Activation of beta2-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 beta-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 beta1- and beta2-adrenergic receptors in phosphorylating proteins implicated in ventricular relaxation.


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 micromol/L) or zinterol (10 micromol/L), mediated through beta2-adrenergic receptors, and of norepinephrine (10 micromol/L), mediated through beta1-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 beta1- and beta2-adrenergic receptors.


CONCLUSIONS
Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both beta1- and beta2-adrenergic receptors, thereby potentially improving diastolic function.
Kaumann
A
A
Babraham Institute, Cambridge, UK. alberto.kaumann@bbsrc.ac.uk
Bartel
S
S
Molenaar
P
P
Sanders
L
L
Burrell
K
K
Vetter
D
D
Hempel
P
P
Karczewski
P
P
Krause
E G
EG
D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D002118:Calcium / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004837:Epinephrine / Q000627:therapeutic use; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D009638:Norepinephrine / Q000627:therapeutic use; D010766:Phosphorylation; D013727:Terminal Care / Q000379:methods; D019210:Troponin I / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use*; D000099211:Phospholamban
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004837:Epinephrine; D009638:Norepinephrine; D019210:Troponin I; D014665:Vasodilator Agents; D000099211:Phospholamban; C020723:citrate-binding transport protein