title: Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: a possible 'anti-proarrhythmic' role for amlodipine.
abstract: Type II diabetes was shown to prolong the QT interval on the ECG and to promote cardiac arrhythmias. This is not so clear for metabolic syndrome, a precursor state of type II diabetes. The objectives of the present study were to generate a guinea pig model of metabolic syndrome by long-term exposure to diabetogenic diets, and to evaluate the monophasic action potential duration (MAPD)-modulating effects of drugs in these animals. Male Hartley guinea pigs were fed with either the control, the High Fat High Sucrose (HFHS) or the High Fat High Fructose (HFHF) diet for 150 days. Evolution of weight, blood cholesterol, triglycerides, urea and glucose tolerance were regularly monitored. Histopathological evolution was also evaluated in target organs such as pancreas, heart, liver and kidneys. Ex vivo experiments using the Langendorff retroperfusion technique, isolated hearts from guinea pigs either fed with the control, the HFHS or the HFHF diet were exposed to dofetilide 20 nM (D), chromanol 293B 10 μM (C) and amlodipine 100 nM (A) in different drug combinations and monophasic action potential duration was measured at 90% repolarization (MAPD₉₀). Our data show that it is possible to generate a guinea pig model of metabolic syndrome by chronic exposure to diabetogenic diets. Minor histopathological abnormalities were observed, mainly in the pancreas and the liver. Metabolic syndrome potentiates the MAPD-prolonging actions of I(Kr)-blocking (dofetilide) and I(Ks)-blocking (chromanol 293B) drugs, an effect that is reversible upon administration of the calcium channel blocker amlodipine.
authors.affiliation: Faculté de Pharmacie, Université Laval, 1050 Avenue de la Médecine, Québec QC, Canada.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Caillier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilote
authors.forename: Dany
authors.initials: D
authors.lastname: Patoine
authors.forename: Xavier
authors.initials: X
authors.lastname: Levac
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.forename: Pascal
authors.initials: P
authors.lastname: Daleau
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.forename: Benoit
authors.initials: B
authors.lastname: Drolet
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004562:Electrocardiography / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*
chemical_list: D000959:Antihypertensive Agents; D017311:Amlodipine