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Non-genomic effect of testosterone on airway smooth muscle.

ABSTRACT: BACKGROUND AND PURPOSE: Recent studies on blood vessels have provided evidence that testosterone may exert direct effects on smooth muscle. However, an acute effect on airway reactivity has not been shown yet. The aim of this study was to assess the direct effect of testosterone on the responsiveness of male adult rabbit airway smooth muscle (ASM), precontracted with 10 microM acetylcholine, 10microM carbachol or 80 mM KCl. EXPERIMENTAL APPROACH: Contractility studies of rabbit tracheal smooth muscle were performed. KEY RESULTS: Testosterone at concentrations of or above 1 nM had a significant relaxant effect on ASM precontracted with acetylcholine or carbachol, but did not affect ASM precontracted with KCl. The mechanical removal of airway epithelium as well as the inhibition of NO synthetase (by 100microM L-NAME) reduced the relaxation caused by testosterone. The effect of testosterone was not altered by impairing prostanoid synthesis (by 10microM indomethacin). The nitric oxide donor, sodium nitroprusside, had the same relaxant effect on ASM precontracted with either carbachol or KCl. Inhibitors of androgen receptors (10microM flutamide) or DNA transcription (100microM actinomycin D) did not alter the effect of testosterone. Prolonged incubation of ASM with 100 nM or 100 microM testosterone for 24 or 48 h did not alter their responsiveness to acetylcholine. BSA-testosterone (1pM to 100nM) relaxed significantly ASM precontracted with carbachol. The mechanical removal of airway epithelium abolished the relaxant effect of BSA-testosterone. CONCLUSIONS AND IMPLICATIONS: Testosterone relaxes precontracted ASM via an epithelium and NO-mediated way. This effect is mediated via a non-genomic pathway.

SUBMITTER: Kouloumenta V

PROVIDER: S-EPMC2014638 | biostudies-other | 2006 Dec

REPOSITORIES: biostudies-other

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Project description:Background: The toxicity of inhaled silver nanoparticles on contractile and pro-inflammatory airway smooth muscle cells (ASMCs) that control airway calibre is unknown. We explored the oxidative activities and sulfidation processes of the toxic-inflammatory response. Method: Silver nanospheres (AgNSs) of 20 nm and 50 nm diameter and silver nanowires (AgNWs), short S-AgNWs, 1.5 μm and long L-AgNWs, 10 μm, both 72 nm in diameter were manufactured. We measured their effects on cell proliferation, mitochondrial reactive oxygen species (ROS) release and membrane potential, and also performed electron microscopic studies. Main results and findings: The greatest effects were observed for the smallest particles with the highest specific surface area and greatest solubility that were avidly internalised. ASMCs exposed to 20 nm AgNSs (25 μg mL-1) for 72 hours exhibited a significant decrease in DNA incorporation (-72.4%; p < 0.05), whereas neither the 50 nm AgNSs nor the s-AgNWs altered DNA synthesis or viability. There was a small reduction in ASMC proliferation for the smaller AgNS, although Ag+ at 25 μL mL-1 reduced DNA synthesis by 93.3% (p < 0.001). Mitochondrial potential was reduced by both Ag+ (25 μg mL-1) by 47.1% and 20 nm Ag NSs (25 μg mL-1) by 40.1% (*both at p < 0.05), but was not affected by 50 nm AgNSs and the AgNWs. None of the samples showed a change in ROS toxicity. However, malondialdehyde release, associated with greater total ROS, was observed for all AgNPs, to an extent following the geometric size (20 nm AgNS: 213%, p < 0.01; 50 nm AgNS: 179.5%, p < 0.01 and L-AgNWs by 156.2%, p < 0.05). The antioxidant, N-acetylcysteine, prevented the reduction in mitochondrial potential caused by 20 nm AgNSs. The smaller nanostructures were internalised and dissolved within the ASMCs with the formation of non-reactive silver sulphide (Ag2S) on their surface, but with very little uptake of L-AgNWs. When ASMCs were incubated with H2S-producing enzyme inhibitors, the spatial extent of Ag2S formation was much greater. Conclusion: The intracellular toxicity of AgNPs in ASMCs is determined by the solubility of Ag+ released and the sulfidation process, effects related to particle size and geometry. Passivation through sulfidation driven by biogenic H2S can outcompete dissolution, thus reducing the toxicity of the smaller intracellular Ag nanostructures.

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Non-genomic effect of testosterone on airway smooth muscle.

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