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NO-1886, a lipoprotein lipase activator, attenuates contraction of rat intestinal ring preparations
Qishisan Wu1, Nagakatsu Harada, Aki Nakamura
1Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
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.
Insights
The lipoprotein lipase activator NO-1886 demonstrates potential in managing intestinal motility issues linked to metabolic disorders. This compound, NO-1886, was found to relax intestinal contractions, offering a novel therapeutic target for diabetes and obesity.
Area of Science:
- Pharmacology
- Gastroenterology
- Metabolic Disorders
Background:
- Intestinal motility is crucial for gut health and can be disrupted by diabetes and obesity.
- Drugs for metabolic disorders must not negatively impact intestinal function.
- Lipoprotein lipase activators, like NO-1886, show anti-diabetic and anti-obese potential.
Purpose of the Study:
- To investigate the effects of NO-1886 on stimulant-induced intestinal contractility.
- To determine if NO-1886 impacts intestinal motility in the context of metabolic disturbances.
Main Methods:
- Isolated rat intestinal preparations (ileum, rectum, colon) from Wistar, LETO, and OLETF rats were used.
- Intestinal contractility was induced by high K+ or acetylcholine (ACh).
- The influence of NO-1886 on contractility, extracellular Ca(2+), and myosin light chain kinase activity was assessed.
Main Results:
- NO-1886 attenuated or relaxed high K+- and ACh-induced contractions in rat intestinal segments.
- Obese OLETF rats exhibited significantly higher ACh-induced colonic contraction than LETO rats.
- This hypercontractility in OLETF rats correlated with elevated M3 ACh receptor levels.
- NO-1886 effectively reduced the obesity-induced hypercontractility in OLETF rat colons.
Conclusions:
- The intestinal contractile system is a potential pharmacological target for NO-1886.
- NO-1886 demonstrates a beneficial effect on intestinal motility, particularly in models of obesity.
- This suggests NO-1886 may be a valuable therapeutic agent for metabolic disorders with gastrointestinal complications.
