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Circulation. 2001;104:424-428
doi: 10.1161/hc2901.093117
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(Circulation. 2001;104:424.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension

L. Zhao, PhD; N. A. Mason, PhD; N. W. Morrell, MD; B. Kojonazarov, MD; A. Sadykov, MD; A. Maripov, MD; M. M. Mirrakhimov, MD; A. Aldashev, PhD; M. R. Wilkins, MD

From the Section on Clinical Pharmacology (L.Z., N.A.M., N.W.M., M.R.W.), Imperial College School of Medicine, Hammersmith Hospital, London, UK, and National Centre of Cardiology (B.K., A.S., A.M., M.M.M., A.A.), Bishkek, Kyrghyz Republic.

Correspondence to Professor Martin Wilkins, Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, Ducane Rd, London, W12 ONN, UK. E-mail m.wilkins{at}ic.ac.uk

Background— This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice.

Methods and Results— In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O2 for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean±SD mm Hg]: normoxia 16.0±2.1 versus hypoxia 25.0±4.8) was almost abolished by sildenafil (normoxia 16.0±2.1 versus hypoxia 18.0±3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg · kg-1 · d-1) throughout 3 weeks of exposure to hypoxia (10% O2) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3±9.9 versus 29.9±9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling.

Conclusions— Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.


Key Words: hypertension, pulmonary • hypoxia • pharmacology




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 Arch Intern MedHome page
K. Chatterjee, T. De Marco, and J. S. Alpert
Pulmonary Hypertension: Hemodynamic Diagnosis and Management
Arch Intern Med, September 23, 2002; 162(17): 1925 - 1933.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
J. C Wanstall, A. Gambino, T. K Jeffery, M. M Cahill, D. Bellomo, N. K Hayward, and G. F Kay
Vascular endothelial growth factor-B-deficient mice show impaired development of hypoxic pulmonary hypertension
Cardiovasc Res, August 1, 2002; 55(2): 361 - 368.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
E. Michelakis, W. Tymchak, D. Lien, L. Webster, K. Hashimoto, and S. Archer
Oral Sildenafil Is an Effective and Specific Pulmonary Vasodilator in Patients With Pulmonary Arterial Hypertension: Comparison With Inhaled Nitric Oxide
Circulation, May 21, 2002; 105(20): 2398 - 2403.
[Abstract] [Full Text] [PDF]

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 JAMAHome page
P. Hackett and D. Rennie
High-Altitude Pulmonary Edema
JAMA, May 1, 2002; 287(17): 2275 - 2278.
[Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
L. S. Shekerdemian, H. B. Ravn, and D. J. Penny
Intravenous Sildenafil Lowers Pulmonary Vascular Resistance in a Model of Neonatal Pulmonary Hypertension
Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1098 - 1102.
[Abstract] [Full Text] [PDF]

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 HeartHome page
M. R WILKINS and J. WHARTON
Progress in, and future prospects for, the treatment of primary pulmonary hypertension
Heart, December 1, 2001; 86(6): 603 - 604.
[Full Text] [PDF]


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