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Friedrich Grimminger - One of the best experts on this subject based on the ideXlab platform.
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Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs
Respiratory Research, 2007Co-Authors: Ralph T Schermuly, Susanne C Breitenbach, Sigrid M Nilius, Jutta Meger-kirchrath, Soni Savai Pullamsetti, Friedrich Grimminger, Norbert Weissmann, Karsten Schror, Hossein Ardeschir Ghofrani, Werner SeegerAbstract:BackgroundThe 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 resultsIn 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.ConclusionA 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.
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Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension
American journal of respiratory and critical care medicine, 2005Co-Authors: Ralph T Schermuly, Soni Savai Pullamsetti, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Hüseyin Yilmaz, Kathrin Woyda, Tobias Gessler, Rio Dumitrascu, Friedrich GrimmingerAbstract:Rationale: Inhaled Iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled Iloprost on changes to pulmonary vascular structure that occur in PAH. Objectives: The present study was designed to investigate chronic antiremodeling effects of inhaled Iloprost in monocrotaline (MCT)-induced PAH in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with Iloprost at a dose of 6 μg · kg–1 · day–1, or underwent sham nebulization with saline. Results: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with Iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to Iloprost. Furthermore, the MC...
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inhaled Iloprost is a potent acute pulmonary vasodilator in hiv related severe pulmonary hypertension
European Respiratory Journal, 2004Co-Authors: Hossein Ardeschir Ghofrani, Ralph T Schermuly, Friedrich Grimminger, Norbert Weissmann, Werner Seeger, Horst Olschewski, Georg Friese, T Discher, Jurgen LohmeyerAbstract:As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue Iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled Iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised Iloprost was investigated. Four patients underwent long-term treatment with inhaled Iloprost. The rank order of pulmonary vasodilatory potency was Iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled Iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled Iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled Iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.
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Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Ralph T Schermuly, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Arne Meidow, Frank Rose, Axel Roehl, Michael E. Hildebrand, Julia Kurz, Friedrich GrimmingerAbstract:Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized Iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized Iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of Iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life ∼3.5 h), mostly attributable to progressive metabolism to dinor- and tetranorIloprost. Inhaled Iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability ∼63%). Compared with infused Iloprost, significantly more rapid metabolism to dinor- and tetranorIloprost was noted for Iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact Iloprost displays the same clearance rate as directly perfusate-admixed prostanoid. We conclude that a high percentage of inhaled Iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing Iloprost via β-oxidation, and more rapid appearance of dinor- and tetranorIloprost is noted for the inhalative as compared with the intravascular route of Iloprost administration.
Ralph T Schermuly - One of the best experts on this subject based on the ideXlab platform.
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Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs
Respiratory Research, 2007Co-Authors: Ralph T Schermuly, Susanne C Breitenbach, Sigrid M Nilius, Jutta Meger-kirchrath, Soni Savai Pullamsetti, Friedrich Grimminger, Norbert Weissmann, Karsten Schror, Hossein Ardeschir Ghofrani, Werner SeegerAbstract:BackgroundThe 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 resultsIn 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.ConclusionA 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.
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Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension
American journal of respiratory and critical care medicine, 2005Co-Authors: Ralph T Schermuly, Soni Savai Pullamsetti, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Hüseyin Yilmaz, Kathrin Woyda, Tobias Gessler, Rio Dumitrascu, Friedrich GrimmingerAbstract:Rationale: Inhaled Iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled Iloprost on changes to pulmonary vascular structure that occur in PAH. Objectives: The present study was designed to investigate chronic antiremodeling effects of inhaled Iloprost in monocrotaline (MCT)-induced PAH in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with Iloprost at a dose of 6 μg · kg–1 · day–1, or underwent sham nebulization with saline. Results: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with Iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to Iloprost. Furthermore, the MC...
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inhaled Iloprost is a potent acute pulmonary vasodilator in hiv related severe pulmonary hypertension
European Respiratory Journal, 2004Co-Authors: Hossein Ardeschir Ghofrani, Ralph T Schermuly, Friedrich Grimminger, Norbert Weissmann, Werner Seeger, Horst Olschewski, Georg Friese, T Discher, Jurgen LohmeyerAbstract:As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue Iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled Iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised Iloprost was investigated. Four patients underwent long-term treatment with inhaled Iloprost. The rank order of pulmonary vasodilatory potency was Iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled Iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled Iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled Iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.
