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.
We evaluated the effects of 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1H)-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.
Sivarao
Digavalli V
DV
Neuroscience Drug Discovery, Pharmaceutical Research Institute, Bristol Myers Squibb Co., Wallingford, CT 06067, USA. siva.digavalli@bms.com
Newberry
Kimberly
K
Langdon
Shaun
S
Lee
Alicia V
AV
Hewawasam
Piyasena
P
Plym
Mary Jane
MJ
Signor
Laura
L
Myers
Robert
R
Lodge
Nicholas J
NJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists* / Q000502:physiology*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry; D015363:Quinolones / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000188:drug therapy* / Q000503:physiopathology; D014781:Viscera / Q000187:drug effects / Q000502:physiology
C501655:4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1H)-one; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011804:Quinolines; D015363:Quinolones