Paradoxal pharmacologic effects observed with beta-blocker agents on cardiac cells in culture

The direct effects of propranolol and metoprolol were studied on cultured neonatal rat ventricular myocytes by recording cellular contraction with a video signal analyzer of cells movements. The experiments were performed on 3-d-old cultures forming a synchronously beating monolayer. The spontaneous beating frequency of preparations depended on cultures and varied from 100 to 330 beats/min with a peak for the interval 140 to 149 beats/min. Propranolol and metoprolol were tested at 1, 5, 10 microM and 10, 50, 100 microM, respectively. At these doses the two beta-blockers induced chronotropic and inotropic effects in the same range. The two agents induced rapid and short-lasting negative inotropic effects, which were dose-dependent and delayed negative chronotropic effects even with the lowest doses. In some preparations paradoxal effects were evidenced: an increase of the amplitude or frequency of the contractions was observed. The results obtained with 5 microM propranolol or 50 microM metoprolol could be separated in two groups depending on the basal beating rate (less than or greater than to 150 beats/min). In cultures with a rapid frequency, the drugs had a marked negative chronotropic effect and, surprisingly, a positive inotropic effect was observed. These findings confirm the interdependence of the two parameters frequency and amplitude of contraction on this model, and evidence the interest of taking into account the control parameters before any interpretation.