FOSINOPRILATE PROLONGS THE ACTION-POTENTIAL - REDUCTION OF I(K) AND ENHANCEMENT OF THE L-TYPE CALCIUM CURRENT IN GUINEA-PIG VENTRICULAR MYOCYTES

Objective: The aim was to study the effect of fosinoprilate, a new ACE inhibitor, on the action potential and plateau currents of cardiac muscle. Methods: Whole cell patch technique was used to record action potentials (n = 6), the L-type i(Ca) (i(CaL); n = 5), in some cases (n = 4) also using Cs+ loaded pipettes; with 5 mM Co2+, the time dependent K+ current (I-K) underlying delayed rectification was analysed in guinea pig ventricular myocytes (n = 3). Results: Fosinoprilate prolonged 50% repolarisation (APD(50)) from 440(SEM 50) ms to 485(48) ms (0.1 mu M), to 525(46) ms (0.3 mu M), to 632(58) ms (1 mu M), and to 702(69) ms (3.0 mu M). The APD(90) was delayed from 510(63) ms to 540(45) ms (0.1 mu M), to 583(42) ms (0.3 mu M), to 702(62) ms (1.0 mu M), and to 765(72) ms (3.0 mu M). Higher concentrations (10-100 mu M) caused early afterdepolarisations, very long action potentials, and irregular oscillations. I-CaL was enhanced by up to 183%, showing a Kd of 0.2 mu M; in contrast to the steady state activation (d(x)), the inactivation curve f(x) was shifted in the depolarising direction, considerably enlarging the Ca2+ window. Slow inactivation time course was unchanged, whereas the fast time constant (tau(f)) was accelerated. Fosinoprilate reduced the outward current during depolarising clamps from 1.7(0.2) nA to 1.41(0.11) nA with a 0.1 mu M dose, and to 0.54(0.14) nA with a 1.0 mu M dose; the tails were decreased from 0.39(0.03) nA to 0.27(0.03) nA with 0.1 mu M and to 0.13(0.02) nA with 1.0 mu M. Kinetics of I-K were unaltered. Computer simulations based on these data using the OXSOFT-HEART program mimicked the results rather closely. Conclusions: The results suggest that fosinoprilate prolongs the plateau due to a partial block of i(K) and an extension of the Ca2+ window by 10 mV, causing a class III antiarrhythmic effect. High concentrations further open the Ca2+ window resulting in early afterdepolarisations and plateau oscillations and may cause an inward transport of Ca2+ ions by the Na-Ca exchange.