title: Mechanisms underlying the frequency dependence of contraction and [Ca(2+)](i) transients in mouse ventricular myocytes.
abstract: In most mammalian species force of contraction of cardiac muscle increases with increasing rate of stimulation, i.e. a positive force-frequency relationship. In single mouse ventricular cells, both positive and negative relationships have been described and little is known about the underlying mechanisms. We studied enzymatically isolated single ventricular mouse myocytes, at 30 degrees C. During field stimulation, amplitude of unloaded cell shortening increased with increasing frequency of stimulation (0.04 +/- 0.01 Delta L/L(0) at 1 Hz to 0.07 +/- 0.01 Delta L/L(0) at 4 Hz, n = 12, P < 0.05). During whole cell voltage clamp with 50 microM [K5-fluo-3](pip), both peak and baseline [Ca(2+)](i) increased at higher stimulation frequencies, but the net Delta[Ca(2+)](i) increased only modestly from 1.59 +/- 0.08 Delta F/F(0) at 1 Hz, to 1.71 +/- 0.11 Delta F/F(0) at 4 Hz (n = 17, P < 0.05). When a 1 s pause was interposed during stimulation at 2 and 4 Hz, [Ca(2+)](i) transients were significantly larger (at 4 Hz, peak F/F(0) increased by 78 +/- 2 %, n = 5). SR Ca(2+) content assessed during caffeine application, significantly increased from 91 +/- 24 micromol l(-1) at 1 Hz to 173 +/- 20 micromol l(-1) at 4 Hz (n = 5, P < 0.05). Peak I(Ca,L) decreased at higher frequencies (by 28 +/- 6 % at 2 Hz, and 45 +/- 8 % at 4 Hz), due to slow recovery from inactivation. This loss of I(Ca,L) resulted in reduced fractional release. Thus, in mouse ventricular myocytes the [Ca(2+)](i)-frequency response depends on a balance between the increase in SR content and the loss of trigger I(Ca,L). Small changes in this balance may contribute to variability in frequency-dependent behaviour. In addition, there may be a regulation of the contractile response downstream of [Ca(2+)](i).
authors.affiliation: Laboratory of Experimental Cardiology, University of Leuven, Belgium.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
authors.forename: Kanigula
authors.initials: K
authors.lastname: Mubagwa
authors.forename: Ines
authors.initials: I
authors.lastname: Nevelsteen
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004558:Electric Stimulation; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016276:Ventricular Function; D016474:Weight-Bearing
chemical_list: D020746:Calcium Channels, L-Type; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D002118:Calcium