Ritanserin blocks CaV1.2 channels in rat artery smooth muscles: electrophysiological, functional, and computational studies  

作　　者：Fabio Fusi Alfonso Trezza Giampietro Sgaragli Ottavia Spiga Simona Saponara Sergio Bova 

机构地区：[1]Dipartimento di Biotecnologie,Chimica e Farmacia,Universitàdegli Studi di Siena,via A.Moro 2,53100,Siena,Italy [2]Dipartimento di Scienze della Vita,Universitàdegli Studi di Siena,via A.Moro 2,53100,Siena,Italy [3]Dipartimento di Scienze del Farmaco,Universitàdegli Studi di Padova,via Marzolo 5,35131,Padova,Italy

出　　处：《Acta Pharmacologica Sinica》2020年第9期1158-1166,共9页中国药理学报（英文版）

摘　　要：CaV1.2 channel blockers or 5-HT2 receptor antagonists constitute effective therapy for Raynaud’s syndrome.A functional link between the inhibition of 5-HT2 receptors and CaV1.2 channel blockade in arterial smooth muscles has been hypothesized.Therefore,the effects of ritanserin,a nonselective 5-HT2 receptor antagonist,on vascular CaV1.2 channels were investigated through electrophysiological,functional,and computational studies.Ritanserin blocked CaV1.2 channel currents(ICa1.2)in a concentration-dependent manner(Kr=3.61µM);ICa1.2 inhibition was antagonized by Bay K 8644 and partially reverted upon washout.Conversely,the ritanserin analog ketanserin(100µM)inhibited ICa1.2 by^50%.Ritanserin concentration-dependently shifted the voltage dependence of the steady-state inactivation curve to more negative potentials(Ki=1.58µM)without affecting the slope of inactivation and the activation curve,and decreased ICa1.2 progressively during repetitive(1 Hz)step depolarizations(use-dependent block).The addition of ritanserin caused the contraction of single myocytes not yet dialyzed with the conventional method.Furthermore,in depolarized rings,ritanserin,and to a lesser extent,ketanserin,caused a concentration-dependent relaxation,which was antagonized by Bay K 8644.Ritanserin and ketanserin were docked at a region of the CaV1.2α1C subunit nearby that of Bay K 8644;however,only ritanserin and Bay K 8644 formed a hydrogen bond with key residue Tyr-1489.In conclusion,ritanserin caused in vitro vasodilation,accomplished through the blockade of CaV1.2 channels,which was achieved preferentially in the inactivated and/or resting state of the channel.This novel activity encourages the development of ritanserin derivatives for their potential use in the treatment of Raynaud’s syndrome.

关 键 词：RITANSERIN CaV1.2 channel Raynaud’s syndrome 5-HT2 receptor docking simulation homology modeling 

分 类 号：R96[医药卫生—药理学]