williams & Wilkins
Objective: To determine whether inhalation of aerosolized sil-
denafil with and without inhaled nitric oxide (NO) causes selective
pulmonary vasodilation in a sheep model of pulmonary hyperten-
sion.
Design: A controlled laboratory study in instrumented, awake,
spontaneously breathing lambs.
Setting: Animal research laboratory affiliated with a university
hospital.
Subject: Twenty Suffolk lambs.
Interventions: Lambs were instrumented with a carotid artery
catheter, a pulmonary artery catheter, and a tracheostomy tube
and studied awake. After baseline measurements, pulmonary
hypertension was induced by the continuous infusion of U46619,
a thromboxane A
2
analog. After breathing three concentrations of
inhaled NO (2, 5, and 20 ppm), lambs were divided into two
groups. Group 1 (n 7) breathed aerosols containing 1, 10, and
30 mg of sildenafil alone, and group 2 (n 4) simultaneously
breathed NO (2 and 5 ppm) and aerosols containing 10 mg of
sildenafil. Hemodynamic measurements were obtained before and
at the end of each drug administration. Venous admixture was
calculated, and plasma cyclic guanosine monophosphate and
sildenafil concentrations were measured.
Measurements and Main Results: Aerosols containing 10 mg
and 30 mg of sildenafil selectively decreased the pulmonary
artery pressure by 21% 3% and 26% 3%, respectively (p <
.05 vs. baseline pulmonary hypertension). When 10 mg of silde-
nafil was inhaled while simultaneously breathing 2 ppm and 5
ppm NO, the pulmonary artery pressure decreased by 35% 3%
and 43% 2% (p < .05 vs. baseline pulmonary hypertension).
Inhaled sildenafil did not impair systemic oxygenation, increase
right-to-left intrapulmonary shunting, or impair the ability of
inhaled NO to reduce right-to-left shunting.
Conclusions: Nebulized sildenafil is a selective pulmonary va-
sodilator that can potentiate the pulmonary vasodilating effects of
inhaled NO. (Crit Care Med 2001; 29:1000 –1005)
KEY WORDS: pulmonary hypertension; pulmonary vasodilator;
nitric oxide; 3,5-cyclic guanosine monophosphate phosphodies-
terase; phosphodiesterase inhibitor; sildenafil; aerosol drug ther-
apy; respiratory therapy; inhalation drug administration; sheep
1000 Crit Care Med 2001 Vol. 29, No. 5