Abstract
The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined. Here we have investigated the involvement of H2S as possible mediator released downstream following muscarinic (M) activation, by using human bladder and urothelial T24 cell line. Carbachol stimulation enhances H2S production and in turn cGMP in human urothelium or in T24 cells. This effect is reversed by cysthationine-β-synthase (CBS) inhibition. The blockade of M1 and M3 receptors reverses the increase in H2S production in human urothelium. In T24 cells, the blockade of M1 receptor significantly reduces carbachol-induced H2S production. In the functional studies, the urothelium removal from human bladder strips leads to an increase in carbachol-induced contraction that is mimicked by CBS inhibition. Instead, the CSE blockade does not significantly affect carbachol-induced contraction. The increase in H2S production and in turn of cGMP is driven by CBS-cGMP/PKG-dependent phosphorylation at Ser227 following carbachol stimulation. The finding of the presence of this crosstalk between the cGMP/PKG and H2S pathway downstream to the M1/M3 receptor in the human urothelium further implies a key role for H2S in bladder physiopathology. Thus, the modulation of the H2S pathway can represent a feasible therapeutic target to develop drugs for bladder disorders.
Highlights
The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined
H2S, is the third gaseous transmitter along with nitric oxide (NO) and carbon monoxide, formed by L-cysteine mainly through the action of cysthationine-β-synthase (CBS) and cysthationine-γ-lyase (CSE)[12,13,14,15]. It is endogenously produced in urinary bladder of trout, mouse, and rat implying that the contribution of this pathway to bladder function is conserved in different species including human[16]
Carbachol-induced contraction is affected by H2S in human bladder strips
Summary
The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined. Carbachol stimulation enhances H2S production and in turn cGMP in human urothelium or in T24 cells This effect is reversed by cysthationine-β-synthase (CBS) inhibition. It has been suggested, from in vitro studies, that UDRF(s) is released within the urothelium upon muscarin (M) receptors stimulation but its chemical nature is still unknown[9,10] It has been proposed a new signal molecule in the control of bladder tone i.e. hydrogen sulfide (H2S)[11]. It has been reported that H2S relaxing effect on human bladder involves potassium-ATP dependent channel activation[17] Both enzymes CBS and CSE are constitutively expressed either in human urothelium or in detrusor muscle and are able to generate H2S11,21. By using human urothelium and the urothelial cell line T24, we have investigated i) whether M receptor activation is downstream triggered the H2S pathway and ii) if H2S can be considered as an UDRF
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