| Autor: |
Fusi F; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy., Trezza A; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy., Sgaragli G; Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy., Spiga O; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy., Saponara S; Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100, Siena, Italy. simona.saponara@unisi.it., Bova S; Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, via Marzolo 5, 35131, Padova, Italy. |
| Abstrakt: |
Ca V 1.2 channel blockers or 5-HT 2 receptor antagonists constitute effective therapy for Raynaud's syndrome. A functional link between the inhibition of 5-HT 2 receptors and Ca V 1.2 channel blockade in arterial smooth muscles has been hypothesized. Therefore, the effects of ritanserin, a nonselective 5-HT 2 receptor antagonist, on vascular Ca V 1.2 channels were investigated through electrophysiological, functional, and computational studies. Ritanserin blocked Ca V 1.2 channel currents (I Ca1.2 ) in a concentration-dependent manner (K r = 3.61 µM); I Ca1.2 inhibition was antagonized by Bay K 8644 and partially reverted upon washout. Conversely, the ritanserin analog ketanserin (100 µM) inhibited I Ca1.2 by ~50%. Ritanserin concentration-dependently shifted the voltage dependence of the steady-state inactivation curve to more negative potentials (K i = 1.58 µM) without affecting the slope of inactivation and the activation curve, and decreased I Ca1.2 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 Ca V 1.2 α 1C 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 Ca V 1.2 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. |
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