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

Sandner P, Tinel H, Affaitati G, Costantini R, Giamberardino MA - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Bayer Health Care AG - Global Drug Discovery, Department of Cardiology - Pharma Research Center Wuppertal, Wuppertal, Germany; Institute of Pharmacology, Hannover Medical School, Hannover, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Contractility of isolated ureters.Noradrenaline (10μM)—induced oscillations of isolated rat ureter (upper panel) which can be blocked by vardenafil (10μM) (lower panel).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4624930&req=5

pone.0141477.g002: Contractility of isolated ureters.Noradrenaline (10μM)—induced oscillations of isolated rat ureter (upper panel) which can be blocked by vardenafil (10μM) (lower panel).

Mentions: Representative original recordings of force from isolated rat ureters are shown in Fig 2. High potassium (20mM) induced spontaneous phasic contractions. When noradrenaline (10μM) was added, the preparations became spontaneously active. Addition of the vehicle was not able to reduce noradrenaline-induced spontaneous activity (Fig 2, upper panel). The application of vardenafil (10μM) reduced the frequency of the oscillations (Fig 2, lower panel).


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

Sandner P, Tinel H, Affaitati G, Costantini R, Giamberardino MA - PLoS ONE (2015)

Contractility of isolated ureters.Noradrenaline (10μM)—induced oscillations of isolated rat ureter (upper panel) which can be blocked by vardenafil (10μM) (lower panel).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4624930&req=5

pone.0141477.g002: Contractility of isolated ureters.Noradrenaline (10μM)—induced oscillations of isolated rat ureter (upper panel) which can be blocked by vardenafil (10μM) (lower panel).
Mentions: Representative original recordings of force from isolated rat ureters are shown in Fig 2. High potassium (20mM) induced spontaneous phasic contractions. When noradrenaline (10μM) was added, the preparations became spontaneously active. Addition of the vehicle was not able to reduce noradrenaline-induced spontaneous activity (Fig 2, upper panel). The application of vardenafil (10μM) reduced the frequency of the oscillations (Fig 2, lower panel).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Bayer Health Care AG - Global Drug Discovery, Department of Cardiology - Pharma Research Center Wuppertal, Wuppertal, Germany; Institute of Pharmacology, Hannover Medical School, Hannover, Germany.

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.

No MeSH data available.


Related in: MedlinePlus