Abstract
Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP) / phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a)the sex-specific PDE5 distribution in the rat ureter; b)the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c)the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats’ ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of “ureteral crises” and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.
Highlights
In the general population, 12 to 15% of subjects develop kidney stones throughout their life span, with incidence rates that have steadily increased in recent years [1,2,3,4]
In this study we used a rat model of artificial ureteral calculosis set up by our group to test the effects of phosphodiesterase type 5 (PDE5) inhibitors and soluble guanylate cyclase (sGC) stimulators on colic pain and referred muscle hyperalgesia vs placebo and vs a classic spasmolytic[22]
Number and global duration of ureteral crises are significantly and directly related to the extent of the muscle hyperalgesia. This validated animal model of artificial ureteral calculosis closely resembles the human condition of urinary colics from calculosis, as it reproduces the spontaneous pain perceived by patients, and the referred muscle hyperalgesia, which is longlasting and has been shown to be correlated to the number of colics experienced [1,6,7]
Summary
12 to 15% of subjects develop kidney stones throughout their life span, with incidence rates that have steadily increased in recent years [1,2,3,4]. In this study we used a rat model of artificial ureteral calculosis set up by our group to test the effects of PDE5 inhibitors and sGC stimulators on colic pain and referred muscle hyperalgesia vs placebo and vs a classic spasmolytic (hyoscine-N-butylbromide)[22]. This model is suitable for testing active compounds on urinary pain. In the present study we aimed at evaluating the effects of PDE5 inhibitors and sGC stimulators on the behaviour indicative of pain, and on the destiny of the stone and stone expulsion rates
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