Activation of b2-Adrenergic Receptors Hastens Relaxation and Mediates Phosphorylation of Phospholamban, Troponin I, and C-Protein in Ventricular Myocardium From Patients With Terminal Heart Failure

Background—Catecholamines hasten cardiac relaxation through b-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 b1and b2-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 (n55) or ischemic cardiomyopathy (n55), were paced at 60 bpm. After measurement of the contractile and relaxant effects of epinephrine (10 mmol/L) or zinterol (10 mmol/L), mediated through b2-adrenergic receptors, and of norepinephrine (10 mmol/L), mediated through b1-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 1563%, 562%, and 2063%, respectively, and reduced the time to half-relaxation by 2663%, 2163%, and 3763%. These effects of epinephrine, zinterol, and norepinephrine were associated with phosphorylation (pmol phosphate/mg protein) of phospholamban 1463, 1264, and 1263; troponin I 4067, 3367, and 3166; and C-protein 7.261.9, 9.361.4, and 7.562.0. Phosphorylation of phospholamban occurred at both Ser16 and Thr17 residues through both b1and b2-adrenergic receptors. Conclusions—Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both b1and b2-adrenergic receptors, thereby potentially improving diastolic function. (Circulation. 1999;99:65-72.)