The vitamin D receptor agonist elocalcitol upregulates L-type calcium channel activity in human and rat bladder
| Autor: | Rosa Mancina, Roberta Squecco, Linda Vignozzi, Giorgia Luciani, Fabio Francini, Benedetta Fibbi, Paola Failli, Enrico Colli, Aravinda K. Chavalmane, Annamaria Morelli, Mauro Gacci, Luciano Adorini, Mario Maggi, Sandra Filippi |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
Agonist medicine.medical_specialty RHOA Calcium Channels L-Type Physiology medicine.drug_class Urinary Bladder chemistry.chemical_element Calcium Calcitriol receptor Rats Sprague-Dawley Calcitriol Internal medicine medicine Animals Humans L-type calcium channel Rho-associated protein kinase Cells Cultured biology Voltage-dependent calcium channel Muscle Smooth Cell Biology 3-Pyridinecarboxylic acid 1 4-dihydro-2 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)- Methyl ester medicine.disease Rats Electrophysiology Endocrinology Gene Expression Regulation chemistry Overactive bladder biology.protein Receptors Calcitriol Muscle Contraction |
| Zdroj: | American Journal of Physiology-Cell Physiology. 294:C1206-C1214 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.90634.2007 |
| Popis: | 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 ( ICa), which were selectively blocked by isradipine and verapamil and enhanced by the selective L-type agonist BAY K 8644. Addition of elocalcitol (10−7M) increased L-type ICasize 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 (10−8M, 48 h), which also showed increased mRNA and protein expression of pore-forming L-type α1C-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 μg·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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|