Evaluation and Interpretation of Voltage- and Frequency-Dependent Electrophysiologic Effects of a New Class I Antiarrhythmic Agent (Nicainoprol) on Guinea Pig Papillary Muscle and Isolated Heart

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Abstract
Summary: Frequency- and voltage-dependent electrophysiologic effects of a chemically novel compound, nicainoprol, were evaluated by recording transmembrane action potentials (APs) from papillary muscles and electrograms (EGs) from isolated perfused hearts of guinea pigs. At 0.2 Hz stimulation, nicainoprol (3.3 x 10−6M and 10−5M) significantly reduces the maximal upstroke velocity (Vmax) of APs without significant change in resting membrane potential (RMP), functional refractory period (FRP), and action potential duration. Nicainoprol prolongs the spread of excitation but has little effect on the duration of the ventricular EG. The Vmax depression is frequency dependent in the range of 0.02–2.5 Hz. showing saturation at higher frequencies. Under resting conditions, nicainoprol (3.3 x 10−6M and 10“ M) has no effect on Vmax. The onset of frequency-dependent Vmax reduction follows monoexponential time courses with rate constants of 0.053 ± 0.007 AP‘(3.3 x 10−6 M) and of 0.066 ± 0.005 AP−1 (10−6M) at 1 Hz. Vmax recovers from frequency-dependent depression with time constants of 45.4 ± 3.2 s (3.3 x 10−6M) and 48.4 ± 3.5 s (10−5M). Nicainoprol significantly shifts the Vmax-RMP relation in hyperpolarizing direction by 2.6 ± 1.1 mV (3.3 x 10−6M) and 5.4 ± 1.3 mV (10−5M) at membrane potentials where Vmax is half maximal. It is concluded that nicainoprol can be classified as a class IC drug and does preferentially bind to inactivated sodium channels with a dissociation constant of about 10−5M.