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Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Ralph T Schermuly, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Arne Meidow, Frank Rose, Axel Roehl, Michael E. Hildebrand, Julia Kurz, Friedrich GrimmingerAbstract:Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized Iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized Iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of Iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life ∼3.5 h), mostly attributable to progressive metabolism to dinor- and tetranorIloprost. Inhaled Iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability ∼63%). Compared with infused Iloprost, significantly more rapid metabolism to dinor- and tetranorIloprost was noted for Iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact Iloprost displays the same clearance rate as directly perfusate-admixed prostanoid. We conclude that a high percentage of inhaled Iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing Iloprost via β-oxidation, and more rapid appearance of dinor- and tetranorIloprost is noted for the inhalative as compared with the intravascular route of Iloprost administration.
Hossein Ardeschir Ghofrani - One of the best experts on this subject based on the ideXlab platform.
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Long-term outcome with intravenous Iloprost in pulmonary arterial hypertension
The European respiratory journal, 2009Co-Authors: Marius M. Hoeper, Hossein Ardeschir Ghofrani, H Gall, H. J. Seyfarth, Michael Halank, J. Winkler, Heiko Golpon, Karen M. Olsson, Nils Nickel, Christian OpitzAbstract:There is limited data on the long-term efficacy of intravenous Iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. Iloprost, in most cases after having received inhaled Iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. Iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn·s·cm −5 at the time of diagnosis and of 1,858 dyn·s·cm −5 at the onset of i.v. Iloprost therapy. Introduction of i.v. Iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. Iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. Iloprost therapy was limited.
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Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs
Respiratory Research, 2007Co-Authors: Ralph T Schermuly, Susanne C Breitenbach, Sigrid M Nilius, Jutta Meger-kirchrath, Soni Savai Pullamsetti, Friedrich Grimminger, Norbert Weissmann, Karsten Schror, Hossein Ardeschir Ghofrani, Werner SeegerAbstract:BackgroundThe 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 resultsIn 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.ConclusionA 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.
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Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension
American journal of respiratory and critical care medicine, 2005Co-Authors: Ralph T Schermuly, Soni Savai Pullamsetti, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Hüseyin Yilmaz, Kathrin Woyda, Tobias Gessler, Rio Dumitrascu, Friedrich GrimmingerAbstract:Rationale: Inhaled Iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled Iloprost on changes to pulmonary vascular structure that occur in PAH. Objectives: The present study was designed to investigate chronic antiremodeling effects of inhaled Iloprost in monocrotaline (MCT)-induced PAH in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with Iloprost at a dose of 6 μg · kg–1 · day–1, or underwent sham nebulization with saline. Results: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with Iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to Iloprost. Furthermore, the MC...
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inhaled Iloprost is a potent acute pulmonary vasodilator in hiv related severe pulmonary hypertension
European Respiratory Journal, 2004Co-Authors: Hossein Ardeschir Ghofrani, Ralph T Schermuly, Friedrich Grimminger, Norbert Weissmann, Werner Seeger, Horst Olschewski, Georg Friese, T Discher, Jurgen LohmeyerAbstract:As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue Iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled Iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised Iloprost was investigated. Four patients underwent long-term treatment with inhaled Iloprost. The rank order of pulmonary vasodilatory potency was Iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled Iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled Iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled Iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.
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Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Ralph T Schermuly, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Arne Meidow, Frank Rose, Axel Roehl, Michael E. Hildebrand, Julia Kurz, Friedrich GrimmingerAbstract:Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized Iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized Iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of Iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life ∼3.5 h), mostly attributable to progressive metabolism to dinor- and tetranorIloprost. Inhaled Iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability ∼63%). Compared with infused Iloprost, significantly more rapid metabolism to dinor- and tetranorIloprost was noted for Iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact Iloprost displays the same clearance rate as directly perfusate-admixed prostanoid. We conclude that a high percentage of inhaled Iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing Iloprost via β-oxidation, and more rapid appearance of dinor- and tetranorIloprost is noted for the inhalative as compared with the intravascular route of Iloprost administration.
Harald Darius - One of the best experts on this subject based on the ideXlab platform.
