Related Experiment Video
Updated: Jul 17, 2026
Isolated Lung Perfusion System in the Rabbit Model
Published on: July 15, 2021
Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs
Ralph T Schermuly1, Soni S Pullamsetti, Susanne C Breitenbach
1University of Giessen Lung Center, Medical Clinic II/V, Justus-Liebig-University Giessen, 35392 Giessen, Germany. Ralph.Schermuly@innere.med.uni-giessen.de
Background:
The rapid desensitization of the human prostacyclin (IP) in response to agonist binding has been shown in cell culture. Phosphorylation of the IP receptor by protein kinase C (PKC) has been suggested to be involved in this process.
Methods And Results:
In this study we investigated the vasodilatory effects of iloprost, a stable prostacyclin analogue, in perfused rabbit lungs. Continuous infusion of the thromboxane mimetic U46619 was employed to establish stable pulmonary hypertension. A complete loss of the vasodilatory response to iloprost was observed in experiments with continuous iloprost perfusion, maintaining the intravascular concentration of this prostanoid over a 180 min period. When lungs under chronic iloprost infusion were acutely challenged with inhaled iloprost, a corresponding complete loss of vasoreactivity was observed. This desensitization was not dependent on upregulation of cAMP-specific phosphodiesterases or changes in adenylate cyclase activity, as suggested by unaltered dose-response curves to agents directly affecting these enzymes. Application of a prostaglandin E1 receptor antagonist 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809) or the PKC inhibitor bisindolylmaleimide I (BIM) enhanced the vasodilatory response to infused iloprost and partially prevented tachyphylaxis.
Conclusion:
A three-hour infusion of iloprost in pulmonary hypertensive rabbit lungs results in complete loss of the lung vasodilatory response to this prostanoid. This rapid desensitization is apparently not linked to changes in adenylate cyclase and phosphodiesterase activation, but may involve PKC function and co-stimulation of the EP1 receptor in addition to the IP receptor by this prostacyclin analogue.
Insights
Continuous iloprost infusion in rabbit lungs caused a complete loss of vasodilatory response. This desensitization may involve protein kinase C (PKC) and EP1 receptor co-stimulation, not adenylate cyclase or phosphodiesterase changes.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Pulmonary Hypertension
Background:
- Prostacyclin (IP) receptor desensitization occurs rapidly after agonist binding.
- Protein kinase C (PKC) mediated phosphorylation is a suspected mechanism in IP receptor desensitization.
Purpose of the Study:
- To investigate the vasodilatory effects of iloprost in a rabbit lung model of pulmonary hypertension.
- To explore the mechanisms underlying rapid desensitization of the IP receptor to iloprost.
Main Methods:
- Utilized perfused rabbit lungs with induced pulmonary hypertension via U46619 infusion.
- Administered continuous and acute inhaled iloprost to assess vasodilatory response and desensitization.
- Investigated the roles of cAMP-specific phosphodiesterases, adenylate cyclase, PKC, and EP1 receptors.
Main Results:
- Complete loss of vasodilatory response to iloprost after 180 min of continuous infusion.
- Acute inhaled iloprost challenge also resulted in complete loss of vasoreactivity in chronically treated lungs.
- Desensitization was independent of adenylate cyclase and phosphodiesterase activity.
- PKC inhibition (BIM) and EP1 receptor antagonism (AH 6809) enhanced iloprost vasodilation and partially prevented desensitization.
Conclusions:
- Sustained iloprost infusion leads to rapid and complete loss of vasodilatory response in pulmonary hypertensive rabbit lungs.
- The observed desensitization is not mediated by changes in adenylate cyclase or phosphodiesterase activity.
- Protein kinase C (PKC) activation and potential EP1 receptor co-stimulation may play a role in iloprost-induced IP receptor desensitization.
