Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

Abstract

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.

Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis

“…Not only vascular tone is affected by Flunarizine, but there are also several endothelium-protective properties described; Flunarizine e.g. leads to less venostatic thrombosis, less endothelial damage induced by citrate-injection27, as well as less permeability2829. Our findings contribute to the knowledge about the variety of Flunarizine’s beneficial pleiotropic effects on the endothelium and expand its importance by showing that Flunarizine-mediated suppression of Angpt-2 might be useful for the treatment of septic vascular barrier breakdown.…”