Cardiotoxic effects of fenfluramine hydrochloride on isolated cardiac preparations and ventricular myocytes of guinea-pigs

1 The cardiotoxic effects of fenfluramine hydrochloride on mechanical and e lectrical activity were studied in papillary muscles, Purkinje fibres, left atria and ventricular myocytes of guinea-pigs. 2 Force of contraction (f(c)) was measured isometrically, action potentials and maximum rate of rise of the action potential (V-max) were recorded by means of the intracellular microelectrode technique and the sodium current (I-Na) with patch-clamp technique in the cell-attached mode. For kinetic an alysis (S)-DPI-201-106-modified Na+ channels from isolated guinea-pig ventr icular heart cells were used. 3 Fenfluramine (1-300 mu M) produced negative chronotropic and inotropic ef fects; additional extracellular Ca2+ competitively antagonized the negative inotropic effect. 4 Fenfluramine concentration-dependently reduced V-max and showed tonic blo ckade of sodium channels, shortened the action potential duration in papill ary muscles and Purkinje fibres. 5 In cell-attached patches, fenfluramine decreased I-Na concentration-depen dently (10-100 mu M), frequency-independently (0.1-3 Hz; 30 mu M). The h(in finity) curve was shifted towards hyperpolarizing direction. At 30 mu M, fe nfluramine blocked the sodium channel at all test potentials to the same de gree, and neither changed the threshold and reversal potentials nor the pea k of the curve. 6 No effect on single channel availability, but a significant decrease in m ean open times and increase in mean closed times was observed. 7 Mean duration of the bursts decreased and number of openings per record i ncreased with increasing drug concentration. 8 It is concluded that the effect on I-Na plays an important role in the ca rdiotoxicity of fenfluramine in addition to primary pulmonary hypertension and valvular disorders.