title: Alendronate affects calcium dynamics in cardiomyocytes in vitro.
abstract: Therapy with bisphosphonates, including alendronate (ALN), is considered a safe and effective treatment for osteoporosis. However, recent studies have reported an unexpected increase in serious atrial fibrillation (AF) in patients treated with bisphosphonates. The mechanism that explains this side effect remains unknown. Since AF is associated with an altered sarcoendoplasmic reticulum calcium load, we studied how ALN affects cardiomyocyte calcium homeostasis and protein isoprenylation in vitro. Acute and long-term (48h) treatment of atrial and ventricular cardiomyocytes with ALN (10(-8)-10(-6)M) was performed. Changes in calcium dynamics were determined by both fluorescence measurement of cytosolic free Ca(2+) concentration and western blot analysis of calcium-regulating proteins. Finally, effect of ALN on protein farnesylation was also identified. In both atrial and ventricular cardiomyocytes, ALN treatment delayed and diminished calcium responses to caffeine. Only in atrial cells, long-term exposure to ALN-induced transitory calcium oscillations and led to the development of oscillatory component in calcium responses to caffeine. Changes in calcium dynamics were accompanied by changes in expression of proteins controlling sarcoendoplasmic reticulum calcium. In contrast, ALN minimally affected protein isoprenylation in these cells. In summary, treatment of atrial cardiomyocytes with ALN-induced abnormalities in calcium dynamics consistent with induction of a self-stimulatory, pacemaker-like behavior, which may contribute to the development of cardiac side effects associated with these drugs.
authors.affiliation: Faculty of Dentistry, McGill University, Montreal, Quebec, Canada H3A 2B2.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kemeny-Suss
authors.forename: Amanda
authors.initials: A
authors.lastname: Kasneci
authors.forename: Daniel
authors.initials: D
authors.lastname: Rivas
authors.forename: Jonathan
authors.initials: J
authors.lastname: Afilalo
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Komarova
authors.forename: Lorraine E
authors.initials: LE
authors.lastname: Chalifour
authors.forename: Gustavo
authors.initials: G
authors.lastname: Duque
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D017368:Protein Prenylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000032:analysis
chemical_list: D050071:Bone Density Conservation Agents; D002110:Caffeine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D019386:Alendronate