H₂O₂ and TCDC impair the contraction induced by CCK-8, ACh and KCl without affecting the actions of PGE₂ and damage functions of membrane proteins except for PGE₂ receptors. The aim of this study was to examine whether this preserved PGE₂ actions contribute to cytoprotective mechanisms against reactive oxygen species. Muscle cells from guinea pig GB were obtained by enzymatic digestion. Levels of lipid peroxidation and activities of SOD and catalase were determined by spectrophotometry. Pretreatment with PGE₂ prevented the inhibition of H₂O₂ or TCDC on agonists (CCK-8, ACh, KCl) induced contraction, reduced the expected increase in lipid peroxidation and activities of catalase and SOD caused by H₂O₂ and TCDC. Incubation with CCK-8 for 60 min desensitized CCK-1 receptors up to 30 min whereas no receptor desensitization was observed after PGE₂-pretreatment. Cholesterol-rich liposomes treatment enhanced the inhibition of H₂O₂ and TCDC on agonists induced contraction including that of PGE₂. Pretreatment with PGE₂ prior to H₂O₂ and TCDC did not block completely their inhibition on agonists induced contraction. Cholesterol-rich liposomes treatment impaired the expected increase in catalase activities in response to PGE₂. We conclude that pretreatment with PGE₂ prevents the muscle cell damage caused by H₂O₂ and TCDC due to the resistance of PGE2 receptors to agonist induced desensitization. The preservation of PGE₂ receptors may be designed to conserve these cytoprotective functions that are however impaired by the presence of excess cholesterol in the plasma membrane.