Background: The P-glycoprotein (P-gp) inhibitor tariquidar, intravenously administered, increases brain uptake of radiolabeled P-gp substrates, commonly used to detect functional alterations of blood – brain barrier pumps in PET imaging [1]. However, the doses that are required — up to 4-fold higher than those already used in clinical trials to reverse multidrug resistance — cause syncopal episodes and hypotension [2]. Therefore, we investigated the toxic hazard of these doses towards the vasculature. Methods: The effects of tariquidar on A7r5 and EA.hy926 cell viability, on the mechanical activity of fresh and cultured rat aorta rings, as well as on A7r5 CaV1.2 channel current (ICa1.2) were analysed [3]. Results: In both A7r5 and EA.hy926 cells, tariquidar was generally devoid of cytotoxic effects up to a concentration of 1 µM. However, at 10 µM, it caused apoptosis already after 24 h treatment. In endothelium-denuded aorta rings, 10 µM tariquidar relaxed contractions induced by phenylephrine but not by high K+. The contractile activity of rings cultured for 7 days was not affected by drug treatment. Finally, tariquidar did not modify ICa1.2 intensity and kinetics. Discussion: Tariquidar exerts both cytotoxic and acute vascular effects at concentrations comparable to those employed in PET imaging. This may limit its use as diagnostic tool. Acknowledgements: This work was supported by the Italian Ministry for Instruction, Universities and Research (Futuro in Ricerca 2012, RBFR12SOQ1 to S. S.).

FROSINI, M., DURANTE, M., FUSI, F., STICOZZI, C., & SAPONARA, S. (2016). In vitro assessement of tariquidar toxicity towards vasculature. INTRINSIC ACTIVITY, 4, A1.5-A1.5.

In vitro assessement of tariquidar toxicity towards vasculature

FROSINI, MARIA;DURANTE, MIRIAM;FUSI, FABIO;STICOZZI, CLAUDIA;SAPONARA, SIMONA
2016

Abstract

Background: The P-glycoprotein (P-gp) inhibitor tariquidar, intravenously administered, increases brain uptake of radiolabeled P-gp substrates, commonly used to detect functional alterations of blood – brain barrier pumps in PET imaging [1]. However, the doses that are required — up to 4-fold higher than those already used in clinical trials to reverse multidrug resistance — cause syncopal episodes and hypotension [2]. Therefore, we investigated the toxic hazard of these doses towards the vasculature. Methods: The effects of tariquidar on A7r5 and EA.hy926 cell viability, on the mechanical activity of fresh and cultured rat aorta rings, as well as on A7r5 CaV1.2 channel current (ICa1.2) were analysed [3]. Results: In both A7r5 and EA.hy926 cells, tariquidar was generally devoid of cytotoxic effects up to a concentration of 1 µM. However, at 10 µM, it caused apoptosis already after 24 h treatment. In endothelium-denuded aorta rings, 10 µM tariquidar relaxed contractions induced by phenylephrine but not by high K+. The contractile activity of rings cultured for 7 days was not affected by drug treatment. Finally, tariquidar did not modify ICa1.2 intensity and kinetics. Discussion: Tariquidar exerts both cytotoxic and acute vascular effects at concentrations comparable to those employed in PET imaging. This may limit its use as diagnostic tool. Acknowledgements: This work was supported by the Italian Ministry for Instruction, Universities and Research (Futuro in Ricerca 2012, RBFR12SOQ1 to S. S.).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/1006995
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