Enhanced cyclooxygenase 2‐mediated vasodilatation in coronary arteries from insulin resistant obese Zucker rats

Abstract

Despite selective inhibitors of COX‐2 are highly effective anti‐inflammatory and analgesic drugs, they have been reported to increase the risk of myocardial infarction and atherothrombotic events. In the current study we investigated the role of arachidonic acid (AA) metabolism via cyclooxygenase 1 (COX)‐1) and 2 (COX‐2) in coronary arteries from prediabetic obese Zucker rats (OZR). Branches from the coronary artery from OZR and from lean Zucker (LZR) rats were mounted in microvascular myographs to assess vascular function and COX expression was determined by both immunohistochemistry and Western blot. AA elicited relaxations of similar magnitude in arteries from LZR and OZR which were abolished by mechanical endothelial cell removal. The AA relaxant responses were enhanced by selective inhibition of COX‐1 in both LZR and OZR. Inhibition of COX‐2 markedly reduced the vasodilatation induced by AA in OZR, but not in LZR. COX‐1 was distributed in the coronary endothelium from both LZR and OZR, while COX‐2 was predominantly expressed in the endothelium from OZR. Whereas COX‐1 protein levels were similar in both strains, COX‐2 protein content was increased by 2.5‐ fold in arteries from OZR. AA is mainly metabolised to vasoconstrictor prostanoids via COX‐1 in coronary arteries from healthy animals. In arteries from insulin resistant OZR, endothelial COX‐2 is up‐regulated to produce vasodilator prostaglandins.