Modulation of Gastrointestinal Smooth Muscle Motility by Losartan in Rats

Abstract

A drug‐induced gastrointestinal disturbance is an important adverse drug reaction. It has been reported to occasionally present with inflammatory bowel disease‐like manifestations. The mechanism by which this occurs for several drugs is yet to be fully understood. Time and money are sometimes wasted in the diagnosis and treatment (owing to inappropriate strategies) of gastroenterological cases that are simply drug‐induced. Proper assessment of the gastrointestinal actions of drugs would contribute to the knowledge required to significantly address this situation. Losartan is an antihypertensive implicated in diarrhoea, constipation and abdominal cramps, mechanisms of which are yet to be well understood. This preclinical study was carried out to examine the action of losartan on gastrointestinal smooth muscles using rat tissues. Albino rats' caecal and duodenal tissues (4–5 cm) were excised, suspended in tissue baths containing aerated Tyrode physiological solution and connected to Powerlab data acquisition system via isometric force transducers. The direct effect of losartan (0.332–990 μg/ml) and its influence on contractile responses to acetylcholine (1.83×10−5–5.45×10−3 μM), carbachol (1.82×10−4–5.42×10−2 μM) and potassium chloride (2.28×10 – 6.64×10 μM) were determined. Concentration‐dependent contraction of the rats' caecum and duodenum tissues by losartan was observed; with median effective concentration (EC50) values of 8.30 μg/ml and 8.41 μg/ml for both tissues respectively. Losartan significantly (p<0.01) reduced acetylcholine‐induced contraction of the rats' caecum. A significant (p<0.0001) reversal of carbachol‐induced contraction by losartan at 990 μg/ml was observed in the caecum and duodenum tissues. Significant (p<0.0001) reduction in potassium chloride‐induced contraction of the duodenum was also noted, and a similar trend was observed with the caecum. These findings demonstrate that losartan modulates intestinal smooth muscle tone by interfering with one or more of the several pathways involved in gastrointestinal motility. One pathway that seems likely from the observations made in this study is the cholinomimetic pathway. Additional studies to further elucidate the involvement of this pathway and other mechanisms through which losartan mediates its action would enhance understanding of its pharmacology in this regard. The knowledge thus gained would allow for possible optimization of its therapeutic benefit to mankind, as a more rational approach to its use would become possible, due to the availability of additional relevant information.Support or Funding InformationThis work was carried out without external funding.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.