Sivarao Digavalli V, Newberry Kimberly, Langdon Shaun, Lee Alicia V, Hewawasam Piyasena, Plym Mary Jane, Signor Laura, Myers Robert, Lodge Nicholas J
Neuroscience Drug Discovery, Pharmaceutical Research Institute, Bristol Myers Squibb Co., Wallingford, CT 06067, USA.
J Pharmacol Exp Ther. 2005 May;313(2):840-7. doi: 10.1124/jpet.104.079285. Epub 2005 Feb 8.
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.
我们评估了4-(5-氯-2-羟基苯基)-3-(2-羟乙基)-6-(三氟甲基)-喹啉-2(1H)-酮（BMS-223131），一种大电导钙激活钾（maxi-K）通道开放剂，对大鼠正常和应激加剧的结肠运动及内脏痛觉的影响。粪便排出量用作运动的指标。使用以下三项指标之一评估对结肠内气囊扩张（10 - 90 mmHg；持续30秒）的内脏痛觉：血压变化、腹部回撤或肌电活动。腹腔注射BMS-223131（2、6或20 mg/kg）可使24小时累积粪便排出量出现小幅度但呈剂量依赖性的显著减少。BMS-223131显著抑制了应激（1小时束缚加面部吹气）引起的粪便排出量，且水分含量显著降低。关于内脏疼痛，麻醉动物中动脉压的短暂且与扩张相关的降低被BMS-223131以剂量依赖性方式抑制。清醒大鼠中扩张诱导的腹部回撤也被BMS-223131剂量依赖性地减弱。20 mg/kg剂量的BMS-223131显著减弱了清醒动物中气囊扩张引起的肌电活动增加。还在内脏超敏大鼠（新生期经结肠内芥子油致敏）中评估了BMS-223131，它在其中产生了强大的剂量依赖性腹部回撤反应减弱。与未致敏动物相比，BMS-223131在致敏动物中更有效。因此，BMS-223131有效降低了应激诱导的结肠运动和内脏痛觉，支持maxi-K通道开放剂在治疗涉及运动功能障碍和内脏敏感性的肠道疾病方面的潜在效用。
