Levitra-induced relaxation and cyclic nucleotide levels in normal and obstructed rat urinary bladderOBJECTIVE To study the effects of the phosphodiesterase-5 inhibitor, Levitra, 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 Levitra (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. RESULTS Levitra 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 Levitra 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 Levitra. In control rats, the levels of cAMP increased from 12.8 (2.5) to 18.9 (0.9) (P < 0.05) after Levitra. In mucosa-denuded preparations the cAMP levels after Levitra 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). Levitra 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. CONCLUSION In normal rats, Levitra 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 Levitra-induced relaxation of rat detrusor, also in obstructed and mucosa-denuded preparations, is mediated via cAMP. |
