Medical Research Society
48. FACTORS INFLUENCING THE BIOAVAILABILITY
OF CHENODEOXYCHOLIC ACID (CDCA)
15P
Leucocytes from each subject were isolated and incubated for
2 h with serum-treated latex particles, after which the acid
phosphatase (AP), ribonuclease (RN) and lactate dehydroA. REUBEN, G. M. MURPHY and R. H. DOWLINO
genase (LDH) content of cells and supernatant medium were
Gastroenterology Unit, Guy's Hospital and Medical School, assayed. The quantity of lysosomal enzyme released was
expressed as a percentage of the total cellular enzyme content
London
(Table 1). There was no significant difference in enzyme release
between normal and emphysematous subjects.
Although CDCA bioavailability has been measured using
peripheral blood concentration time curves (van BergeHenegouwen & Hofmann, 1977, Gastroenterology, 73, 300TABLE 1. Latex-induced lysosomal enzyme release as % of total
309; Ponz de Leon & Hermon Dowling, 1977, Gut, 18, In
cellular enzyme content (mean ± SD)
press) the magnitude and timing of peak serum CDCA levels
vary widely from subject to subject. The role played by such
AP
RN
factors as gastric emptying and the pharmaceutical formulation
of CDCA in the peripheral blood CDCA response is not known
nor have studies of within subject variation been made.
Normal subjects
36-3 (+ 7-1)
31-5 (± 2-2)
Emphysema
29-4 (+ 10·0)
31-5 (±7-8)
We therefore compared 4 h serum CDCA concentrationP
> 0-05
> 005
time curves (measured by RIA) in fasting control subjects given
250 mg oral CDCA, first as a capsule and later as an entericcoated tablet, and related results to corresponding 'tolerance
curves' for two poorly-metabolizable sugars, 3-O-methylglucose
The same experiments were performed with the addition of
and D-xylose given simultaneously as markers of gastric
cigarette smoke solution (filtered to remove paniculate matter)
emptying and proximal intestinal absorption.
to the latex particles (Table 2). In the normal subjects there was
Gastric emptying was rapid as shown by first appearance of
a depression of enzyme release compared with latex used alone.
both sugars in peripheral blood 5-15 min after ingestion in all
This depression was not observed in the emphysematous
but one patient (40 min). Thereafter, serum 3-O-methylglucose
subjects and the difference between the two groups of subjects
and D-xylose levels rose quickly to reach maxima 15—50 min
was in this respect highly significant (P < 0-001).
after initial appearance with little variation (5-15 min) between
results for repeat studies in individual subjects—-suggesting
TABLE 2. Depression of latex-induced enzyme release by
efficient and consistent absorption. By contrast, the rise in serum
soluble fraction of cigarette smoke as % of total (mean + SD)
CDCA was later and the concentration-time curve more
protracted with greater intra- and inter-individual variation than
was seen with the marker sugars. There were no consistent
AP
RN
differences in CDCA tolerance curves with different phar­
maceutical formulations.
Normal
11·4(±2·6)
9-2 ( + 1 1 )
Individual variability in CDCA bioavailability was unrelated
Emphysema
1-5 (±4-0)
1-4 (+4-3)
to variable gastric emptying. Poor reproducibility and inter< 0-001
P
< 0-001
subject differences make comparative bioavailability studies
difficult CDCA absorption was independent of the phar­
maceutical formulation used.
There was no significant difference between the relative
amounts of AP and RN released in a given experiment. LDH
release was minimal (<10% in all cases) and did not alter
49. THE INDUCTION OF LYSOSOMAL ENZYME
significantly upon addition of latex particles or smoke solution.
RELEASE FROM LEUCOCYTES OF NORMAL AND
We have demonstrated in this study that lysosomal enzyme
EMPHYSEMATOUS SUBJECTS AND THE EFFECTS OF
release from the leucocytes of both normal and emphysematous
CIGARETTE SMOKE
subjects is equally potentiated by the addition of a phagocytic
stimulus, and the participate fraction of cigarette smoke may act
R. DESAI, H. BAUM, D. BELLAMY and D. C. S. HUTCHISON
in the same manner. The minimal cytoplasmic enzyme release
Department of Biochemistry, Chelsea College, and Chest Unit,
indicates that the cells remain viable. In normal subjects, the
King's College Hospital Medical School, London
observed inhibition of lysosomal enzyme release by the soluble
fraction of cigarette smoke may be brought about by the
The lysosomal granules of neutrophil leucocytes contain a
presence of a factor such as carbon monoxide. Although the
potent elastase (Janoff & Scherer, 1968, Journal ofExperimenresults showed no relationship to arterial 0 ; tension or smoking
talMedicine, 128,1137), and it is thought that the release of this
status, the leucocytes of emphysematous patients may have
enzyme may bring about pulmonary emphysema in patients
become adapted to hypoxic conditions so that inhibition of
both with and without alpha,-antitrypsin deficiency. Lysosomal
enzyme release does not occur.
