Activation of beta(2)-adrenergic receptors hastens relaxation and mediatesphosphorylation of phospholamban, troponin I, and C-protein in ventricularmyocardium from patients with terminal heart failure

Background-Catecholamines hasten cardiac relaxation through beta-adrenergic receptors, presumably by phosphorylation of several proteins, but it is un known which receptor subtypes are involved in human ventricle. We assessed the role of beta(1)- and beta(2)-adrenergic receptors in phosphorylating pr oteins implicated in ventricular relaxation. Methods and Results-Right ventricular trabeculae, obtained from freshly exp lanted hearts of patients with dilated cardiomyopathy (n=5) or ischemic car diomyopathy (n=5), were paced at 60 bpm. After measurement of the contracti le and relaxant effects of epinephrine (10 mu mol/L) or zinterol (10 mu mol /L), mediated through beta(2)-adrenergic receptors, and of norepinephrine ( 10 mu mol/L), mediated through beta(1)-adrenergic receptors, tissues were f reeze clamped. We assessed phosphorylation of phospholamban, troponin I, an d 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 r elaxation by 15+/-3%, 5+/-2%, and 20+/-3%, respectively, and reduced the ti me to half-relaxation by 26+/-3%, 21+/-3%, and 37+/-3%. These effects of ep inephrine, zinterol, and norepinephrine were associated with phosphorylatio n (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 beta(1)- and beta(2)-adrenergic receptors. Conclusions-Norepinephrine and epinephrine hasten human ventricular relaxat ion and promote phosphorylation of implicated proteins through both beta(1) - and beta(2)-adrenergic receptors, thereby potentially improving diastolic function.