Impact of extracellular buffer composition on cardioprotective
efficacy of na+/h+ exchanger inhibitors.
Shimada, Yasuyuki, David J Hearse, and Metin Avkiran.
Cardiovascular Research, The Rayne Institute, St Thomas' Hospital,
London SE1 7EH, United Kingdom
APStracts 2:0369H, 1995.
There is controversy over whether the cardioprotective effects of
Na+/H+ exchanger inhibitors are exerted primarily during ischemia or
during subsequent reperfusion, possibly due to inter-study
differences in experimental conditions. We studied the impact of
perfusate buffer composition on the relative degree of protection
afforded by Na+/H+ exchanger inhibition during ischemia as opposed to
during reperfusion. Isolated rat hearts (n=8/group) were perfused (37
degrees C, 75 mmHg) with bicarbonate- or HEPES-buffered medium and
subjected to 20 min of global zero-flow ischemia and 45 min of
reperfusion. There was a transient (5 min) infusion of one of two
structurally distinct Na+/H+ exchanger inhibitors (5-(N,N-dimethyl)
-amiloride [DMA] or (3-methylsulphonyl-4-piperidinobenzoyl)-guanidine
methanesulphonate [HOE694]; 10 [mu]mol/L) (i) immediately before
ischemia, (ii) during initial reperfusion, or (iii) during both of
these periods. With bicarbonate-buffered medium, neither drug
improved the post-ischemic recovery of left ventricular developed
pressure (LVDP) when given only during reperfusion. In contrast,
HOE694 improved the post-ischemic recovery of LVDP from 39+/-5% in
control to 66+/-6%* (*p<0.05) when given before ischemia, and
from 33+/-4% in control to 65+/-4%* when given before ischemia plus
during reperfusion. With the latter protocol, the cardioprotective
effect of HOE694 occurred in a dose-dependent manner, over the range
0.1-10 [mu]mol/L. In contrast to the results with bicarbonate
-buffered medium, in the presence of HEPES-buffered medium both DMA
and HOE694 significantly improved recovery of LVDP (from 34+/-5 % in
controls to 56+/-3* and 71+/-8%*) when given only during reperfusion.
They also provided significant protection when given before ischemia
or before ischemia plus during reperfusion; with the latter protocol,
HOE694 produced an almost complete recovery of LVDP (88+/-9%* versus
30+/-7% in controls). In conclusion, our results suggest that the
influence of Na+/H+ exchanger activity during reperfusion on the
extent of functional recovery is modulated significantly by perfusate
buffer composition. As a consequence, the cardioprotective efficacy
of Na+/H+ exchanger inhibitors may be overestimated under
bicarbonate-free conditions.
Received 24 February 1995; accepted in final form 31 July 1995.
APS Manuscript Number H174-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 August 1995.