enzymes can be released from these cells during phagocytosis of
inert material, and during pilot experiments we have shown that
cigarette smoke can provoke such release. In the present study
we have measured the latex-induced release of lysosomal
enzymes from leucocytes of normal and emphysematous
50. BEDSIDE MEASUREMENT OF CARBON MONOX­
subjects and the modification of this release after additional
IDE DIFFUSING CAPACITY
treatment of the cells with the soluble components of cigarette
ELIZABETH H. CLARK, HAZEL A. JONES and J. M. B. HUGHES
smoke.
Thirty-two patients with radiological evidence of pulmonary
Department of Medicine, Royal Postgraduate Medical School,
emphysema were studied. Their mean age was 59 years (range
Hammersmith Hospital, London
28-71). Their mean FEV, (±SD) as % of predicted was 37-5%
(±20-0), vital capacity 79-3% (+20-9) and single breath CO
Measurement of the transfer factor for carbon monoxide
transfer factor 48·2% (±28-2). Their mean arterial 0 2 tension
(TLCO) by rebreathing has been described by several authors,
was 8·6 kPa (+1-7). Seven healthy non-smoking subjects (mean
most recently by Marshall (1977, Am. Rev. Resp. Dis. 115,
age 34 + 6 years) were also studied. Fourteen were current
537). Except for patients with a small vital capacity, the
cigarette smokers and the remaining 18 were ex-smokers. Only
advantages over the single breath method (Ogilvie et al., 1957,
one of the patients was a female and two had α,-antitrypsin
Journal of Cinical Investigation, 36, 1) have not been
deficiency being homozygous for Pi type Z.
impressive, and the method has never been widely used. Serial
Medical Research Society
16P
We have measured kCO (D L CO/VA) by the single breath
method in 25 patients attending the Lipid Clinic at Ham­
mersmith Hospital. There were 20 males and five females
ranging from 22 to 66 years of age. Fasting serum triglyceride
levels ranged from 1-5 to 30-3 mmol/1 and serum cholesterol
from 3-7-9-9 mmol/1. The results showed no correlation
between kCO (corrected for Hb) and either serum triglyceride or
serum cholesterol level. In the non-smoking group all patients
had a kCO within the predicted range. In the smokers (eight
patients) there was a wider scatter of kCO but no correlation
with triglyceride values.
In view of the finding that intravenous administration of fat
emulsions can sometimes cause a fall in pulmonary diffusing
capacity (Sundstrom et al„ 1973, J. Appl. Physiol. 34, 816;
Greene et al., 1976, Amer. J. Clin. Nut., 29, 127) we gave three
normal, fasting, non-smoking subjects an infusion of 20%
Intralipid and, on a further occasion, a comparable amount of
intravenous egg lecithin (i.e. Intralipid without its triglyceride).
Serum triglyceride levels reached up to 8 mmolA after Intralipid
but there was no statistical difference between the serial kCO up
to 2 h after Intralipid as compared with egg lecithin.
Serial kCO measurements have also been made on a patient
with mild hypertriglyceridaemia, who was undergoing plasma
exchange. The kCO rose immediately following plasma ex­
change as the triglyceride level fell but it remained elevated as
the triglyceride level returned to pre-exchange level.
In conclusion our results, using the single-breath methodof
determining kCO, do not support the concept that hyperlipidaemia, whether spontaneous or induced, has any effect on
pulmonary diffusing capacity for carbon monoxide.
measurements of T L CO or T L CO/VA (kCO) can detect and
monitor pulmonary haemorrhage (Ewan et al., 1976, N. Eng!. J.
Med., 295, 1391) and could distinguish between haemorrhage
and oedema or infection as causes of abnormal shadowing on
chest radiographs. Since these patients are likely to be ill and
tachypnoeic with a reduced vital capacity, the measurement of
T L CO or kCO must be done by rebreathing and at the bedside.
