title: Excitation-contraction coupling in rat heart: influence of cyclosporin A.
abstract: OBJECTIVE
  The aim was to investigate the steps in the excitation-contraction coupling process by which chronic exposure to cyclosporin A (cyclosporin) affects twitch force development by rat cardiac trabeculae.
  
  
  METHODS
  The interval dependence and [Ca2+]o dependence of twitch force development by intact trabeculae isolated from myocardium of untreated rats and rats treated with cyclosporin (15 mg.kg-1.d-1 for 21 d) were studied in Krebs-Henseleit solution (K-H; pH 7.4 and 25 degrees C) and the force-pCa relation was examined in all trabeculae.
  
  
  RESULTS
  The force-[Ca2+]o relation of cyclosporin treated trabeculae was shifted leftward compared to that of controls, but these trabeculae generated 35% less stress (force/cross sectional area) at optimal [Ca2+]o. Unlike control trabeculae, cyclosporin treated trabeculae showed spontaneous activity at all diastolic intervals, even at low [Ca2+]o. Treated and control trabeculae generated the same maximum stress [control: 78.1 (SEM 7.7) mN.mm-2, cyclosporin treated: 70.2(7.4) mN.mm-2] in the presence of extracellular Sr2+ ions in the Krebs-Henseleit medium. Maximum stress observed in the presence of Sr2+ was similar to the stress generated by maximum activation of chemically skinned trabeculae in both groups [control: 70(4.6) mN.mm-2; cyclosporin treated: 73(6.2) mN.mm-2). The force-pCa relation of cyclosporin treated muscles and control muscles after skinning were also indistinguishable [control pCa50 = 5.56(0.04); cyclosporin treated pCa50 = 5.58(0.03)]. The twitch force-interval relation at 0.7 mM [Ca2+]o in intact control trabeculae revealed postrest potentiation with a maximum [equivalent to 70% of twitch force at optimal [Ca2+]o -61.0(2.1) mN.mm-2] at 100 s and subsequent rest depression. Under the same conditions, twitch force development by cyclosporin treated trabeculae was closer to optimal force [41.4(7.1) mN.mm-2] at all intervals, and rest potentiation was reduced. Pronounced rest potentiation (as well as postextrasystolic potentiation) was still observed in cyclosporin treated trabeculae at [Ca2+]o < 0.7 mM. Postextrasystolic potentiation was reduced at 0.7 mM [Ca2+]o in these trabeculae, but the rate of decay of postextrasystolic potentiation and the rate of relaxation of the twitch force were unaffected.
  
  
  CONCLUSIONS
  These results suggest that the changes in the sensitivity of intact rat myocardium to [Ca2+]o and in maximum force development induced by cyclosporin are not due to changes in myofilament properties. The increased twitch force development as well as the spontaneous activity at low [Ca2+]o may be due to facilitated Ca2+ release from the sarcoplasmic reticulum due to altered properties of the sarcoplasmic reticular Ca2+ release channel, as both are observed when twitch force is submaximal, suggesting that the sarcoplasmic reticulum was not overloaded with Ca2+. The decline in peak stress with cyclosporin at [Ca2+]o > approximately 1.0 mM can be explained on the basis of spontaneous release of Ca2+ during the interval between twitches which leaves less Ca2+ for release from the sarcoplasmic reticulum with each action potential.
authors.affiliation: Department of Medicine, University of Calgary, Alberta, Canada.
authors.forename: H S
authors.initials: HS
authors.lastname: Banijamali
authors.forename: M H
authors.initials: MH
authors.lastname: ter Keurs
authors.forename: L C
authors.initials: LC
authors.lastname: Paul
authors.forename: H E
authors.initials: HE
authors.lastname: ter Keurs
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012518:Sarcomeres / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D016572:Cyclosporine; D002118:Calcium