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Respiratory Research Biomed Central Respiratory Research BioMed Central Research Open Access Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs Ralph T Schermuly*1, Soni S Pullamsetti1, Susanne C Breitenbach1, Norbert Weissmann1, Hossein A Ghofrani1, Friedrich Grimminger1, Sigrid M Nilius2, Karsten Schrör2, Jutta Meger-Kirchrath2, Werner Seeger1 and Frank Rose1 Address: 1University of Giessen Lung Center (UGLC), Medical Clinic II/V, Justus-Liebig-University Giessen, 35392 Giessen, Germany and 2Institut fuer Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universitaet Duesseldorf, 40225 Duesseldorf, Germany Email: Ralph T Schermuly* - [email protected]; Soni S Pullamsetti - [email protected]; Susanne C Breitenbach - [email protected]; Norbert Weissmann - [email protected] giessen.de; Hossein A Ghofrani - [email protected]; Friedrich Grimminger - [email protected]; Sigrid M Nilius - [email protected]; Karsten Schrör - [email protected]; Jutta M Kirchrath - [email protected]; Werner Seeger - [email protected] giessen.de; Frank Rose - [email protected] * Corresponding author Published: 26 January 2007 Received: 24 February 2006 Accepted: 26 January 2007 Respiratory Research 2007, 8:4 doi:10.1186/1465-9921-8-4 This article is available from: http://respiratory-research.com/content/8/1/4 © 2007 Schermuly et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract 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. Page 1 of 13 (page number not for citation purposes) Respiratory Research 2007, 8:4 http://respiratory-research.com/content/8/1/4 Background vasodilatory response to PGI2 and its analogues [28-30]. Prostacyclin (PGI2) is the major product of cyclooxygen- In the present study, we employed the model of pulmo- ases (COX) in the vascular endothelium and mediates nary hypertensive perfused rabbit lungs to investigate the potent anti-platelet, vasodilator, and anti-inflammatory dose-response relationship and features of tolerance actions by a prostacyclin receptor (IP) [1]. This receptor is development upon continuous iloprost infusion in the a member of the G protein-coupled receptor (GPCR) intact lung vasculature. superfamily and is coupled to adenylate cyclase (AC) and phospholipase C (PLC) [2-4]. The prostanoid receptors Materials and methods are classified into DP, IP, EP (EP 1–4), FP and TP receptors Materials [5-7] with different affinities for agonists and different Sterile Krebs-Henseleit buffer (KHB) was obtained from roles in signal transduction. The IP, EP2, EP4 and DP Serag-Wiessner (Naila, Germany). The thromboxane-A2 receptors are coupled to stimulation of adenylate cyclase, mimetic U46619 was supplied by Paesel-Lorei (Frankfurt, while the TP, EP1 and FP receptors are coupled to Ca2+ Germany) and iloprost by Schering (Berlin, Germany). All mobilization. The EP3 receptor is an alternative spliced other chemicals were purchased from Merck (Darmstadt, gene, with at least 8 isoforms identified so far. Depending Germany). on the subtype, this receptor can be negatively or posi- tively coupled to Gs [8,9]. Agonist (PGI2 or PGI2 mimetics Isolated lung model such as cicaprost, iloprost, carbacyclin, and prostaglandin The perfused rabbit lung model has previously been E1)-binding to the IP receptor leads to activation of pro- described in detail [31]. Briefly, rabbits of either sex tein kinase A (PKA) by cyclic adenosine monophosphate weighing 2.6 to 2.9 kg were anticoagulated with heparin (cAMP) [10]. Although, the above mentioned agonist spe- (1000 U/kg) and anaesthetized with intravenous keta- cificities for IP receptors vary and none of them were mine/xylazine. Tracheostomy was performed and the ani- highly selective for IP receptors alone. The affinity of cic- mals were ventilated with room air. After mid-sternal aprost for human IP receptors is merely 3-fold higher than thoracotomy, catheters were placed into the pulmonary for the prostaglandin E2 EP4 subtype of receptor, which artery and the left atrium, and perfusion with KHB was also couples to Gs [11], and only 17-fold higher than for started. For washout of blood, perfusate was initially not the EP3 receptor in the mouse [12]. Iloprost is equipotent recirculated and the lungs were removed without inter- at both human and mouse IP and EP1 receptors, and car- ruption of ventilation and perfusion. The lungs were bacyclin and prostaglandin E1 show even greater affinity placed in a temperature-equilibrated chamber at 37.5°C, for EP3 than for IP receptors [11,12]. freely suspended from a force transducer for monitoring of organ weight. In a recirculating system the flow was Disturbances to PGI2 synthesis [13,14], as well as poly- slowly increased to 120 ml/min (total volume 350 ml). morphisms of the PGI2-synthase (PGIS) [15], have been Left atrial pressure was set at 2 mmHg in all experiments. linked to severe pulmonary hypertension. Substitution of In parallel with onset of artificial perfusion, an air mixture PGI2, either by overexpression of the PGIS [16] in an of 80.5% N2, 15% O2 and 4.5% CO2 was used for ventila- experimental model or by application of PGI2 [17,18] or tion. Tidal volume (11 ml/kg) and frequency (10 – 13 its analogues iloprost [19,20] or beraprost [21,22] in breaths/min) were adapted to maintain the pH of the patients decreases pulmonary artery pressure. However, recirculating buffer in the range between 7.35 and 7.37. A tolerance of the lung vasodilatory response to continu- positive end-expiratory pressure of 1 mmHg was used ously infused PGI2 rapidly develops in patients with throughout. The PO2 and PCO2 values in the post-lung severe pulmonary hypertension, and dose adjustments buffer fluid ranged between 100 and 120 mmHg and 38 have to be made [17,23]. In COPD patients with pulmo- and 43 mmHg, respectively. Pressures in the pulmonary nary hypertension, the pulmonary vasodilatory response artery, the left atrium and the trachea were registered by to continuously infused PGI2 was found to dissipate means of small diameter tubing threaded into the per- within 24 h [24]. Marked tolerance to the anti-mitogenic fusion catheters and the trachea and connected to pressure actions of PGI2 developed within 24 h in coronary artery transducers (zero referenced at the hilum). The whole sys- smooth muscle cells [25]. Basic studies demonstrated that tem was heated to 37.5°C. desensitization of the IP receptor occurs within minutes after exposure to agonists and is due to agonist-induced Lungs included in the study had 1) a homogeneous white receptor phosphorylation, mainly mediated by PKC [26], appearance with no signs of hemostasis, edema or atel- with subsequent sequestration of the intact receptor and ectasis; 2) pulmonary artery and ventilation pressures in removal from the cell surface [26,27]. In addition, there is the normal range; and were 3) isogravimetric (lung weight evidence for changes in adenylate cyclase and phosphodi- gain < 0.2 g/h) during an initial steady state period of at esterase (PDE) activation occurring in response to IP least 45–60 min. receptor stimulation, which may contribute to loss of the Page 2 of 13 (page number not for citation purposes) Respiratory Research 2007, 8:4 http://respiratory-research.com/content/8/1/4 Experimental protocols injection of 200 ng, followed by a continuous infusion of Isolated lung experiments 33 ng/kg/h. 240 min after starting the iloprost infusion, As described
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