Stimulation frequency and nmr-determined intracellular sodium in
the beating rat heart. evidence for the na-k pump lag theory for the
cardiac staircase.
Lotan, Chaim S., Sandra K. Miller, Tam[acute]as Simor, and Gabriel A.
Elgavish.
Division of Cardiovascular Disease, Department of Medicine,
University of Alabama at Birmingham, Birmingham, Alabama 35294
USA
APStracts 2:0056H, 1995.
The increase in myocardial developed force resulting from an increase
in stimulation frequency is known as the staircase (treppe)
phenomenon, or the positive interval-strength relationship. It has
been suggested that a rise in intracellular sodium ion concentration
([Nai]), attributed to a "sodium pump lag", and subsequent changes in
Na/Ca exchanger activities during the heart cycle are the main causes
for the observed changes in developed force. 23Na and 31P NMR
spectroscopy were used to assess the relationship between stimulation
frequency, [Nai], and high energy phosphate stores in the isolated,
perfused, beating rat heart. Changes in these parameters were
correlated with simultaneous pressure measurements. Isolated,
perfused rat hearts (30 oC, n=13) were paced upward from their
spontaneous heart rate (218+/-4 bpm) to 433+/-4 bpm and back to
baseline (221+/-3 bpm) in a stepwise manner with 3 minute periods for
each step while monitoring [Nai], and systolic and diastolic
pressure. [Nai] increased progressively with upward pacing in all
hearts reaching a maximum of 128+/-5% of control at the peak pacing
rate, and decreased progressively with downward pacing. In seven of
the above hearts an initial, progressive increase in systolic
pressure was observed, which reached a maximum of 110+/-6% of control
at 287+/-2 bpm. In contrast to the frequency dependence of [Nai],
however, this initial increase was followed by a decrease in pressure
at the higher pacing rates (Group I). In the other six hearts, from
the onset a progressive decrease in systolic pressure was observed in
response to upward pacing (Group II). A comparison of [Nai] changes
in these two groups revealed a significant difference in the rate and
extent of [Nai] increase. Group I, displaying an initial positive
pressure response, sustained a [Nai] increase of up to 134+/-7% of
control (p<0.001), while in Group II the gain in [Nai] with
increasing pacing rate was attenuated, reaching a maximum of 120+/-3%
of control (p<0.02). In nine additional hearts the levels of high
energy phosphates were monitored by 31P NMR, using the same perfusion
and pacing protocol as in the 13 above hearts. Assessment of
phosphocreatine (PCr), intracellular pH, and ATP levels (n=4, same
pressure response as in Group I and n=5, same pressure response as in
Group II), revealed no significant change in high energy phosphate
stores with either upward or downward pacing, thus excluding a lack
of metabolic support as a possible reason for the pressure decline,
as well as for the difference in presssure response among the two
groups. The differential pressure response between Group I and Group
II hearts may reflect an enhanced sensitivity of rat hearts to the
shortening of the restitution period of the sarcoplasmic reticulum,
outweighing the positive inotropic effect induced by an increased
[Nai]. Only in rat hearts whose [Nai] increments outweigh the
restitution deficit, would a complete positive inotropic effect be
anticipated. Thus, a large enough increase in [Nai] is sufficient
cause for the positive inotropic response observed with increasing
stimulation frequency.
Received 19 July 1994; accepted in final form 7 February 1995.
APS Manuscript Number H635-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 1 March 1995.