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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/C1206    most recent 90634.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Morelli, A. Articles by Maggi, M. PubMed PubMed Citation Articles by Morelli, A. Articles by Maggi, M.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

The vitamin D receptor agonist elocalcitol upregulates L-type calcium channel activity in human and rat bladder

Department of ¹Clinical Physiopathology, ²Physiological Sciences, ³Pharmacology, ⁴Urology, University of Florence, Florence; ⁵Bioxell, Milan; and ⁶National Institute of Biostructures and Biosystems, Rome, Italy

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 _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 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.

vitamin D analogue; human bladder smooth muscle cells; voltage-gated calcium channel; overactive bladder