Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

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.

Viscero‐visceral hyperalgesia in dysmenorrhoea plus previous urinary calculosis: Role of myofascial trigger points and their injection treatment in the referred area

“…Dysmenorrhoea and urinary calculosis are both frequent and highly painful clinical conditions, whose treatment can be per se very difficult even in the case they occur in isolation in the patients, with unsatisfactory results in many cases of pharmacological therapies aimed at a direct control of each of the conditions (e.g. with NSAIDs or spasmolytics; Berkley, ; Sandner, Tinel, Affaitati, Costantini, & Giamberardino, ). The situation becomes exponentially critical when they co‐exist in the same patients, giving rise to viscero‐visceral hyperalgesia, with long‐term consequences which may outlive the presence of the disease in one viscera, as in the cases discussed in the present paper.…”

Inhibition of PDE‐4 isoenzyme attenuates frequency and overall contractility of agonist‐evoked ureteral phasic contractions

“…Several clinical trials have suggested that PDE‐5 inhibitors, such as tadalafil and sildenafil, have potential for promoting the passage of kidney stones 20–22 . These inhibitors were also reported to attenuate the tension of isolated human, 23 porcine, 24 and rat 25 ureteral smooth muscle. These findings suggest that PDE‐5 inhibitors may have therapeutic potential for promoting ureteral stone passage by relaxing ureteral smooth muscle.…”

An objective and automated method for evaluating abdominal hyperalgesia in a rat model for endometriosis

“…19,20 Unfortunately, monitoring spontaneous pain is considered challenging in animal pain studies and can be addressed by studying spontaneous behaviour. 11,15,17,18,[21][22][23][24][25] After irritation of the peritoneum, chemical inflammation of the uterus, artificial ureteral calculosis or abdominal surgery, changes in spontaneous behaviours have been observed including for instance hunching, licking of the abdomen, stretching and arching of the back, loss of balance during grooming or rearing and pushing the abdomen to the floor. 12,18,[22][23][24][25] Also, the absence of behavioural aspects can be indicative of pain/discomfort.…”