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Prostacyclin Receptor Desensitization Is a Reversible Phenomenon in Human Platelets
Circulation, 1997Co-Authors: Andreas Fisch, Karen Tobusch, K. Veit, Jürgen Meyer, Harald DariusAbstract:BACKGROUND: Long-term exposure of platelets to endogenous or exogenous prostacyclin or its analogues might result in desensitization of the platelet prostacyclin receptor in vitro and in vivo accompanied by a loss in receptor density on the platelet surface and a reduced sensitivity toward the inhibitory effects of prostacyclins. However, the reversibility of this process in platelets has not yet been investigated. METHODS AND RESULTS: Human platelets desensitized by the chemically stable prostacyclin analogue Iloprost showed a significant reduction in [3H]-Iloprost binding sites that was reversed by saponin permeabilization. This indicates functionally active internalized prostacyclin receptors. To assess whether the internalized prostacyclin receptors recycle to the cell surface after withdrawal of the agonist, Iloprost sensitivity and prostacyclin receptor binding properties of Iloprost (30 nmol/L, 2 hours) desensitized platelets incubated in Iloprost-free autologous plasma were investigated. While desensitized platelets showed a significant increase in IC50 for Iloprost inhibition of thrombin-induced platelet aggregation, serotonin release, and p-selectin expression and a reduced Iloprost-stimulated cAMP formation, platelet Iloprost sensitivity was restored 3 hours after Iloprost withdrawal. In addition, the significant reduction in Bmax and the increase in K(D) of prostacyclin receptors in desensitized platelets as revealed by [3H]-Iloprost binding studies also returned to the initial values. CONCLUSIONS: These results indicate that prostacyclin receptors internalized during short-term desensitization are not degraded but can be recycled rapidly to the platelet surface in a functionally active form after withdrawal of the agonist.
Norbert Weissmann - One of the best experts on this subject based on the ideXlab platform.
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Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs
Respiratory Research, 2007Co-Authors: Ralph T Schermuly, Susanne C Breitenbach, Sigrid M Nilius, Jutta Meger-kirchrath, Soni Savai Pullamsetti, Friedrich Grimminger, Norbert Weissmann, Karsten Schror, Hossein Ardeschir Ghofrani, Werner SeegerAbstract:BackgroundThe 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 resultsIn 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.ConclusionA 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.
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Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension
American journal of respiratory and critical care medicine, 2005Co-Authors: Ralph T Schermuly, Soni Savai Pullamsetti, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Hüseyin Yilmaz, Kathrin Woyda, Tobias Gessler, Rio Dumitrascu, Friedrich GrimmingerAbstract:Rationale: Inhaled Iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled Iloprost on changes to pulmonary vascular structure that occur in PAH. Objectives: The present study was designed to investigate chronic antiremodeling effects of inhaled Iloprost in monocrotaline (MCT)-induced PAH in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with Iloprost at a dose of 6 μg · kg–1 · day–1, or underwent sham nebulization with saline. Results: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with Iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to Iloprost. Furthermore, the MC...
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inhaled Iloprost is a potent acute pulmonary vasodilator in hiv related severe pulmonary hypertension
European Respiratory Journal, 2004Co-Authors: Hossein Ardeschir Ghofrani, Ralph T Schermuly, Friedrich Grimminger, Norbert Weissmann, Werner Seeger, Horst Olschewski, Georg Friese, T Discher, Jurgen LohmeyerAbstract:As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue Iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled Iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised Iloprost was investigated. Four patients underwent long-term treatment with inhaled Iloprost. The rank order of pulmonary vasodilatory potency was Iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled Iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled Iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled Iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.
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Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Ralph T Schermuly, Norbert Weissmann, Hossein Ardeschir Ghofrani, Andreas Schulz, Arne Meidow, Frank Rose, Axel Roehl, Michael E. Hildebrand, Julia Kurz, Friedrich GrimmingerAbstract:Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized Iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized Iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of Iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life ∼3.5 h), mostly attributable to progressive metabolism to dinor- and tetranorIloprost. Inhaled Iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability ∼63%). Compared with infused Iloprost, significantly more rapid metabolism to dinor- and tetranorIloprost was noted for Iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact Iloprost displays the same clearance rate as directly perfusate-admixed prostanoid. We conclude that a high percentage of inhaled Iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing Iloprost via β-oxidation, and more rapid appearance of dinor- and tetranorIloprost is noted for the inhalative as compared with the intravascular route of Iloprost administration.
