Calcium blocking properties of piprofurol

Piprofurol is a benzofuran chalcon derivative. It was studied under various experimental conditions which allow the recognition of calcium antagonistic activity. Piprofurol inhibited in a concentration-dependent manner the calcium-induced contractions in isolated potassium depolarized preparations of rat aorta (pA2: 9.29) and relaxed the K+-induced contraction of the dog coronary artery and the rabbit basilar artery (IC's 50: 2 10(-8) M; 3 10(-9) M). Piprofurol also inhibited noradrenaline-induced vascular smooth muscle contractions but the antagonism was clearly noncompetitive and the contractions induced were altered by concentrations two orders of magnitude higher than the concentration inhibiting calcium-induced contractions. Calcium antagonism was demonstrated in cardiac muscle: calcium mediated slowly rising action potentials were evoked in partially depolarized guinea-pig papillary muscle by electrical stimulation in the presence of isoprenaline. Piprofurol decreased the rate of rise of these slow action potentials. The inhibitory effect was reversed by an elevation of the calcium concentration in the bath fluid. Piprofurol exerts a negative inotropic effect (IC50: 5 10(-6) M) on guinea-pig papillary muscle. The ratio IC50 inotropic action/IC50 relaxant activity was 230, i.e. higher than that obtained with verapamil or diltiazem, and near that observed for cinnarizine. The pharmacological profile from in vivo dog experiments is in agreement with its in vitro properties: coronary sinus blood flow was increased and heart rate decreased. These effects suggested a potentially anti-ischaemic activity. This is confirmed in anaesthetized dogs, where piprofurol reduced the epicardial ST-segment elevation following coronary artery occlusion, and in isolated heart preparations, where it decreased the leakage of LDH during periods of anoxia and reoxygenation.