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

Background: We have shown that rapid atrial activation, as occurs during atrial fibrillation (AF), reduces L-type Ca²⁺ current (I(Ca)) 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 β-adrenergic receptors. Methods: In canine atrial sarcolemmal preparations, the number and binding affinity of dihydropyridine receptors were determined with the use of ³H-nitrendipine and that of β-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). Results: Pacing reduced the β(max) 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 K(d) averaging 711±102 pM, 656±74 pM, 633±155 pM and 585±92 pM in P0, P1, P7 anti P42 dogs. Neither B(max) nor K(d) of β- adrenergic receptors was altered by rapid pacing. Values of B(max) of dihydropyridine receptors correlated with atrial I(Ca) current density (r²=0.95) and ERP (r²=0.99). Conclusions: Rapid atrial activation results in downregulation in the number of dihydropyridine receptors without altering the number or affinity of β-adrenergic receptors. The reductions in I(Ca) 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.