Effects of ATP-sensitive potassium channel blockers on vascular hyporeactivity, mesenteric blood flow, and survival in lipopolysaccharide-induced septic shock model

• Published in: Canadian journal of physiology and pharmacology 2016-08, Vol.94 (8), p.858-867
• Main Authors: Boz, Mustafa, Atilla, Pergin, Iskit, Alper B, Ilhan, Mustafa
• Format: Article
• Language: English
• Subjects: 5-HD; Adenosine triphosphatase; Adenosine triphosphate; Animals; ATP; Blood; Blood flow; Blood Flow Velocity - drug effects; Blood Flow Velocity - physiology; bloqueurs du canal K; Cardiovascular system; Causes of; channel blockers; choc septique; Dose-Response Relationship, Drug; Effects; glibenclamide; Health aspects; HMR-1098; KATP Channels - antagonists & inhibitors; KATP Channels - physiology; Lipopolysaccharides; Lipopolysaccharides - toxicity; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Mice; Potassium channel blockers; Potassium Channel Blockers - pharmacology; Potassium Channel Blockers - therapeutic use; Prognosis; Rats; Rats, Wistar; Regional Blood Flow - drug effects; Regional Blood Flow - physiology; repaglinide; Sepsis; Septic shock; Shock, Septic - chemically induced; Shock, Septic - drug therapy; Shock, Septic - mortality; Survival Rate - trends; Vasoconstriction - drug effects; Vasoconstriction - physiology
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2015-0381

In this study, the possible therapeutic effects of various ATP-sensitive potassium channel (K ATP ) blockers (glibenclamide, repaglinide, 5-HD, HMR-1098) have been tested in experimental septic shock model. Rats were given lipopolysaccharide (1 mg·kg −1 ) to create experimental shock model and 4 h later, under 400 mg·kg −1 chloral hydrate anesthesia, parameters such as blood pressure, mesenteric blood flow, the response of mesenteric circulation to phenylephrine (vasoconstrictor stimulation), and organ and oxidative damage were analyzed. Also 75 mg·kg −1 lethal dose of lipopolysaccharide was given to mice and effects of K ATP blockers on survival have been tested. Non-selective blocker glibenclamide with sulphonylurea structure and sarcolemmal K ATP channel blocker HMR-1098, which have the similar chemical structure, have improved the pathological parameters such as decrease in mesenteric blood flow, vascular hyporeactivity, but could not prevent the decrease in blood pressure, and oxidative and organ damage that were observed in the shock model. Also, both blockers have decreased the mortality rate from 80% to 40%–50%. Similar (preventive) therapeutic effects were not observed with non-selective blocker repaglinide and mitochondrial K ATP channel blocker 5-HD, which were non-sulphonylurea structure. As a result, only K ATP channel blockers that have sulphonylurea structure can be a new therapeutic approach in septic shock.