title: Arrhythmogenic actions of the Ca2+ channel agonist FPL-64716 in Langendorff-perfused murine hearts.
abstract: The experiments explored the extent to which alterations in L-type Ca(2+) channel-mediated Ca(2+) entry triggers Ca(2+)-mediated arrhythmogenesis in Langendorff-perfused murine hearts through use of the specific L-type Ca(2+) channel modulator FPL-64716 (FPL). Introduction of FPL (1 microm) resulted in a gradual development (>10 min) of diastolic electrical events and alternans in spontaneously beating hearts from which monophasic action potentials were recorded. In regularly paced hearts, they additionally led to non-sustained and sustained ventricular tachycardia (nsVT and sVT). Programmed electrical stimulation (PES) resulted in nsVT and sVT after 5-10 and >10 min perfusion, respectively. Pretreatments with nifedipine, diltiazem and cyclopiazonic acid abolished arrhythmogenic tendency induced by subsequent introduction of FPL, consistent with its dependence upon both extracellular Ca(2+) entry and the degree of filling of the sarcoplasmic reticular Ca(2+) store. Values for action potential duration at 90% repolarization when any of these agents were applied to FPL-treated hearts became indistinguishable from those shown by untreated control hearts, in contrast to earlier reports of their altering in long QT syndrome type 3 and hypokalaemic murine models for re-entrant arrhythmogenesis. These arrhythmic effects instead correlated with alterations in Ca(2+) homeostasis at the single-cell level found in investigations of the effects of both FPL and the same agents in regularly stimulated fluo-3 loaded myocytes. These findings are compatible with a prolonged extracellular Ca(2+) entry that potentially results in an intracellular Ca(2+) overload and produces the cardiac arrhythmogenecity following addition of FPL.
authors.affiliation: Physiological Laboratory, University of Cambridge, UK.
authors.forename: Nina S
authors.initials: NS
authors.lastname: Ghais
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000009:adverse effects* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007211:Indoles; D011758:Pyrroles; C071658:FPL 64176; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium; C000543:cyclopiazonic acid