VOLTAGE- AND TIME-DEPENDENT DEPRESSION OF MAXIMUM RATE OF DEPOLARIZATION OF GUINEA-PIG VENTRICULAR ACTION POTENTIALS BY TWO STEROIDAL ANTIARRHYTHMIC DRUGS, CCI 22277 AND ORG 6001

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Abstract
1 The voltage- and time-dependence of the depression of the maximum rate of depolarization (V̇max) by two steroidal anti-arrhythmic drugs, CCI 22277 and Org 6001 were studied in guinea-pig ventricle. 2 At normal resting potentials CCI 22277 (2 μm and 4 μm) produced very little depression of V̇max at very low driving rates (resting block) but trains of stimuli at interstimulus intervals (ISI) of less than 10,000 ms led to an exponential decline in V̇max to a new plateau over 100–200 beats. 3 This ‘rate-dependent block’ (RDB) increased with rate over the range ISI = 4800 to ISI = 200 ms. 4 Org 6001 30 μm and 60 μm produced a similar degree of RDB over the same range of frequencies but the new plateau level of V̇max was reached much more rapidly (20–30 beats) and there was a moderate degree of depression of V̇max in the resting tissue. 5 Recovery from RDB in the presence of both drugs was an exponential process with time constants (τre) of 80.4 ± 7.4 s for CCI 22277 and 4.6 ± 0.5 s for Org 6001. 6 Both drugs shifted the steady-state inactivation curve, relating V̇max to resting membrane potential, in the hyperpolarizing direction, implying selective depression of depolarized cells.

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