Hypoxia-induced pulmonary hypertension: different impact of iloprost, sildenafil, and nitric oxide.
OBJECTIVE
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 (FiO(2)=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.


CONCLUSIONS
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.
Weissmann
Norbert
N
University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig University Giessen, Klinikstrasse 36, 35392 Giessen, Germany. Norbert.Weissmann@innere.med.uni-giessen.de
Gerigk
Boris
B
Kocer
Ozlem
O
Nollen
Matthias
M
Hackemack
Sascha
S
Ghofrani
Hossein Ardeschir
HA
Schermuly
Ralph Theo
RT
Butrous
Ghazwan
G
Schulz
Andreas
A
Roth
Markus
M
Seeger
Werner
W
Grimminger
Friedrich
F
D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D016285:Iloprost / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D016285:Iloprost