Inhibition of cardiac Na+
currents by isoproterenol
The mechanism by which the β-adrenergic agonist isoproterenol (ISO) modulates voltage-dependent cardiac Na+ currents (I(Na)) was studied in single ventricular myocytes of neonatal rat using the gigaseal patch-clamp technique. ISO inhibited I(Na) reversibly, making the effect readily distinguishable from the monotonic disease of I(Na) caused by the shift in gating that customarily occurs during whole cell patch-clamp experiments (E. Fenwick, A. Marty, and E. Neher, J. Physiol. Lond. 331: 599-635, 1982; and J.M. Fernandez, A.P. Fox, and S. Krasne, J. Physiol. Lond. 356: 565-585, 1984). The inhibition was biphasic, having fast and slow components, and was voltage-dependent, being more pronounced at depolarized potentials. In whole cell experiments the membrane-permeable adenosine 3',5'-cyclic monophosphate (cAMP) congener 8-bromo-cAMP reduced I(Na). In cell-free inside-out patches with ISO present in the pipette, guanosine 5'-triphosphate (GTP) applied to the inner side of the membrane patch inhibited single Na+ channel activity. This inhibition could be partly reversed by hyperpolarizing prepulses. The nonhydrolyzable GTP analogue guanosine-5'-O-(3-thiotriphosphate) greatly reduced the probability of single Na+ channel currents in a Mg2+-dependent manner. We propose that ISO inhibits cardiac Na+ channels via the guanine nucleotide binding, signal-transducing G protein that acts through both direct (membrane delimited) and indirect (cytoplasmic) pathways.
Schubert, B; Vandongen, AMJ; Kirsch, GE; Brown, AM
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