Fosinoprilate prolongs the action potential: reduction of iK 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 iCa (iCaL; n = 5), in some cases (n = 4) also using Cs+ loaded pipettes; with 5 mM Co2+, the time dependent K+ current (IK) underlying delayed rectification was analysed in guinea pig ventricular myocytes (n = 3).


RESULTS
Fosinoprilate prolonged the 50% repolarisation (APD50) from 440(SEM 50) ms to 485(48) ms (0.1 microM), to 525(46) ms (0.3 microM), to 632(58) ms (1 microM), and to 702(69) ms (3.0 microM). The APD90 was delayed from 510(63) ms to 540(45) ms (0.1 microM), to 583(42) ms (0.3 microM), to 702(62) ms (1.0 microM), and to 765(72) ms (3.0 microM). Higher concentrations (10-100 microM) caused early afterdepolarisations, very long action potentials, and irregular oscillations. ICaL was enhanced by up to 183%, showing a Kd of 0.2 microM; in contrast to the steady state activation (d infinity), the inactivation curve f infinity 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 microM dose, and to 0.54(0.14) nA with a 1.0 microM dose; the tails were decreased from 0.39(0.03) nA to 0.27(0.03) nA with 0.1 microM and to 0.13(0.02) nA with 1.0 microM. Kinetics of IK 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 iK 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.
Räcke
H F
HF
Physiologisches Institut II, Bonn, Germany.
Koppers
D
D
Lemke
P
P
Casaretto
H
H
Hauswirth
O
O
D000200:Action Potentials / Q000187:drug effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D017328:Fosinopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D016623:Ion Pumps / Q000187:drug effects*; D008297:Male; D008955:Models, Cardiovascular; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D016623:Ion Pumps; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D017328:Fosinopril; C046965:fosinoprilat