(Circulation. 1999;99:65-72.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Activation of ß2-Adrenergic Receptors Hastens Relaxation and Mediates Phosphorylation of Phospholamban, Troponin I, and C-Protein in Ventricular Myocardium From Patients With Terminal Heart Failure
From the Babraham Institute, Cambridge, UK (A.K., L.S.); Department of Pharmacology, University of Melbourne, Victoria, Australia (P.M., K.B.); and Max-Delbrück Centre of Molecular Medicine, Cardiology, Berlin, Germany (S.B., D.V., P.H., P.K., E.-G.K.).
Correspondence to Alberto Kaumann, MD, PhD, Babraham Institute, Cambridge CB2 4AT, United Kingdom. E-mail alberto.kaumann{at}bbsrc.ac.uk
Background—Catecholamines hasten cardiac relaxation through ß-adrenergic receptors, presumably by phosphorylation of several proteins, but it is unknown which receptor subtypes are involved in human ventricle. We assessed the role of ß1- and ß2-adrenergic receptors in phosphorylating proteins implicated in ventricular relaxation.
Methods and Results—Right ventricular trabeculae, obtained from freshly explanted hearts of patients with dilated cardiomyopathy (n=5) or ischemic cardiomyopathy (n=5), were paced at 60 bpm. After measurement of the contractile and relaxant effects of epinephrine (10 µmol/L) or zinterol (10 µmol/L), mediated through ß2-adrenergic receptors, and of norepinephrine (10 µmol/L), mediated through ß1-adrenergic receptors, tissues were freeze clamped. We assessed phosphorylation of phospholamban, troponin I, and C-protein, as well as specific phosphorylation of phospholamban at serine 16 and threonine 17. Data did not differ between the 2 disease groups and were therefore pooled. Epinephrine, zinterol, and norepinephrine increased contractile force to approximately the same extent, hastened the onset of relaxation by 15±3%, 5±2%, and 20±3%, respectively, and reduced the time to half-relaxation by 26±3%, 21±3%, and 37±3%. These effects of epinephrine, zinterol, and norepinephrine were associated with phosphorylation (pmol phosphate/mg protein) of phospholamban 14±3, 12±4, and 12±3; troponin I 40±7, 33±7, and 31±6; and C-protein 7.2±1.9, 9.3±1.4, and 7.5±2.0. Phosphorylation of phospholamban occurred at both Ser16 and Thr17 residues through both ß1- and ß2-adrenergic receptors.
Conclusions—Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both ß1- and ß2-adrenergic receptors, thereby potentially improving diastolic function.
Key Words: heart failure • receptors, adrenergic, beta 2 • catecholamines • phosphoproteins • contractility, diastole
This article has been cited by other articles:
 |
|
 |
|
  J. DeSantiago, X. Ai, M. Islam, G. Acuna, M. T. Ziolo, D. M. Bers, and S. M. Pogwizd Arrhythmogenic Effects of {beta}2-Adrenergic Stimulation in the Failing Heart Are Attributable to Enhanced Sarcoplasmic Reticulum Ca Load Circ. Res., June 6, 2008; 102(11): 1389 - 1397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Ryall, J. D. Schertzer, K. T. Murphy, A. M. Allen, and G. S. Lynch Chronic {beta}2-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca2+-ATPase protein and activity Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2587 - H2595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Rhodes, K. M. Ropella, A. K. S. Camara, Q. Chen, M. L. Riess, P. S. Pagel, and D. F. Stowe Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts J Appl Physiol, March 1, 2006; 100(3): 940 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Molenaar, T. Christ, U. Ravens, and A. Kaumann Carvedilol blocks {beta}2- more than {beta}1-adrenoceptors in human heart Cardiovasc Res, January 1, 2006; 69(1): 128 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Saba, A. M. Janczewski, L. C. Baker, V. Shusterman, E. C. Gursoy, A. M. Feldman, G. Salama, C. F. McTiernan, and B. London Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha} Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1456 - H1467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Heubach, U. Ravens, and A. J. Kaumann Epinephrine Activates Both Gs and Gi Pathways, but Norepinephrine Activates Only the Gs Pathway through Human {beta}2-Adrenoceptors Overexpressed in Mouse Heart Mol. Pharmacol., May 1, 2004; 65(5): 1313 - 1322. