Pharmacodynamic studies with flunarizine, a calcium influx blocker

Flunarizine, a difluoro derivative of cinnarizine, has been used to study its antivasoconstrictor effects on isolated perfused rat mesentery. The vasoconstrictor responses induced by sequential intra-arterial injections of phenylephrine (PhE) and norepinephrine (NE), were measured as an increase in the perfusion pressure (mm Hg). Flunarizine was administered either by i.v. route in a dose of 3 mg/kg, 15-20 min before the isolation of the mesentery or it was added to the perfusing medium, in concentrations ranging from 100 pg to 1 microgram/ml (PhE experiments) and from 1 ng to 1 microgram/ml (NE experiments). Intravenous administration of flunarizine significantly decreased the vascular reactivity of rat mesentery to PhE and NE at all dose levels. Continuous perfusion of flunarizine attenuated the vasoconstrictor responses induced by PhE and NE. Flunarizine was further studied for its hemodynamic effects in anaesthetized rats using the radioactive microspheres technique. Flunarizine (5 mg/kg i.p.) was administered 60 min prior to the determination of hemodynamic parameters. It was found not to affect general hemodynamics (mean blood pressure, heart rate, cardiac output and hematocrit). However, it produced a significant decrease of renal and splenic blood flows. The changes in blood flows were associated with similar changes in the percentage distribution of cardiac output to these organs, thus indicating that local regulatory mechanisms were influenced by flunarizine. It appears that flunarizine has preferential effects on the different vasculatures in vivo, whereas it produces nonspecific inhibition of exogenous PhE and NE in the rat mesentery in vitro.