NO-1886, a lipoprotein lipase activator, attenuates contraction of rat intestinal ring preparations.

Abstract

Various intestinal symptoms or diseases are closely associated with intestinal motility, which may be altered by metabolic disturbances associated with diabetes and obesity. It is therefore important that drugs used in the treatment of metabolic disorders should not have any adverse effects on the intestine. In the present study, we examined whether [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886), a lipoprotein lipase activator with anti-diabetic and/or anti-obese activity, affects stimulant-induced intestinal contractility. Administration of NO-1886 to intestinal ring preparations of ileum, rectum and colon isolated from Wistar rats attenuated or relaxed contraction induced by a high K+ environment or acetylcholine (ACh). This effect of NO-1886 was dependent on extracellular Ca(2+) and intracellular myosin light chain kinase activity. Our results also showed that ACh-induced colonic contraction was significantly higher in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) than in the non-obese Long-Evans Tokushima Otsuka (LETO) rats. The hypercontractility observed in the colons of OLETF rats occurred concomitantly with an elevation in muscarinic M3 ACh receptor protein levels. Administration of NO-1886 attenuated the obesity-induced hypercontractility of the colonic rings of OLETF rats. Thus, intestinal contractile system would be a novel pharmacological target of the lipoprotein lipase activator NO-1886.

• Authors: Qishisan Wu, Nagakatsu Harada, Aki Nakamura, Masaki Yoshida, Kazuaki Mawatari, Atsushi Hattori, Qinkai Li, Takaaki Shimohata, Yinhua, Xin Lian, Masayuki Nakano, Toshio Hosaka, Akira Takahashi, Yutaka Nakaya
• Journal: The journal of medical investigation : JMI (J Med Invest) Vol. 55 Issue 1-2 Pg. 61-70 (Feb 2008) ISSN: 1343-1420 [Print] Japan
• PMID: 18319547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Hypolipidemic Agents
• Lipoprotein Lipase Activators
• Organophosphorus Compounds
• Peptides
• 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide
• Myosin-Light-Chain Kinase
• Calcium

Topics

• Animals
• Benzamides (pharmacology)
• Calcium (physiology)
• Diabetes Mellitus, Type 2 (complications)
• Gastrointestinal Motility (drug effects)
• Hypolipidemic Agents (pharmacology)
• In Vitro Techniques
• Intestinal Diseases (etiology, physiopathology)
• Intestines (drug effects)
• Lipoprotein Lipase Activators
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects)
• Myosin-Light-Chain Kinase (physiology)
• Obesity (complications)
• Organophosphorus Compounds (pharmacology)
• Peptides (pharmacology)
• Rats
• Rats, Inbred OLETF
• Rats, Wistar