This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fisch, A. Articles by Darius, H. Search for Related Content PubMed PubMed Citation Articles by Fisch, A. Articles by Darius, H.

(Circulation. 1997;96:756-760.)
© 1997 American Heart Association, Inc.

Articles

Prostacyclin Receptor Desensitization Is a Reversible Phenomenon in Human Platelets

Andreas Fisch, PhD; Karen Tobusch, BS; Kerstin Veit, MA; Jürgen Meyer, MD; ; Harald Darius, MD

From the Department of Medicine II, Johannes Gutenberg University, Mainz, Germany.

Correspondence to Harald Darius, MD, Department of Medicine II, Johannes Gutenberg University, 55101 Mainz, Germany. E-mail darius{at}2-med.klinik.uni-mainz.de

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 B_max 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.

Key Words: platelets • prostacyclin • receptors • platelet aggregation inhibitors • prostaglandins

This article has been cited by other articles:

				S. Zhang, H. H. Patel, F. Murray, C. V. Remillard, C. Schach, P. A. Thistlethwaite, Paul. A. Insel, and J. X.-J. Yuan Pulmonary artery smooth muscle cells from normal subjects and IPAH patients show divergent cAMP-mediated effects on TRPC expression and capacitative Ca2+ entry Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1202 - L1210. [Abstract] [Full Text] [PDF]

				P. Borgdorff, G. J. Tangelder, and W. J. Paulus Cyclooxygenase-2 Inhibitors Enhance Shear Stress-Induced Platelet Aggregation J. Am. Coll. Cardiol., August 15, 2006; 48(4): 817 - 823. [Abstract] [Full Text] [PDF]

				J. B. Park and N. Schoene Clovamide-Type Phenylpropenoic Acid Amides, N-Coumaroyldopamine and N-Caffeoyldopamine, Inhibit Platelet-Leukocyte Interactions via Suppressing P-Selectin Expression J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 813 - 819. [Abstract] [Full Text] [PDF]

				S. J. Wilson and E. M. Smyth Internalization and Recycling of the Human Prostacyclin Receptor Is Modulated through Its Isoprenylation-dependent Interaction with the {delta} Subunit of cGMP Phosphodiesterase 6 J. Biol. Chem., April 28, 2006; 281(17): 11780 - 11786. [Abstract] [Full Text] [PDF]

				F. ROSE, K. ZWICK, H. A. GHOFRANI, U. SIBELIUS, W. SEEGER, D. WALMRATH, and F. GRIMMINGER Prostacyclin Enhances Stretch-induced Surfactant Secretion in Alveolar Epithelial Type II Cells Am. J. Respir. Crit. Care Med., September 1, 1999; 160(3): 846 - 851. [Abstract] [Full Text]

				F. Neuschäfer-Rube, M. Oppermann, U. Möller, U. Böer, and G. P. Püschel Agonist-Induced Phosphorylation by G Protein-Coupled Receptor Kinases of the EP4 Receptor Carboxyl-Terminal Domain in an EP3/EP4 Prostaglandin E2 Receptor Hybrid Mol. Pharmacol., August 1, 1999; 56(2): 419 - 428. [Abstract] [Full Text]

				H. J. Rupprecht, H. Darius, U. Borkowski, T. Voigtlander, B. Nowak, S. Genth, and J. Meyer Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation Circulation, March 24, 1998; 97(11): 1046 - 1052. [Abstract] [Full Text] [PDF]