title: Stretch-dependent modulation of [Na+]i, [Ca2+]i, and pHi in rabbit myocardium--a mechanism for the slow force response.
abstract: OBJECTIVE
  Rabbit ventricular myocardium is characterized by a biphasic response to stretch with an initial, rapid increase in force followed by a delayed, slow increase in force (slow force response, SFR). The initial phase is attributed to increased myofilament Ca(2+) sensitivity, but the mechanisms of the delayed phase are only incompletely understood. We tested whether stretch-dependent stimulation of Na(+)/H(+) exchange (NHE1) and consecutive changes in pH(i) and/or [Na(+)](i) may underlie the SFR.
  
  
  METHODS
  Isometric contractions of rabbit ventricular muscles were recorded in bicarbonate-containing Tyrode's (Tyrode) or bicarbonate-free HEPES-buffered solution (HEPES). Muscles were loaded with the Ca(2+) indicator aequorin, the pH indicator BCECF, or the Na(+) indicator SBFI and rapidly stretched from 88% (L(88)) to 98% (L(98)) of optimal length. The resulting immediate and slow increases in twitch force (1st phase and SFR) as well as changes in [Ca(2+)](i), [Na(+)](i), or pH(i) were quantified before and after inhibition of NHE1 by HOE 642 (3 microM) or reverse-mode Na(+)/Ca(2+) exchange (NCX) by KB-R 7943 (5 microM).
  
  
  RESULTS
  In both Tyrode (n=21) and HEPES (n=22), developed force increased to approximately 160% during the 1st phase followed by a further increase to approximately 205% during the SFR. The SFR was accompanied by a 21% increase of the aequorin light transient (n=4; normalized to the 1st phase) and a approximately 3 mM increase in [Na(+)](i) (n=4-7). The SFR was also associated with an increase in pH(i). However, this increase was delayed and was significant only after the SFR had reached its maximum. The delayed pH(i) increase was larger in HEPES than in Tyrode. HOE 642 and/or KB-R 7943 reduced the SFR by approximately 30-40%. In addition, HOE 642 diminished the stretch-mediated elevation of [Na(+)](i) by 72% and the delayed alkalinization.
  
  
  CONCLUSIONS
  The data are consistent with the hypothesis that SFR results from increases in [Ca(2+)](i) secondary to altered flux via NCX in part resulting from increases in [Na(+)](i) mediated by NHE1.
authors.affiliation: Department of Cardiology and Pneumology, University of Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Luers
authors.forename: Florian
authors.initials: F
authors.lastname: Fialka
authors.forename: Andreas
authors.initials: A
authors.lastname: Elgner
authors.forename: Danan
authors.initials: D
authors.lastname: Zhu
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000494:pharmacology; D006352:Heart Ventricles; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008856:Microscopy, Fluorescence; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013314:Stress, Mechanical; D013450:Sulfones / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D001639:Bicarbonates; D027682:Cation Transport Proteins; D006146:Guanidines; D008565:Membrane Proteins; C490998:SLC9A1 protein, human; D019831:Sodium-Calcium Exchanger; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D012964:Sodium; D013890:Thiourea; D002118:Calcium