title: Suppression of store overload-induced calcium release by hydroxylated metabolites of carvedilol.
abstract: Carvedilol is a drug widely used in the treatment of heart failure and associated cardiac arrhythmias. A unique action of carvedilol is its suppression of store overload-induced calcium release (SOICR) through the cardiac ryanodine receptor (RyR2), which can trigger ventricular arrhythmias. Since the effects of carvedilol metabolites on SOICR have not yet been investigated, three carvedilol metabolites hydroxylated at the 3-, 4' and 5'-positions were synthesized and assayed for SOICR inhibition in mutant HEK 293 cells expressing the RyR2 mutant R4496C. This cell line is especially prone to SOICR and calcium release through the defective RyR2 channel was measured with a calcium-sensitive fluorescent dye. These results revealed that the 3- and 4'-hydroxy derivatives are slightly more effective than carvedilol in suppressing SOICR, while the 5'-analog proved slightly less active. Metabolic deactivation of carvedilol via these hydroxylation pathways is therefore insignificant.
authors.affiliation: Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Malig
authors.affiliation: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada. Electronic address: swchen@ucalgary.ca.
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada. Electronic address: tgback@ucalgary.ca.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Back
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000077261:Carvedilol; D005456:Fluorescent Dyes / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D002227:Carbazoles; D005456:Fluorescent Dyes; D011412:Propanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D000077261:Carvedilol; D002118:Calcium
keywords: Carvedilol metabolites; HEK 293 mutant cell line (R4496C); Ryanodine receptor; Store overload-induced calcium release