Therefore it would be worthwhile investigating if cGMP mediated treatment approaches are here different. It might also be interesting to investigate in future studies how cGMP effects in such kinds of in vivo models compare with effects of alpha1 antagonists, which are already in use clinically for stone expulsion 12 This is also interesting since it has been found that alpha blockers fasten stone expulsion but have little effect on overall expulsion rate.

BAY 41-2272 had more pronounced effects than vardenafil and the classic spasmolytic hyposcine-N-butylbromide. Therefore, we tested if the treatment with vardenafil and BAY 41-2272 has an impact on the ureteral pain behaviour/referred muscle hyperalgesia and on stone expulsion in an animal model of ureteral calculosis. The results of the present study show that PDE5 mRNA is abundantly expressed in the ureter of male and female rats and expression levels in ureteral tissues are as high as in corpus cavernosum in which PDE5 plays a significant functional role.

Except vardenafil alone, all experimental compounds promoted a higher stone elimination with respect to placebo, with a two-fold increase by BAY 41-2272 alone (similarly to ketoprofen, and higher than hyoscine-N-butylbromide) and a three-fold increase by ketoprofen + BAY 41-2272. The application of vardenafil (10μM) reduced the frequency of the oscillations ( Fig 2 , lower panel). Addition of the vehicle was not able to reduce noradrenaline-induced spontaneous activity ( Fig 2 , upper panel).

Rats were studied for the minimum period necessary to verify the effects of the drugs administered (4 days, based on previous work) and were killed at the end of the observation period via an overdose of barbiturate. One-way ANOVA and ANOVA for repeated measures (in the case of thresholds) were applied to assess the effects of the various treatments on the different behavioural parameters. Over the whole study period the rats were housed one per cage (plexiglass 35 x 23 x 18 cm) in a temperature / humidity-controlled environment, subjected to a 12:12 h dark-light cycle (8:00 a.m.- 8:00 p.m. artificial light), with free access to food and water 29 The video-tape recording was interrupted for 30 min each morning (9:00-9:30) to allow sensitivity testing of the left oblique muscle and weighing of the animals from the 1st day post-muscle implantation to the 4th day post-stone formation, as well as administration of the experimental compounds during the treatment phase.

As already stated above, this validated animal model of artificial ureteral calculosis closely resembles the human condition of urinary colics from calculosis, as it reproduces not only the spontaneous pain perceived by patients, but also the referred muscle hyperalgesia, which is longlasting and has been shown to be correlated to the number of colics experienced 1 , 6 , 7 As in humans, the destiny” of the stone in implanted rats differs, as shown by autopsy findings at the end of the behavioural evaluation period; in some animals the stone appears to have been expelled, in others it has moved along the ureter, and in others it remains in the original position creating obstruction of the urinary tract.
https://medschool.ucsd.edu/som/anesthesia/research/faculty-research/Documents/Hottinger-Liang_AJLM%20NTIDrugsFinal_38.4.pdf
https://www.healthaffairs.org/doi/10.1377/hlthaff.28.5.w957
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