Ritanserin blocks Cav1.2 channels in rat artery smooth muscles: electrophysiological, functional, and computational studies

• 作者: Alfonso Trezza Fabio Fusi Giampietro Sgaragli Ottavia Spiga Sergio Bova Simona Saponara
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2020,（9）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 1158-1166
• 页数: 9页
• 语种: 英文

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 concentrationdependent manner (Kr =3.61 μM);ICa1.2 inhibition was antagonized by Bay K 8644 and partially reverted upon washout.Conversely,the ritanserin analog ketanserin (100 μM) inhibited ICa1.2 by ～50％.Ritanserin concentration-dependently shifted the voltage dependence of the steady-state inactivation curve to more negative potentials (Ki =1.58 μM) without affecting the slope of inactivation and the activation curve,and decreased ICa1.2 progressively during repetitive (1 Hz) step depolarizations (usedependent 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 Cav1.2 α1C 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.