cyclic-gmp and Urethral-Obstruction

To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO).. Fifty-six male Sprague-Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization.. Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P < 0.05). In obstructed rats vardenafil, BAY 41-2272, and BAY 60-2770 increased IMI (2.77 ± 1.12, 2.62 ± 0.52, and 3.22 ± 1.04 min; all P < 0.05) and decreased MMP (54.4 ± 2.8, 61.5 ± 11.3, and 51.2 ± 6.3 cmH2O; all P < 0.05). When vardenafil was given following BAY 41-2272 or BAY 60-2770 no further urodynamic effects were observed. PDE5 as well as sGC protein expression was reduced in obstructed bladder tissue.. Targeting sGC via stimulators or activators, which increase the levels of cGMP independent of endogenous NO, is as effective as vardenafil to reduce urodynamic signs of BO. Targeting the NO/cGMP pathway via compounds acting on sGC might become a new approach to treat BO.

Topics: Animals; Benzoates; Biphenyl Compounds; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Drug Therapy, Combination; Guanylate Cyclase; Hydrocarbons, Fluorinated; Male; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Urethral Obstruction; Urinary Bladder; Urinary Bladder, Overactive

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.. 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 microm) assessed on carbachol-activated (1 microm) preparations, and on contractions induced by transmural activation of nerves (electrical field stimulation, EFS). Levels of cGMP and cAMP were determined using radioimmunoassays.. Vardenafil caused concentration-dependent relaxations of carbachol-contracted detrusor, the mean (sd) of which at 100 microm was 91 (4)% in control and 100% in PUO rats. The -log 50% inhibitory concentration (IC(50)) 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 microm (P < 0.05) although -log IC(50) 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 microm 19 (3)% of the control contraction remained, vs 8 (1)% for preparations from obstructed rats, and 11 (4)% in mucosa-denuded preparations.. 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.

Topics: Animals; Cyclic AMP; Cyclic GMP; Female; Imidazoles; Muscle Relaxation; Muscle, Smooth; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; Sulfones; Triazines; Urethral Obstruction; Urinary Bladder; Vardenafil Dihydrochloride