title: The vitamin D receptor agonist elocalcitol upregulates L-type calcium channel activity in human and rat bladder.
abstract: Human bladder contraction mainly depends on Ca2+ influx via L-type voltage-gated Ca2+ channels and on RhoA/Rho kinase contractile signaling, which is upregulated in overactive bladder (OAB). Elocalcitol is a vitamin D receptor agonist inhibiting RhoA/Rho kinase signaling in rat and human bladder. Since in the normal bladder from Sprague-Dawley rats elocalcitol treatment delayed the carbachol-induced contraction without changing maximal responsiveness and increased sensitivity to the L-type Ca2+ channel antagonist isradipine, we investigated whether elocalcitol upregulated L-type Ca2+ channels in human bladder smooth muscle cells (hBCs). In hBCs, elocalcitol induced a rapid increase in intracellular [Ca2+], which was abrogated by the L-type Ca2+ channel antagonist verapamil. Moreover, hBCs exhibited L-type voltage-activated Ca2+ currents (I Ca), which were selectively blocked by isradipine and verapamil and enhanced by the selective L-type agonist BAY K 8644. Addition of elocalcitol (10(-7) M) increased L-type I Ca size and specific conductance by inducing faster activation and inactivation kinetics than control and BAY K 8644, while determining a significant negative shift of the activation and inactivation curves, comparable to BAY K 8644. These effects were strengthened in long-term treated hBCs with elocalcitol (10(-8) M, 48 h), which also showed increased mRNA and protein expression of pore-forming L-type alpha(1C)-subunit. In the bladder from Sprague-Dawley rats, BAY K 8644 induced a dose-dependent increase in tension, which was significantly enhanced by elocalcitol treatment (30 microg.kg(-1).day(-1), 2 wk). In conclusion, elocalcitol upregulated Ca2+ entry through L-type Ca2+ channels in hBCs, thus balancing its inhibitory effect on RhoA/Rho kinase signaling and suggesting its possible efficacy for the modulation of bladder contractile mechanisms.
authors: Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors: Annamaria
authors: A
authors: Morelli
authors: Roberta
authors: R
authors: Squecco
authors: Paola
authors: P
authors: Failli
authors: Sandra
authors: S
authors: Filippi
authors: Linda
authors: L
authors: Vignozzi
authors: Aravinda K
authors: AK
authors: Chavalmane
authors: Benedetta
authors: B
authors: Fibbi
authors: Rosa
authors: R
authors: Mancina
authors: Giorgia
authors: G
authors: Luciani
authors: Mauro
authors: M
authors: Gacci
authors: Enrico
authors: E
authors: Colli
authors: Fabio
authors: F
authors: Francini
authors: Luciano
authors: L
authors: Adorini
authors: Mario
authors: M
authors: Maggi
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000097:blood / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists*; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: C487049:BXL628; D020746:Calcium Channels, L-Type; D018167:Receptors, Calcitriol; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002117:Calcitriol; D002118:Calcium