Effects of selective channel blocking agents on contractions and action potentials in K+-depolarized guinea-pig atria

Contractions and transmembrane action potentials were induced by 1 microM isoprenaline in K+-depolarized guinea-pig left atria driven at 0.5 Hz. The stability of these responses was significantly increased by doubling the extracellular glucose concentration to 22 mM. Action potential overshoot increased by 28 mV per ten fold increase in extracellular calcium concentration suggesting that the inward current in this preparation is carried by Ca2+. In depolarized driven preparations, nanomolar concentrations of nifedipine and nisoldipine reduced contractility, maximum rate of depolarization (dV/dt max) and action potential height, whereas the fast channel blocking agents tetrodotoxin and mexiletine (in micromolar concentrations) produced little change. Nifedipine also rendered spontaneously beating depolarized right atrial preparations quiescent. In concentrations which reduced dV/dt of normal action potentials, the sodium channel blocking agents quinidine and Org 6001 reduced the amplitude of contractions and reduced the maximum rate of phase 0 depolarization (dV/dt) of action potentials in depolarized tissue. These actions were reversed by Ca2+ and suggest calcium antagonistic activity. However action potential height was not reduced. Like bepridil, both drugs also reduced the frequency of spontaneous contractions in depolarized right atrial preparations. Unlike Org 6001, quinidine failed to produce a shift in calcium log dose-response curves in driven depolarized preparations and induced positive inotropy in the presence of functional sodium channels. Bepridil inhibited contractions in depolarized atria in the absence of a reduction in dV/dt suggesting that any calcium antagonistic action in atrial tissue is mainly located at an intracellular site. In conclusion, action potentials elicited by isoprenaline in potassium-depolarized atria bathed in high glucose appear to be Ca2+ mediated. In concentrations which inhibit the inward Na+ current, both quinidine and Org 6001 exhibit calcium channel blocking properties.