Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice.
OBJECTIVE
Phosphodiesterase type 4 (PDE4) has been previously shown to regulate colonic contractile activity in vitro. In this study, the effects of PDE4 inhibition were assessed in a model of stress-induced defecation previously demonstrated to be due to increased colonic transit/evacuation.


METHODS
Rats were individually placed in a mild restraint cage and placed into a 12 degrees C environment (cold-restraint stress) for 60 min. Mice received restraint (only) stress at room temperature for 30 min. Loperamide (positive control compound) or two different PDE4 inhibitors (rolipram and roflumilast) were administered orally at several doses to the rodents 1 h before stress began. Vehicle alone was administered for comparison. The number of fecal pellets expelled during stress (fecal pellet output), total fecal pellet wet weight and total fecal water content were measured.


RESULTS
Loperamide produced a dose-related decrease (ID(50)s in mg/kg) in fecal pellet output (rat = 7.4, mouse = 0.7) and significantly decreased fecal wet weight (72.9%) and decreased fecal percent water content (9.4%). The two PDE4 inhibitors produced a similar dose-related inhibition of fecal pellet output. Rolipram exhibited ID(50)s in rat and mouse of 14.1 and 27.1, respectively. Rolipram significantly decreased fecal wet weight (58.8%) but increased fecal percent water content (15.0%). For roflumilast, ID(50)s were 24.2 mg/kg and 12.4 in the rat and mouse, respectively. Although roflumilast also significantly (p < 0.05) decreased fecal wet weight (47.2%), it did not significantly increase fecal percent water content.


CONCLUSIONS
These data indicate that PDE4 inhibition is effective in reducing rodent stress-induced defecation, provides the first functional data on a potential role for PDE4 activity in the colonic evacuation response to stress, and indicates the potential utility of PDE4 inhibitors in functional bowel disease such as irritable bowel syndrome requires further evaluation.
Barone
Frank C
FC
Discovery Research, High Throughput Biology, GlaxoSmithKline, King of Prussia, PA 19406, USA. frank.c.barone@verizon.net
Barton
Matthew E
ME
White
Ray F
RF
Legos
Jeffrey J
JJ
Kikkawa
Hideo
H
Shimamura
Midori
M
Kuratani
Kazuyoshi
K
Kinoshita
Mine
M
D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000930:Antidiarrheals / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003080:Cold Temperature; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003672:Defecation / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D043183:Irritable Bowel Syndrome / Q000209:etiology / Q000517:prevention & control; D008139:Loperamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013315:Stress, Psychological / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*
D000631:Aminopyridines; D000930:Antidiarrheals; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D008139:Loperamide; D020889:Rolipram