β3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current
- 1 August 2008
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (9), 3219-3227
- https://doi.org/10.1172/jci32519
Abstract
β3-adrenergic receptor (β3-AR) activation produces a negative inotropic effect in human ventricles. Here we explored the role of β3-AR in the human atrium. Unexpectedly, β3-AR activation increased human atrial tissue contractility and stimulated the L-type Ca2+ channel current (ICa,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 ICa,L and isometric contraction were recorded using a whole-cell patch-clamp technique and a mechanoelectrical force transducer. Two selective β3-AR agonists, SR58611 and BRL37344, and a β3-AR partial agonist, CGP12177, stimulated ICa,L in HAMs with nanomolar potency and a 60%–90% efficacy compared with isoprenaline. The β3-AR agonists also increased contractility but with a much lower efficacy (~10%) than isoprenaline. The β3-AR antagonist L-748,337, β1-/β2-AR antagonist nadolol, and β1-/β2-/β3-AR antagonist bupranolol were used to confirm the involvement of β3-ARs (and not β1-/β2-ARs) in these effects. The β3-AR effects involved the cAMP/PKA pathway, since the PKA inhibitor H89 blocked ICa,L stimulation and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) strongly increased the positive inotropic effect. Therefore, unlike in ventricular tissue, β3-ARs are positively coupled to L-type Ca2+ channels and contractility in human atrial tissues through a cAMP-dependent pathway.Keywords
This publication has 81 references indexed in Scilit:
- Enhanced Inhibition of L-type Ca2+ Current by β3-Adrenergic Stimulation in Failing Rat HeartJournal of Pharmacology and Experimental Therapeutics, 2005
- Endogenous β3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failureAmerican Journal of Physiology-Heart and Circulatory Physiology, 2004
- Immunohistochemical identification of the β3-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeineInternational Journal of Obesity, 2002
- Physiological antagonism between ventricular β1‐adrenoceptors and α1‐adrenoceptors but no evidence for β2‐ and β3‐adrenoceptor function in murine heartBritish Journal of Pharmacology, 2002
- β -Adrenergic Cardiac Hypertrophy is Mediated Primarily by the β1-Subtype in the Rat HeartJournal of Molecular and Cellular Cardiology, 2001
- The tissue distribution of the human β3-adrenoceptor studied using a monoclonal antibody: Direct evidence of the β3-adrenoceptor in human adipose tissue, atrium and skeletal muscleInternational Journal of Obesity, 1999
- β3-Adrenergic activation of adenylyl cyclase in mouse white adipocytes: modulation by GTP and effect of obesityJournal of Cellular Biochemistry, 1995
- Nitric oxide regulates the calcium current in isolated human atrial myocytes.JCI Insight, 1995
- Evidence against spare or uncoupled β-adrenoceptors in the human heartAmerican Heart Journal, 1990
- Discrepancies between the affinities of binding and action of the novel β-adrenergic agonist BRL 37344 in rat brown adipose tissueBiochemical and Biophysical Research Communications, 1988