Effect of 4-(5-Chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1H)-one (BMS-223131), a Novel Opener of Large Conductance Ca2+-Activated K+ (Maxi-K) Channels on Normal and Stress-Aggravated Colonic Motility and Visceral Nociception

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 313; no. 2; pp. 840 - 847
• Main Authors: Sivarao, Digavalli V, Newberry, Kimberly, Langdon, Shaun, Lee, Alicia V, Hewawasam, Piyasena, Plym, Mary Jane, Signor, Laura, Myers, Robert, Lodge, Nicholas J
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.05.2005
• Subjects: Animals; Blood Pressure - drug effects; Blood Pressure - physiology; Colon - drug effects; Colon - physiology; Dose-Response Relationship, Drug; Female; Gastrointestinal Motility - drug effects; Gastrointestinal Motility - physiology; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; Large-Conductance Calcium-Activated Potassium Channels; Pain Measurement - drug effects; Pain Measurement - methods; Potassium Channels, Calcium-Activated - agonists; Potassium Channels, Calcium-Activated - physiology; Quinolines - administration & dosage; Quinolines - chemistry; Quinolones - administration & dosage; Quinolones - chemistry; Rats; Rats, Wistar; Stress, Physiological - drug therapy; Stress, Physiological - physiopathology; Viscera - drug effects; Viscera - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.079285

We evaluated the effects of 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1 H )-one (BMS-223131), an opener of large conductance Ca 2+ -activated potassium (maxi-K) channels, on normal and stress-exacerbated colonic motility and visceral nociception in the rat. Fecal output was employed as an index of motility. Visceral nociception, in response to intracolonic balloon distension (10–90 mm Hg; 30 s duration), was evaluated using one of three indices: change in blood pressure, abdominal withdrawal, or myoelectrical activity. BMS-223131 (2, 6, or 20 mg/kg i.p.) produced a small but dose-dependent and significant reduction in cumulative 24-h fecal output. Fecal output in response to stress (1-h restraint plus bursts of air to the face) was markedly inhibited by BMS-223131, and moisture content was significantly reduced. With regard to visceral pain, the transient and distention-dependent reduction in arterial pressure in anesthetized animals was inhibited by BMS-223131 in a dose-dependent manner. Distension-induced abdominal withdrawal in conscious rats was also dose-dependently attenuated by BMS-223131. BMS-223131 at a dose of 20 mg/kg markedly attenuated the increase in myoelectrical activity evoked by balloon distention in conscious animals. BMS-223131 was also evaluated in viscerally hypersensitive rats (sensitized as neonates by intracolonic mustard oil) where it produced a robust dose-dependent attenuation of the abdominal withdrawal response. Compared with naive animals, BMS-223131 was more potent in the sensitized animals. Thus, BMS-223131 effectively reduced stress-induced colonic motility and visceral nociception supporting the potential utility of maxi-K channel openers for the treatment of bowel disorders involving dysfunctional motility and visceral sensitivity.