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Foerster, F. Groner, J. Matthes, W. J. Koch, L. Birnbaumer, and S. Herzig Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through {beta}2-adrenoceptors PNAS, November 25, 2003; 100(24): 14475 - 14480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bartel, E.-G. Krause, G. Wallukat, and P. Karczewski New insights into {beta}2-adrenoceptor signaling in the adult rat heart Cardiovasc Res, March 1, 2003; 57(3): 694 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Kilts, T. Akazawa, M. D. Richardson, and M. M. Kwatra Age Increases Cardiac Galpha i2 Expression, Resulting in Enhanced Coupling to G Protein-coupled Receptors J. Biol. Chem., August 16, 2002; 277(34): 31257 - 31262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.-P. Xiao {beta}-Adrenergic Signaling in the Heart: Dual Coupling of the {beta}2-Adrenergic Receptor to Gs and Gi Proteins Sci. Signal., October 16, 2001; 2001(104): re15 - re15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Devic, Y. Xiang, D. Gould, and B. Kobilka beta -Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from beta 1 and beta 2 Adrenoceptor Knockout Mice Mol. Pharmacol., September 1, 2001; 60(3): 577 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M D Lowe, E Rowland, M J Brown, and A A Grace {beta}2 Adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium Heart, July 1, 2001; 86(1): 45 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Molenaar, S. Bartel, A. Cochrane, D. Vetter, H. Jalali, P. Pohlner, K. Burrell, P. Karczewski, E.-G. Krause, and A. Kaumann Both {beta}2- and {beta}1-Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of {beta}2-Adrenergic Receptors to Gs-Protein Circulation, October 10, 2000; 102(15): 1814 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Shan, R. J. Bick, B. J. Poindexter, S. Shimoni, G. V. Letsou, M. J. Reardon, J. F. Howell, W. A. Zoghbi, and S. F. Nagueh Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans J. Am. Coll. Cardiol., September 1, 2000; 36(3): 891 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Isaaz What are we actually measuring by Doppler tissue imaging? J. Am. Coll. Cardiol., September 1, 2000; 36(3): 897 - 899. [Full Text] [PDF]
|
|
|
|
|
|
H. K. Ranu, J. C. W. Mak, P. J. Barnes, and S. E. Harding Gi-dependent suppression of beta 1-adrenoceptor effects in ventricular myocytes from NE-treated guinea pigs Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1807 - H1814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Burrell, P. Molenaar, P. J. Dawson, and A. J. Kaumann Contractile and Arrhythmic Effects of Endothelin Receptor Agonists in Human Heart In Vitro: Blockade with SB 209670 J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 449 - 459. [Abstract] [Full Text]
|
|
|
|
|
|
K. Yuasa, H. Michibata, K. Omori, and N. Yanaka A Novel Interaction of cGMP-dependent Protein Kinase I with Troponin T J. Biol. Chem., December 24, 1999; 274(52): 37429 - 37434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.-P. Xiao, H. Cheng, Y.-Y. Zhou, M. Kuschel, and E. G. Lakatta Recent Advances in Cardiac {beta}2-Adrenergic Signal Transduction Circ. Res., November 26, 1999; 85(11): 1092 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kuschel, Y.-Y. Zhou, H. Cheng, S.-J. Zhang, Y. Chen, E. G. Lakatta, and R.-P. Xiao Gi Protein-mediated Functional Compartmentalization of Cardiac beta 2-Adrenergic Signaling J. Biol. Chem., July 30, 1999; 274(31): 22048 - 22052. [Abstract] [Full Text] [PDF]
|
|