TY - JOUR
T1 - Vardenafil-induced relaxation and cyclic nucleotide levels in normal and obstructed rat urinary bladder
AU - Werkström, Viktoria
AU - Hedlund, Petter
AU - Lee, Tack
AU - Andersson, Karl Erik
PY - 2009/12
Y1 - 2009/12
N2 - Objective To study the effects of the phosphodiesterase-5 inhibitor, vardenafil, on contraction and cyclic nucleotide levels in isolated detrusor preparations with and without mucosa, from control rats and rats with partial urethral obstruction (PUO) and intact mucosa. MATERIALS AND METHODS Female Sprague-Dawley rats were divided into groups subjected to PUO for 14 days (six), and sham-operated control rats (12). Detrusor preparations were mounted in organ baths and effects of increasing concentrations of vardenafil (1 nm to 100 μm) assessed on carbachol-activated (1 μm) preparations, and on contractions induced by transmural activation of nerves (electrical field stimulation, EFS). Levels of cGMP and cAMP were determined using radioimmunoassays. Results Vardenafil caused concentration-dependent relaxations of carbachol-contracted detrusor, the mean (sd) of which at 100 μm was 91 (4)% in control and 100% in PUO rats. The -log 50% inhibitory concentration (IC50) was 4.41 (0.08) and 4.73 (0.05) (P <0.01), respectively. Removing the mucosa increased the relaxant effect of vardenafil at 1-10 μm (P <0.05) although -log IC50 values were unaffected compared to the control. The cGMP levels (pmol/mg protein) in control preparations increased from 2.5 (0.6) to 5.0 (0.8), and from 1.4 (0.2) to 7.2 (1.3) in obstructed bladders. In mucosa-denuded preparations the cGMP content increased from 0.6 (0.1) to 1.6 (0.4) in response to vardenafil. In control rats, the levels of cAMP increased from 12.8 (2.5) to 18.9 (0.9) (P <0.05) after vardenafil. In mucosa-denuded preparations the cAMP levels after vardenafil increased from 16.5 (2.11) to 37.8 (3.4) (P <0.01). In PUO bladders, the tissue content of cAMP increased from 12.6 (2.4) to 20.6 (3.4) (P <0.01). Vardenafil concentration-dependently inhibited nerve-induced contractions in all groups studied. At 100 μm 19 (3)% of the control contraction remained, vs 8 (1)% for preparations from obstructed rats, and 11 (4)% in mucosa-denuded preparations. CONCLUSION In normal rats, vardenafil relaxed carbachol- and inhibited EFS-induced contractions of detrusor preparations with and without urothelium, and in PUO rats with urothelium. Relaxations were accompanied by increases in both cAMP and cGMP content. It is proposed that vardenafil-induced relaxation of rat detrusor, also in obstructed and mucosa-denuded preparations, is mediated via cAMP.
AB - Objective To study the effects of the phosphodiesterase-5 inhibitor, vardenafil, on contraction and cyclic nucleotide levels in isolated detrusor preparations with and without mucosa, from control rats and rats with partial urethral obstruction (PUO) and intact mucosa. MATERIALS AND METHODS Female Sprague-Dawley rats were divided into groups subjected to PUO for 14 days (six), and sham-operated control rats (12). Detrusor preparations were mounted in organ baths and effects of increasing concentrations of vardenafil (1 nm to 100 μm) assessed on carbachol-activated (1 μm) preparations, and on contractions induced by transmural activation of nerves (electrical field stimulation, EFS). Levels of cGMP and cAMP were determined using radioimmunoassays. Results Vardenafil caused concentration-dependent relaxations of carbachol-contracted detrusor, the mean (sd) of which at 100 μm was 91 (4)% in control and 100% in PUO rats. The -log 50% inhibitory concentration (IC50) was 4.41 (0.08) and 4.73 (0.05) (P <0.01), respectively. Removing the mucosa increased the relaxant effect of vardenafil at 1-10 μm (P <0.05) although -log IC50 values were unaffected compared to the control. The cGMP levels (pmol/mg protein) in control preparations increased from 2.5 (0.6) to 5.0 (0.8), and from 1.4 (0.2) to 7.2 (1.3) in obstructed bladders. In mucosa-denuded preparations the cGMP content increased from 0.6 (0.1) to 1.6 (0.4) in response to vardenafil. In control rats, the levels of cAMP increased from 12.8 (2.5) to 18.9 (0.9) (P <0.05) after vardenafil. In mucosa-denuded preparations the cAMP levels after vardenafil increased from 16.5 (2.11) to 37.8 (3.4) (P <0.01). In PUO bladders, the tissue content of cAMP increased from 12.6 (2.4) to 20.6 (3.4) (P <0.01). Vardenafil concentration-dependently inhibited nerve-induced contractions in all groups studied. At 100 μm 19 (3)% of the control contraction remained, vs 8 (1)% for preparations from obstructed rats, and 11 (4)% in mucosa-denuded preparations. CONCLUSION In normal rats, vardenafil relaxed carbachol- and inhibited EFS-induced contractions of detrusor preparations with and without urothelium, and in PUO rats with urothelium. Relaxations were accompanied by increases in both cAMP and cGMP content. It is proposed that vardenafil-induced relaxation of rat detrusor, also in obstructed and mucosa-denuded preparations, is mediated via cAMP.
KW - CAMP
KW - CGMP
KW - Detrusor
KW - Nerve function
KW - Outflow obstruction
KW - Smooth muscle
KW - Urothelium
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U2 - 10.1111/j.1464-410X.2009.08651.x
DO - 10.1111/j.1464-410X.2009.08651.x
M3 - Article
C2 - 19694713
AN - SCOPUS:70449368561
VL - 104
SP - 1740
EP - 1745
JO - BJU International
JF - BJU International
SN - 1464-4096
IS - 11
ER -