ABSTRACT
BACKGROUND AND OBJECTIVES: Ischemic post-conditioning (PostC) has been demonstrated as a novel strategy to harness nature's protection against myocardial ischemia-reperfusion (I/R). Hypercholesterolemia (HC) has been reported to block the effect of PostC on the heart. Angiotensin II type-1 (AT1) modulators have shown benefits in myocardial ischemia. The present study investigates the effect of a novel inhibitor of AT1, azilsartan in PostC of the heart of normocholesterolemic (NC) and HC rats. MATERIALS AND METHODS: HC was induced by the administration of high-fat diet to the animals for eight weeks. Isolated Langendorff's perfused NC and HC rat hearts were exposed to global ischemia for 30 min and reperfusion for 120 min. I/R-injury had been assessed by cardiac hemodynamic parameters, myocardial infarct size, release of tumor necrosis factor-alpha troponin I, lactate dehydrogenase, creatine kinase, nitrite in coronary effluent, thiobarbituric acid reactive species, a reduced form of glutathione, superoxide anion, and left ventricle collagen content in normal and HC rat hearts. RESULTS: Azilsartan post-treatment and six episodes of PostC (10 sec each) afforded cardioprotection against I/R-injury in normal rat hearts. PostC protection against I/R-injury was abolished in HC rat hearts. Azilsartan prevented the HC-mediated impairment of the beneficial effects of PostC in I/R-induced myocardial injury, which was inhibited by L-N⁵-(1-Iminoethyl)ornithinehydrochloride, a potent inhibitor of endothelial nitric oxide synthase (eNOS). CONCLUSION: Azilsartan treatment has attenuated the HC-induced impairment of beneficial effects of PostC in I/R-injury of rat hearts, by specifically modulating eNOS. Azilsartan may be explored further in I/R-myocardial injury, both in NC and HC conditions, with or without PostC.
Subject(s)
Animals , Rats , Angiotensin II , Collagen , Creatine Kinase , Diet, High-Fat , Glutathione , Heart , Heart Ventricles , Hemodynamics , Hypercholesterolemia , Ischemia , Ischemic Postconditioning , L-Lactate Dehydrogenase , Myocardial Infarction , Myocardial Ischemia , Nitric Oxide Synthase Type III , Reperfusion , Reperfusion Injury , Superoxides , Troponin I , Tumor Necrosis Factor-alphaABSTRACT
<p><b>AIM</b>To design and synthesize novel quinoxaline derivatives as antitumor agents.</p><p><b>METHODS</b>Using 4-chloro-2-nitroaniline as a starting compound, followed by substitution, reductive cyclization, oxidation, and chlorination, to give the key intermediate 2,7-dichloroquinoxaline (7), which reacted with different phenolic compounds to afford quinoxaline derivatives.</p><p><b>RESULTS</b>The structures of the target molecules were characterized by elemental analysis, 1H NMR, MS, and IR.</p><p><b>CONCLUSION</b>At concentration of 1 x 10(-4) mol x L(-1), some of the derivatives showed equal antitumor activities to XK469.</p>