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Mechanisms underlying the frequency dependence of contraction and [Ca2+]i transients in mouse ventricular myocytes

By Gudrun Antoons, Kanigula Mubagwa, Ines Nevelsteen and Karin R Sipido


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 °C. During field stimulation, amplitude of unloaded cell shortening increased with increasing frequency of stimulation (0.04 ± 0.01 ΔL/L0 at 1 Hz to 0.07 ± 0.01 ΔL/L0 at 4 Hz, n = 12, P < 0.05). During whole cell voltage clamp with 50 μM [K5-fluo-3]pip, both peak and baseline [Ca2+]i increased at higher stimulation frequencies, but the net Δ[Ca2+]i increased only modestly from 1.59 ± 0.08 ΔF/F0 at 1 Hz, to 1.71 ± 0.11 ΔF/F0 at 4 Hz (n = 17, P < 0.05). When a 1 s pause was interposed during stimulation at 2 and 4 Hz, [Ca2+]i transients were significantly larger (at 4 Hz, peak F/F0 increased by 78 ± 2 %, n = 5). SR Ca2+ content assessed during caffeine application, significantly increased from 91 ± 24 μmol l−1 at 1 Hz to 173 ± 20 μmol l−1 at 4 Hz (n = 5, P < 0.05). Peak ICa,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 ICa,L resulted in reduced fractional release. Thus, in mouse ventricular myocytes the [Ca2+]i-frequency response depends on a balance between the increase in SR content and the loss of trigger ICa,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 [Ca2+]i

Topics: Original Articles
Publisher: Blackwell Science Inc
OAI identifier: oai:pubmedcentral.nih.gov:2290543
Provided by: PubMed Central
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