Effects of pinacidil on guinea-pig isolated perfused heart with particular reference to the proarrhythmic effect

1. The effects of pinacidil (10, 30, 50 microM) on contractility (+dP/dtmax), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant-flow perfused guinea-pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz). 2. Pinacidil decreased +dP/dtmax, cP and the QT interval in a dose-dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q-wave to T-wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation. 3. In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon). 4. In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 10 microM to 100 microM (8 experiments for each concentration). In control conditions and at the lowest concentrations of pinacidil tested (10 microM) VF could never be induced; in the presence of 30 microM pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher than 50 microM permitted the induction of VF in every case. 5. Although the concentrations of pinacidil producing ventricular fibrillation are 30-40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.