Mechanism of spironolactone-induced Ca2+ increase in rat testicular arteriole smooth muscle cells revealed by real-time laser scanning confocal microscopy
Archives of Histology and Cytology(2013)
Abstract
We reported previously that spironolactone (SPL) induced an increase in intracellular Ca2+ concentration ([Ca2+]i) in rat testicular arteriole smooth muscle cells. In the present study, we further investigated the mechanism of SPL-induced [Ca2+]i dynamics in rat arteriole smooth muscles. The increase in [Ca2+]i induced by SPL (300 μM) was markedly inhibited in extracellular Ca2+-free conditions and in the presence of diltiazem or gadolinium. In contrast, the phospholipase C inhibitor (U73122), did not affect the SPL-induced increase in [Ca2+]i, similar to what was observed for 2-aminoethoxydiphenyl borate (2- APB: an inhibitor of inositol triphosphate (IP3)dependent Ca2+ mobilization). Moreover, the protein kinase A (PKA) inhibitor H89 partially inhibited the SPL-induced increase in [Ca2+]i, whereas the protein kinase C (PKC) inhibitor GF109203X did not. Either suramin (a non-specific G protein antagonist) or NF449 (an inhibitor of the α-subunit of the stimulatory G protein Gsα), partially blocked the SPL-induced increase in [Ca2+]i. Similarily, either mifepristone, a glucocorticoid-receptor antagonist, or flutamide, a non-steroidal antiandrogen drug, partially blocked the SPL-induced increase in [Ca2+]i. We suggest that the SPL-induced increase in [Ca2+]i in arterioles is mediated both by Ca2+ influx from the extracellular fluid and by Ca2+ mobilization from internal Ca2+ stores, with the former being dominant. We thus propose that SPL interacts with both extracellular (i.e., G-proteincoupled-type) and intracellular (e.g., glucocorticoid) receptors in rat testicular arterioles, which is followed by an increase in intracellular Ca2+ that causes smooth-muscle contraction.
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Key words
Spironolactone Therapy
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