title: I(CaL) inhibition prevents arrhythmogenic Ca(2+) waves caused by abnormal Ca(2+) sensitivity of RyR or SR Ca(2+) accumulation.
abstract: OBJECTIVE
  Arrhythmogenic Ca(2+) waves result from uncontrolled Ca(2+) release from the sarcoplasmic reticulum (SR) that occurs with increased Ca(2+) sensitivity of the ryanodine receptor (RyR) or excessive Ca(2+) accumulation during β-adrenergic stimulation. We hypothesized that inhibition of the L-type Ca(2+) current (I(CaL)) could prevent such Ca(2+) waves in both situations.
  
  
  RESULTS
  Ca(2+) waves were induced in mouse left ventricular cardiomyocytes by isoproterenol combined with caffeine to increase RyR Ca(2+) sensitivity. I(CaL) inhibition by verapamil (0.5 µM) reduced Ca(2+) wave probability in cardiomyocytes during electrostimulation, and during a 10 s rest period after ceasing stimulation. A separate type of Ca(2+) release events occurred during the decay phase of the Ca(2+) transient and was not prevented by verapamil. Verapamil decreased Ca(2+) spark frequency, but not in permeabilized cells, indicating that this was not due to direct effects on RyR. The antiarrhythmic effect of verapamil was due to reduced SR Ca(2+) content following I(CaL) inhibition. Computational modelling supported that the level of I(CaL) inhibition obtained experimentally was sufficient to reduce the SR Ca(2+) content. Ca(2+) wave prevention through reduced SR Ca(2+) content was also effective in heterozygous ankyrin B knockout mice with excessive SR Ca(2+) accumulation during β-adrenergic stimulation.
  
  
  CONCLUSIONS
  I(CaL) inhibition prevents diastolic Ca(2+) waves caused by increased Ca(2+) sensitivity of RyR or excessive SR Ca(2+) accumulation during β-adrenergic stimulation. In contrast, unstimulated early Ca(2+) release during the decay of the Ca(2+) transient is not prevented, and merits further study to understand the full antiarrhythmic potential of I(CaL) inhibition.
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway. m.k.stokke@medisin.uio.no
authors: Mathis K
authors: MK
authors: Stokke
authors: Nils
authors: N
authors: Tovsrud
authors: William E
authors: WE
authors: Louch
authors: Leiv
authors: L
authors: Øyehaug
authors: Karina
authors: K
authors: Hougen
authors: Ole M
authors: OM
authors: Sejersted
authors: Fredrik
authors: F
authors: Swift
authors: Ivar
authors: I
authors: Sjaastad
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012508:Sarcolemma / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D014700:Verapamil; D002118:Calcium