Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension.
BACKGROUND
Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction.


METHODS
In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6).


RESULTS
Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation.


CONCLUSIONS
Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.
Weimann
J
J
Departments of Anesthesia and Critical Care, Respiratory Care, and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Ullrich
R
R
Hromi
J
J
Fujino
Y
Y
Clark
M W
MW
Bloch
K D
KD
Zapol
W M
WM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D012756:Sheep; D000068677:Sildenafil Citrate; D013450:Sulfones; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014851:Wakefulness
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011688:Purinones; D013450:Sulfones; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester