Hypoxia-induced pulmonary hypertension: Different impact of iloprost, sildenafil, and nitric oxide

Weissmann, Norbert; Gerigk, Boris; Kocer, Özlem; Nollen, Matthias; Hackemack, Sascha; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Butrous, Ghazwan; Schulz, Andreas; Roth, Markus; Seeger, Werner; Grimminger, Friedrich

doi:10.1016/j.rmed.2007.05.025

« Previous Next »Respiratory Medicine
Volume 101, Issue 10 , Pages 2125-2132, October 2007

Hypoxia-induced pulmonary hypertension: Different impact of iloprost, sildenafil, and nitric oxide☆

Norbert Weissmann
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
- Corresponding author. Tel.: +496419942422; fax: +496419942419.
Boris Gerigk
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Özlem Kocer
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Matthias Nollen
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Sascha Hackemack
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Hossein Ardeschir Ghofrani
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Ralph Theo Schermuly
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Ghazwan Butrous
- Pfizer Global Research and Development Sandwich Laboratories, Sandwich, UK
Andreas Schulz
- Schering Deutschland, Berlin, Germany
Markus Roth
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Werner Seeger
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany
Friedrich Grimminger
- University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany

Received 29 January 2007; accepted 20 May 2007. published online 28 July 2007.

Summary

Objectives

Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxia-induced pulmonary hypertension.

Methods

Exposure of rabbits to chronic hypoxia (FiO₂=0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide.

Results

We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.26±0.01 to 0.44±0.01, (b) PAP, and (c) the degree of muscularization from 14.0±4.0% to 43.5±5.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO.

Conclusion

We demonstrated (a) that the parameters characterizing hypoxia-induced pulmonary hypertension are not functionally linked, (b) that the downregulation of HPV under chronic hypoxia can be prevented by inhaled NO but not by sildenafil and iloprost, and (c) that iloprost is particularly effective in preventing vascular remodeling and sildenafil in preventing RVH.

KEYWORDS: Pulmonary hypertension, Right heart failure, Iloprost, NO, Sildenafil