beta3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current.
beta3-adrenergic receptor (beta3-AR) activation produces a negative inotropic effect in human ventricles. Here we explored the role of beta3-AR in the human atrium. Unexpectedly, beta3-AR activation increased human atrial tissue contractility and stimulated the L-type Ca2+ channel current (I Ca,L) in isolated human atrial myocytes (HAMs). Right atrial tissue specimens were obtained from 57 patients undergoing heart surgery for congenital defects, coronary artery diseases, valve replacement, or heart transplantation. The I(Ca,L) and isometric contraction were recorded using a whole-cell patch-clamp technique and a mechanoelectrical force transducer. Two selective beta3-AR agonists, SR58611 and BRL37344, and a beta3-AR partial agonist, CGP12177, stimulated I(Ca,L) in HAMs with nanomolar potency and a 60%-90% efficacy compared with isoprenaline. The beta3-AR agonists also increased contractility but with a much lower efficacy (approximately 10%) than isoprenaline. The beta3-AR antagonist L-748,337, beta1-/beta2-AR antagonist nadolol, and beta1-/beta2-/beta3-AR antagonist bupranolol were used to confirm the involvement of beta3-ARs (and not beta1-/beta2-ARs) in these effects. The beta3-AR effects involved the cAMP/PKA pathway, since the PKA inhibitor H89 blocked I(Ca,L) stimulation and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) strongly increased the positive inotropic effect. Therefore, unlike in ventricular tissue, beta3-ARs are positively coupled to L-type Ca2+ channels and contractility in human atrial tissues through a cAMP-dependent pathway.
Skeberdis
V Arvydas
VA
Institute of Cardiology, Kaunas University of Medicine, Kaunas, Lithuania.
Gendviliene
Vida
V
Zablockaite
Danguole
D
Treinys
Rimantas
R
Macianskiene
Regina
R
Bogdelis
Andrius
A
Jurevicius
Jonas
J
Fischmeister
Rodolphe
R
D058667:Adrenergic beta-3 Receptor Agonists; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D018408:Patch-Clamp Techniques; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*
D058667:Adrenergic beta-3 Receptor Agonists; D020746:Calcium Channels, L-Type; D022702:Receptors, Adrenergic, beta-3; D009569:Nitric Oxide