An anaesthetic bag was filled with 750 ml of the standard
mixture of carbon monoxide (0-3%), helium (10%) and oxygen
(21%), and the CO and He concentrations measured. The
subject was turned into the bag at end-expiration and emptied it
completely ten times in 10 s, timed with a stop-watch. He was
disconnected and the concentrations of CO and He were
measured. kCO and T L CO were calculated in the normal way.
In 11 normal subjects and 11 patients (without airway
obstruction) there was a close correlation between the rebreath­
ing kCO and the single-breath kCO (at full inflation). With the
rebreathing method the kCO rose, as expected, when measure­
ments were made in five normal subjects supine compared to
erect (mean rise 31%: range 23-44%).
In a patient with Goodpasture's syndrome, serial measure­
ments of kCO were made using both methods on seven
occasions. There was good agreement. Typical comparisons
(rebreathing value first) were 2·3 and 2-4 mmol min ' k P a - 1 1 " 1
(suggesting haemorrhage), 1-28 and 1-2, and 1-0 and 1-3 (sug­
gesting resolution).
Where the patient cannot come to the laboratory, or is
unsuitable for the single breath measurement of T L CO, a simple
rebreathing method can be substituted without loss of accuracy.
51. THE EFFECT OF HYPERLIPIDAEMIA ON PUL­
MONARY DIFFUSING CAPACITY FOR CARBON
MONOXIDE
M. R. PARTRIDGE, J. M. B. HUGHES, K.
THOMPSON
PATEL and
G.
52. INTRACELLULAR POTASSIUM IN RAT CARDIAC
AND SKELETAL MUSCLE DURING PROLONGED
HYPOXIA OR HYPERCAPNIA
R.
N. T. BATEMAN and I. R. CAMERON
Department of Medicine, Royal Postgraduate Medical School,
and MFC Lipid Metabolism Unit, Hammersmith Hospital,
London
Department of Medicine, St Thomas' Hospital Medical School,
London
There is conflicting evidence on the effect of hyperlipidaemia on
pulmonary diffusing capacity for carbon monoxide (D L CO) in
man. Enzi et al. (1976, Bull, europ, Physiopath. resp. 12, 433)
showed a significant reduction of D L CO (steady state method)
in hypertriglyceridaemic patients. However, Newball et al.
(1975, Amer. Rev. Resp. Dis., 112, 83) studied normal
volunteers and patients with hyperlipidaemia and found no
significant change of D L CO (single-breath method) during fat
tolerance tests nor during diets that increased or decreased
serum triglyceride concentrations.
In acute respiratory acidosis cardiac muscle takes up potassium,
skeletal muscle loses it and the plasma potassium concentration
is raised (Lade & Brown, 1963, American Journal of Physio­
logy, 204,761-764; Poole-Wilson & Cameron, 1975, American
Journal of Physiology, 1305-1310). Respiratory alkalosis
induced by hyperventilation was reported by Spurr & Lambert
(1960, Journal of Applied Physiology, 15, 456-464) to increase
myocardial potassium content and intracellular concentration
and to leave skeletal muscle potassium unchanged, but PooleWilson & Cameron (1975) found that neither myocardial nor
quadriceps potassium content was changed. Changes in tissue
TABLE 1. Plasma potassium and intracellular potassium In left ventricular muscle and quadriceps muscle in hypoxia and hypercapnia
Mean ±SEM. *P < 0 0 5 ; **P < 0 0 1 ; ***/> < 0 0 0 5 .
n
Intracellular K +
Plasma K +
(mmol/1)
Quadriceps
Left ventricle
mmol/kg
FFDS
Control
mmol/kg
cell water
mmol/kg
FFDS
mmol/kg
cell water
19
3-70 + 0-08
354 + 2-3
145 + 2-0
489 ± 2 - 7
167 ± 1-6
Hypoxia
1 day
7 days
28 days
11
11
17
3-74 + 0-11
3-80 + 0-07
4-00 ±0-12
354 + 3-6
363 + 3-3*
360 + 2-4
145 + 2-5
150 ± 1-6
145 ± 1-8
484 + 4-4
502+ 5-5*
480 ± 2 - 9 *
163+ 1-6
176+ 1-8"
163 + 2-2
Hypercapnia
1 day
7 days
28 days
10
10
14
4-69 + 0 - 1 8 "
3-91 +0-08*
3-95 + 0-08*
360+ 5-0
374 + 3 - 4 " *
357 + 5-1
141 + 2-6
140 + 3 0
150 + 2 0
459 + 9 0 "
449 + 8 - 8 * "
474 ± 8 - 6
152+ 3 1 * "
144 + 2 - 7 * "
157 + 3-6·