vasopressin and bradykinin) or activation
of tyrosine kinase (in the case of epidermal
growth factor and fibroblast growth factor),
both resulting in modification to the Na+/H+
antiporter, changing its pH sensitivity.
Insulin and insulin-like growth factor also
cause similar changes in pHi(Moore, 1983),
probably through similar mechanisms
(Bryer-Ash, 1988). The increase in sodium
ions entering the cell is met by an increase
in the rate of Na+extrusion by the sodium
pump. There is an inhibitor of Na+/H+
exchange, amiloride, which has enabled
studies of the activity of this process,
although it has been reported that its
inhibitory action is not specific for this
antiporter but that it may inhibit Na+,K+-
ATPase activity as well (Park et al., 1992).
Such studies have been undertaken in a
similar manner to those described above for
the sodium pump. Instead of ouabain being
added to the cell suspension, amiloride is
added and the reduction in oxygen con-
sumption observed is assumed to be due to
a decrease in sodium pump activity brought
about by a decrease in Na+/H+exchange.
Thyroid hormone levels have been
shown to alter the rate of ion transport
across the cell membrane. Gregg and
Milligan (1987) measured Na+,K+-ATPase
activity in sheep that had their thyroid
gland removed surgically. Supplementation
of the thyroid hormone T 3 to these animals,
increased the activity of this enzyme by
one-third. Gregg and Milligan (1982a)
showed increases in Na+,K+-ATPase activity
in muscle of cold-exposed sheep when
compared with animals kept in warmer
conditions. Cold stress causes increased
thyroid hormone levels (Park et al., 1992),
and increasing the energy use for sodium
pumping would be one mechanism
whereby heat production could be
increased. It is not clear how these
hormones exert their effect, but they must
increase Na+entry into cells substantially.
Weak acidsIntracellular pH can be affected directly by
weak acids. Weak acids, such as acetic and
carbonic acids, exist in equilibrium in
aqueous solution:
Acetic acid:
CH 3 COOH ↽ ⇀H++ CH 3 COO
Carbonic acid:
CO 2 + H 2 O ↽⇀H 2 CO 3 ↽⇀H++ HCO 3 The undissociated (and uncharged) forms of
these acids can cross biological membranes
readily by diffusion. Ketelaars and Tolkamp
(1992) proposed that weak acids such as
acetic and carbonic acids can act as proton
ionophores, and thus their presence in
extracellular media would incur an energy
cost to the cell in counteracting acidification
of the cytosol in the manner depicted for
acetic acid in Fig. 7.2. Increased activity of
Na+/H+exchange will lead to an increase in
the intracellular concentration of Na+, stim-
ulating Na+,K+-ATPase activity (Smith and
Rozengurt, 1978). What is new about the
explanation put forward by Ketelaars and
Tolkamp is that it requires the plasma mem-
brane to be permeable to small anions, e.g.
acetate, to a significant degree. It has been
argued that the plasma membrane is perme-
able to HCO 3 and NH 4 +(Boron and De
Weer, 1976) with permeabilities of 5 10 ^7
and 10^6 cm s^1 , respectively (compared
with the much greater permeabilities of 6
10 ^3 cm s^1 for both CO 2 and NH 3 – mole-
cules which carry no charge and therefore
cross biological membranes relatively
easily), and that leakage of HCO 3 occurs
independently of carrier-mediated transport
(Boron, 1983).
Jessop and Leng (1993) examined the
effect of nutrient balance on Na+,K+-
ATPase activity. Sheep were fed on poor-
quality diets limiting in rumen-degradable
nitrogen (the effective rumen-degradable
protein to fermentable metabolizable
energy ratio, eRDP:FME, was 6.0), which
were either supplemented with additional
rumen-undegradable protein (UDP) or not.
Thus the protein to energy ratio of
absorbed nutrients was expected to vary
between the two dietary treatments.
Hepatocytes were prepared and incubated
over a range of acetate concentrations from
0 to 2.5 mM. Total respiration was
unchanged, but the proportion of totalAspects of Cellular Energetics 153