Download Thermodynamic considerations of carbon dioxide evolution in

Biochemical Society Transactions (199 1) 20 33s
lher-mdynaric considerations of carbon dioxide
evolution in respiratory insufficiency
EMMANUEL T. RAKITZLIS and ANNA POTAMIANOU
Department of Biological Chemistry, University of
Athens Medical School, Athens, 11527 Greece
Identification of the rate-limiting steps involved
in metabolic control processes is accomplished by the
determination of the free energy change value, AG, of
the reaction steps under consideration. The assumption underlying this procedure is that the thermodynamic system involved is in a steady-state situation.
In consequence, the AG value of each reaction step is
not changing with time, and thus is a measure of the
departure of that step from equilibrium. This procedure has been applied to the identification of the
rate-limiting steps of the citric acid cycle, glycolysis and alcohol fermentation [l-41. In the present
communication the determination of the free energy
change of the reaction leading from blood hydrogen
and bicarbonate ions to expired air (lung alveoli)
carbon dioxide is described. The purpose of this study is to determine the magnitute of the AG value of
the aforementioned reaction, and also to investigate
whether respiratory insufficiency has a bearing on
the extent of the IX value of this same reaction.
The reaction pathway considered is with plasma bicarbonate and hydrogen ions as reactants, and expired
air carbon dioxide as the reaction product. The reaction sequence is:
where CO,,q.
is dissolved carbon dioxide, COZa__. is
expired air carbon dioxide, and also where K,, K,,,
and K, are the equilibrium constants for the three
separate reaction steps. The values of these constants are: K, = 5,888 d l ( H * + HCO;-> H,CO,),
K,, =
384.6 (H,CO, - > CO=-q. ), and ;K
= 29.41 (C02,yI->
COZa,,.).
Of these reactions, the first one, the association of hydrogen and bicarbonate ions to produce
carbonic acid is a quick equilibrium reaction, i.e.,
a reaction of which the AG value maybe assumed to be
equal to zero [51. The determination of AG for the
reaction 'H + HCO; - > CO, has been accomplished in
567 cases of healthy human subjects as well as of patients with respiratory insufficiency.
Data from the patient records of Sotiria General
Chest Hospital, Athens, were used in the present study. The findings correlated in each case were blood
pH, bicarbonate concentration, and expired air CO,
partial pressure. Blood samples (2 ml) were obtained
from the radial artery with an heparinized 26 G insulin syringe. Blood gases concentration was determined
with an ABL3 Radiometer instrument. Expired air CO,
partial pressure was determined by letting the subject breath into a freshly washed Douglas bag, and
tranferring the contents of the bag to the ABL3 Radiometer instrument. The free energy change of the
overall reaction of carbon dioxide evolution is:
(2)
where Dc, = RT In (K,K,,K,)
= -10.883 kcal mol-'at
37"C, and where [H*I, [HCO,] and [CO,u__. 1 are in
is obtainunits of molarity. The value for [CO,u,,-l
ed by dividing expired air CO, partial pressure, in
t o m , by 760. The AG value of this reaction, for the
whole sample of the 567 cases studied, is 0.109 ?
0.039 1 S.D. kcal mol-', i.e., a uniform AG value is
obtained at all plasma pH values (range of values was
from pH 7.12 to 7-62], bicarbonate concentration values (range from 11.8 to 60.3 mEq l - ' ) , and of expired air CO, partial pressure values (range from 32 to
95 torr) studied. The conclusions to be drawn from
the present study are as follows:
is
(i) The reaction, pathway 'H + HCO; - > COzo,,close to equilibrium, since the free energy change of
the overall process is only a fraction of 1 kcal
mol-'. This value may be compared to the free energy
change of the glycolytic pathway in human erythrocytes (-25.2 kcal mol-' of lactate produced [ 3 1 ) .
(ii) The reaction +'H HCO; - > C?za(...
consists of
a quick equilibriium component (H t HCO; -> \CO,),
a step mediated by carbonic anhydrase (H,CO, ->
CO,) and the CO, transfer from lung capillacy blood
- > COZa__.). It is not clear
to lung alveoli (CO,,,.
whether the last two steps are both rate-limiting, or
whether the carbonic anhydrase reaction (as was suggested by Roughton C51) is the only step that is removed from equilibrium. Inhibition of carbonic anhydrase by acetazolamide has been found to result in
the production of respiratory acidosis 16,71.
(iii) The degree of respiratory insufficiency,
with its concomitant rise in blood hydrogen ion, and
bicarbonate ion, concentration has no effect on the
energetics of the overall reaction of carbon dioxide
evolution. Since, in a metabolic pathway, the AG value of each reaction is a measure of the departure of
that reaction from equilibrium, it follows that respiratory insufficiency, however severe, has no effect on the extent to which, the steps leading from
blood hydrogen and bicarbonate ions to lung alveoli
carbon dioxide, are rate-limiting. In other words,
although in respiratory insufficiency the physiological mechanisms of carbon dioxide evolution are highly
taxed, the metabolic workload is nevertheless performed without distorting the individual facets of
the physiological mechanisms themselves. It would be
of interest to investigate whether the s a w conclusions can be reached in cases where the primary cause
of an altered level of blood hydrogen and bicarbonate
ion concentration is metabolic in origin.
(iv) On the assumption that the Ki value of each
individual case under consideration is 0.109 kcal
mol-', the Henderson-Hasselbalch equation may be extended to an equation correlating blood hydrogen, and
bicarbonate ions with lung alveoli carbon dioxide:
pH = 7.73 + log
([HCO;I/([C0,1/760)
( 31
where [CO,] is lung alveoli CO, partial pressure in
is blood bicarbonate in units of
torr, and 1HCO;I
molarity. It will be noted that eqn. ( 3 ) differs from
the Henderson-Hasselbalch equation in the apparent
pK, value for the first ionization of carbonic acid
(7.73 in place of 6.1) [5-81.
1. Burton, K. 8 Krebs, H.: Biochem. J. 54 (1953)
94-105
2. Minakami, 5. & Yoshikawa, H. (1965) Biochem.
Biophys. Res. Commun. 18 345-349
3 . Minakami, 5. & Yoshikawa, H. J. Biochem. 59 (1966)
139-1 44
4. Edsall, J. T. & Gutfreund, H. (1983) Biothermodynamics, pp. 134-136. John Wiley, New York
5. Edsall, J. T. 8 Wyman, J. (1958) Biophysical Chemistry, Vol. I , pp. 550-590, Academic Press, N.Y.
6. Teppema, L. J., Rochette, F. & Demcdts, M.
(1988) Respiration 74, 373-382
7. Wstrand, P. J. (1989) in Design of Enzyme Inhibitors as Drugs (M. Sandler and H. J. Smith, eds),
pp. 698-723. Oxford University Press
8. Gamble, J. L. (1960)Chemical Anatomy, Physiology
and Pathology of the Extracellular Fluid. Harvard
University Press, Cambridge, Massachussetts