Isoproterenol, DBcAMP, and forskolin inhibit cardiac sodium current.
We studied the effects of isoproterenol (ISP), dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), and forskolin on the sodium current (INa) of guinea pig ventricular myocytes using the tight-seal, whole cell voltage-clamp method. The extracellular [Na+] [( Na+]o) was decreased to 60 mM by replacing NaCl with sucrose (temperature, 32-33 degrees C). Ionic currents other than Na+ were suppressed using appropriate channel blockers. Depolarizing clamp pulse (duration, 30 ms) was applied at a rate of 0.2 Hz from a holding potential of -80 mV. ISP (1 microM) decreased the peak INa by 34% from 6.1 +/- 1.9 (SD) nA (control) to 4.0 +/- 1.5 nA (n = 7). The inhibition was more prominent at less negative potentials and disappeared in the presence of a beta-blocker (10 microM atenolol). The effects of DBcAMP (1-5 mM) and forskolin (3 microM) mimicked those of ISP and depressed the peak INa reversibly. DBcAMP (5 mM) shifted the inactivation curve of INa [h infinity-membrane potential (Em) relationship] to a hyperpolarizing direction, by 3.4 +/- 0.8 mV (n = 5). These findings suggest that ISP inhibits the cardiac INa+, probably by altering the gating mechanism of the Na+ channel, and that the effect is secondary to the increased levels of intracellular cAMP, with possible acceleration of cAMP-dependent phosphorylation of the channel.
Ono
K
K
Department of Physiology, Medical College of Oita, Japan.
Kiyosue
T
T
Arita
M
M
D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology*; D004553:Electric Conductivity; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D016276:Ventricular Function
D015222:Sodium Channels; D005576:Colforsin; D001262:Atenolol; D003994:Bucladesine; D007545:Isoproterenol