Dihydropyridine and beta adrenergic receptor binding in dogs with tachycardia-induced atrial fibrillation

• Published in: Cardiovascular research 1999-05, Vol.42 (2), p.434-442
• Main Authors: Gaspo, R, Sun, H, Fareh, S, Levi, M, Yue, L, Allen, B G, Hebert, T E, Nattel, S
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacology; Analysis of Variance; Animals; Atrial Fibrillation - metabolism; Binding Sites; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels - metabolism; Cardiac Pacing, Artificial; Dihydropyridines - metabolism; Dogs; Female; Iodocyanopindolol - pharmacology; Linear Models; Male; Myocardium - metabolism; Nitrendipine - pharmacology; Receptors, Adrenergic, beta - metabolism; Sarcolemma - metabolism; Statistics, Nonparametric
• ISSN: 0008-6363
• DOI: 10.1016/S0008-6363(99)00036-X

We have shown that rapid atrial activation, as occurs during atrial fibrillation (AF), reduces L-type Ca2+ current (ICa) and that this is the principal mechanism of the action potential duration and refractoriness changes that characterize tachycardia-induced atrial remodeling. The present study was designed to determine whether atrial tachycardia alters biochemical indices of the number of L-type Ca2+ channels and/or of the number and binding affinity of beta-adrenergic receptors. In canine atrial sarcolemmal preparations, the number and binding affinity of dihydropyridine receptors were determined with the use of 3H-nitrendipine and that of beta-adrenergic receptors with 125I-iodocyanopindolol. Results were obtained with preparations from dogs paced at 400/min for 1 (P1, n = 20), 7 (P7, n = 9), and 42 (P42, n = 9) days, and compared with observations in sham-operated controls (P0, n = 14). Pacing reduced the Bmax of dihydropyridine receptors, from 157 +/- 18 fmol/mg (P0) to 116 +/- 9 fmol/mg (P1, P < 0.05), 100 +/- 14 fmol/mg (P7, P < 0.05) and 94 +/- 9 fmol/mg (P42, P < 0.01). The affinity of dihydropyridine receptors was unchanged, with the Kd averaging 711 +/- 102 pM. 656 +/- 74 pM, 633 +/- 155 pM and 585 +/- 92 pM in P0, P1, P7 and P42 dogs. Neither Bmax nor Kd of beta-adrenergic receptors was altered by rapid pacing. Values of Bmax of dihydropyridine receptors correlated with atrial ICa current density (r2 = 0.95) and ERP (r2 = 0.99). Rapid atrial activation results in downregulation in the number of dihydropyridine receptors without altering the number or affinity of beta-adrenergic receptors. The reductions in ICa that play an important role in the atrial electrical remodeling by which 'AF begets AF' appear to be due at least in part to a decrease in the number of L-type Ca2+ channels in cardiac cell membranes.