Activation of β ₂ -Adrenergic Receptors Hastens Relaxation and Mediates Phosphorylation of Phospholamban, Troponin I, and C-Protein in Ventricular Myocardium From Patients With Terminal Heart Failure

Abstract

Background-Catecholamines hasten cardiac relaxation through ␤-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 ␤ 1 -and ␤ 2 -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 (nϭ5) or ischemic cardiomyopathy (nϭ5), were paced at 60 bpm. After measurement of the contractile and relaxant effects of epinephrine (10 mol/L) or zinterol (10 mol/L), mediated through ␤ 2 -adrenergic receptors, and of norepinephrine (10 mol/L), mediated through ␤ 1 -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 15Ϯ3%, 5Ϯ2%, and 20Ϯ3%, respectively, and reduced the time to half-relaxation by 26Ϯ3%, 21Ϯ3%, and 37Ϯ3%. These effects of epinephrine, zinterol, and norepinephrine were associated with phosphorylation (pmol phosphate/mg protein) of phospholamban 14Ϯ3, 12Ϯ4, and 12Ϯ3; troponin I 40Ϯ7, 33Ϯ7, and 31Ϯ6; and C-protein 7.2Ϯ1.9, 9.3Ϯ1.4, and 7.5Ϯ2.0. Phosphorylation of phospholamban occurred at both Ser16 and Thr17 residues through both ␤ 1 -and ␤ 2 -adrenergic receptors. Conclusions-Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both ␤ 1 -and ␤ 2 -adrenergic receptors, thereby potentially improving diastolic function. (Circulation. 1999;99:65-72.)

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

“…In cardiomyocytes, the extrusion and sequestration of free calcium during diastole is dependent on cyclic AMP, is modulated by b-receptors, and is influenced by several ion transport mechanisms including the Na + /H + exchanger. [30][31][32][33][34][35][36] Cardiac b-receptors couple to a G-protein-stimulated adenylcyclase, which in turn stimulates cyclic AMP-dependent regulatory mechanisms. 30,31,33,37 Recent studies in rodent cardiomyocytes revealed that b 2 -receptors couple to G-proteins, which lead to inhibition of cyclic AMP formation downstream.…”

Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-α

“…Data were acquired using an IonOptix setup and analyzed with IonWizard 5.0 software (IonOptix, Milton, MA). Cross-sectional area (CSA) of the atrium was determined from the length and weight of the muscle after the experiment, assuming a density of 1.063 (26).…”

Epinephrine Activates Both Gs and Gi Pathways, but Norepinephrine Activates Only the Gs Pathway through Human β2-Adrenoceptors Overexpressed in Mouse Heart

“…␤ 2 -Adrenoceptors participate with ␤ 1 -adrenoceptors in the mediation of cardiostimulant effects of epinephrine in human atrium (Gille et al, 1985;Hall et al, 1990;Kaumann et al, 1999), ventricle (Kaumann and Lemoine 1987;Gille et al, 1985;Bristow et al, 1989;Kaumann et al, 1999;Del Monte et al, 1993;Molenaar et al, 2000), and sinoatrial node (Daul et al, 1995). Norepinephrine can also cause cardiostimulation through human ␤ 2 -adrenoceptors (Kaumann and Lemoine, 1987;Hall et al, 1990).…”