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Aims: 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)., Methods: 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., Results: 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., Conclusions: 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., (© 2014 Wiley Periodicals, Inc.)

Aims: We evaluated effects of BoNT-A injections on bladder function and histomorphology in a male-rat-overactive-bladder model, created by partial urethral obstruction., Methods: A total of 45 male Sprague-Dawley rats were separated into 5 groups. Partial urethral obstruction (PUO) was created in all rats except the control group. At the 6th week after PUO, intradetrusor injections of 50 µl of saline (2 sham groups) or 50 µl BoNT-A (2 treatment groups) was performed. Treatment and sham groups were studied 5 and 30 days after injection and neuropharmacological and histomorphological findings on bladder tissues were compared to the control group., Results: Bladder muscle hypertrophy and connective tissue increase were detected at 5th and more prominent at 30th day after saline injection. Intradetrusor BoNT-A injection significantly reduced PUO-induced histological changes in the bladder tissue both at 5th and 30th day after injection. At 5th day after saline injection, a significantly increased contractile response to electrical field stimulation (EFS) and carbachol were recorded in the saline group and this effect disappeared at 30th day. There was no statistically significant difference between BoNT-A and control groups in terms of contractile responses to EFS and carbachol, both at 5th and 30th days., Conclusion: Partial urethral obstruction induces increased bladder tissue contractile responses to neurogenic and pharmacological stimulation and intradetrusor BoNT-A injections decrease these responses at 5th days after injection. As the unique finding of this study, intradetrusor BoNT-A injections appear to decrease bladder fibrosis secondary to PUO in the male rat model., (Copyright © 2012 Wiley Periodicals, Inc.)

Aims: Beta3-adrenoceptor selective agonists are evaluated as a new treatment for patients with lower urinary tract symptoms . It is believed that β3-AR selective agonists exert their effects via a peripheral site of action. However, β3-ARs have been found in brain tissue. This study examined whether β3-ARs are present in rat sacral spinal cord, and whether there are differences in β3-AR expression between normal and partial urethral obstruction (PUO) animals, and furthermore assessed the functional relevance of spinal β3-ARs for micturition., Methods: Thirty-eight male Sprague-Dawley rats underwent either PUO or sham-operation. Two weeks after operation, half of the animals were used for histomorphological analysis. Remaining animals were used for functional experiments, where a β3-AR selective agonist, BRL 37344, was given intrathecally. Bladder function was assessed by continuous cystometry in non-anesthetized animals before and after drug administration., Results: Beta3-ARs were found in sacral spinal cord segments with an accumulation in the ventral horn. There was a significant increase of β3-AR expression in obstructed rats. In functional experiments obstructed rats showed increased bladder weight, micturition frequency, spontaneous activity, and bladder pressures (all P < 0.05) compared to controls. Intrathecally administered BRL 37344 showed no effect in non-obstructed rats. In obstructed rats intrathecal BRL 37344 significantly reduced bladder pressures, spontaneous activity, and micturition frequency (all P < 0.05)., Conclusions: Beta3-ARs are present in rat sacral spinal cord, and are significantly up-regulated after PUO. Besides their well-established peripheral site of action in the treatment of voiding dysfunction, β3-AR selective agonists might exert relevant effects at a central nervous site of action., (Copyright © 2011 Wiley-Liss, Inc.)

Aims: Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists., Methods: We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil., Results: In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED(15)/ID(50)) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65)., Conclusions: Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients., ((c) 2006 Wiley-Liss, Inc.)