title: Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy.
abstract: OBJECTIVE
  Recent work has identified reductions in the systolic Ca(2+) transient in cardiac disease states. The aim of the present study was to identify the mechanisms responsible for perturbations of intracellular calcium homeostasis in isolated cardiac myocytes and determine if such changes can quantitatively explain the reduced systolic Ca(2+) transient.
  
  
  METHODS
  Left ventricular hypertrophy (LVH) was induced by aortic coarctation in adult ferrets. Changes in intracellular Ca(2+) regulation, sarcolemmal Ca(2+) fluxes and SR function were measured in single left ventricular cardiac myocytes.
  
  
  RESULTS
  Cardiac hypertrophy was associated with a 29% increase in action potential duration (APD(90)); a 48% reduction in the amplitude of and 19% slowing in the rate of decay of the systolic Ca(2+) transient; a 20% decrease in SR Ca(2+) content and a 36% increase in inward Na(+)-Ca(2+) exchange current for a given change in [Ca(2+)](i) (all P<0.05). Peak L-type Ca(2+) current density, integrated Ca(2+) influx and SERCA2a protein levels remained unchanged in hypertrophy. By determining the relationship between SR Ca(2+) content and systolic Ca(2+), the reduction in SR Ca(2+) content quantitatively explained the smaller systolic Ca(2+) transient. The reduced SR Ca(2+) content also accounted for a smaller fractional release of Ca(2+) from the SR and lower gain of excitation contraction coupling in cardiac hypertrophy. The increased sarcolemmal-mediated Ca(2+) efflux was sufficient to explain the reduction in SR Ca(2+) content.
  
  
  CONCLUSIONS
  The findings indicate that the primary mechanism underlying the smaller systolic Ca(2+) transient amplitude in cardiac hypertrophy is decreased SR Ca(2+) content occurring as a consequence of reduced SR Ca(2+)-ATPase-mediated Ca(2+) uptake and increased sarcolemmal-mediated Ca(2+) efflux from the cell. The increased Na(+)-Ca(2+) exchange-mediated current for a given change in intracellular Ca(2+) concentration provides a mechanism for the development of arrhythmias in the face of a reduced SR Ca(2+) load in cardiac hypertrophy.
authors.affiliation: Unit of Cardiac Physiology, The University of Manchester, 1.523 Stopford Building, Manchester M13 9PT, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Díaz
authors.forename: H K
authors.initials: HK
authors.lastname: Graham
authors.forename: A W
authors.initials: AW
authors.lastname: Trafford
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D005289:Ferrets; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D015151:Immunoblotting / Q000379:methods; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction; D018408:Patch-Clamp Techniques; D012508:Sarcolemma / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013599:Systole
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium