Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs.
Ralph T Schermuly, Soni S Pullamsetti, Susanne C Breitenbach, Norbert Weissmann, Hossein A Ghofrani, Friedrich Grimminger, Sigrid M Nilius, Karsten Schrör, Jutta M Kirchrath, Werner Seeger, Frank Rose
University of Giessen Lung Center, Medical Clinic II/V, Justus-Liebig-University Giessen, 35392 Giessen, Germany. Ralph.Schermuly@innere.med.uni-giessen.de
Respiratory research 2007The 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. 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. 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.
Citation
Ralph T Schermuly, Soni S Pullamsetti, Susanne C Breitenbach, Norbert Weissmann, Hossein A Ghofrani, Friedrich Grimminger, Sigrid M Nilius, Karsten Schrör, Jutta M Kirchrath, Werner Seeger, Frank Rose. Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs. Respiratory research. 2007;8:4
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PMID: 17257398
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