Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

Previous work has established that there is an increase in endothelial permeability in hyperthermic rats. This work assessed the potential of the calcium channel blocker (E)-1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine) as a pretreatment to ameliorate this extravasation. Five groups of male rats (n=12 rats per group, 400-500 g) were given 0, 0.3, 1, 2, or 3 mg/kg flunarizine (FL0, FL0.3, FL1, FL2, and FL3, respectively) by gavage 30 min prior to induction of hyperthermia. Hyperthermia was achieved by placing unrestrained animals in their own cages in a chamber maintained at 41.5 degrees C until a core temperature (Tc) of 42.6 degrees C was attained. Then, 25 mg/kg of Evans blue in saline was administered via a jugular cannula. After 15 min the animals were anesthetized, exsanguinated, tissues removed and washed in saline, and Evans blue extracted with formamide. As the dose of flunarizine was increased, there was a significant (P<0.05) reduction of Evans blue recovered from the liver, kidney, lung, spleen, and intestinal tissue. Endurance time in the heat to reach a Tc of 42.6 degrees C increased significantly from 194+/-39 min (mean+/-SD) with FL0 to 275+/-33 min with FL1, but decreased again with FL2 (206+/-42) and FL3 (199+/-60). Thus, flunarizine pretreatment attenuated hyperthermia-induced extravasation, and 1 mg/kg flunarizine markedly increased the tolerance time to heat exposure.