24p
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to the mid-point of the small bowel (Miazza, Levan, Vaja &
Dowling, 1980, Gut, abstract in press) in both orally and
parenterally fed rats (12 in each group). Eight days after
transposition, we compared the effects of pancreatico-biliary
diversion (PBD) on the gut and the pancreas with the results in
transected animals. The surprising findings in the pancreas are
reported here.
In orally fed rats, after PBD, the pancreatic wet weight
increased from 451·3 ± SEM 35·3 in controls to 901·4 ± 69·1
mg/IOO g body weight (P < 0·001) in experimental animals,
protein (127·0 ± 14·5 to 254·1 ± 25·9 mg per whole pancreas,
P < 0·001) and DNA (8·3 ± 0·97 to 16·9 ± 1·47 mg per whole
pancreas, P < 0·001). Histological studies showed this increase
to be due to hyperplasia and not to inflammatory cells
infiltration. However, despite the doubling of pancreatic mass,
the total amount of enzyme in the gland did not change, trypsin
from 168·4 ± 30·0 to 150·3 ± 1·8 pmol/min per whole
pancreas and amylase from 3·7 ± I· I to 3·3 ± I· I k unit per
whole pancreas, because of a reduced enzyme content per mg of
DNA for trypsin (20·2 ± 2·9 to 9·6 ± 1·8 pmol min- I rng" of
DNA, P < 0·01) and for amylase (487·9 ± 148·3 to
188·9 ± 54·9 units/mg of DNA).
After TPN, the pancreatic wet weight decreased by 30% in
controls (P < 0·01), but PBD again stimulated pancreatic
growth, its weight being significantly higher than in TPN
controls (318·9 ± 19·4 to 466·7 ± 30·0, P < 0·01) and not
different from orally fed controls.
Conclusion: PBD stimulated pancreatic growth not only in
orally fed rats but also during TPN. These findings strongly
support the concept of an enteropancreatic trophic axis.
78. A COMPARISON OF THE DIRECT AND SLOW
PRESSOR EFFECTS OF ANGIOTENSIN II IN THE
CONSCIOUS RAT
A. J. BROWN, J. CASALS-STENZEL AND A. F. LEVER
MRC Blood Pressure Unit, Western Infirmary, Glasgow,
Scotland, U.K.
We compared the direct vasoconstrictor effect of angiotensin II
(All) with its slow pressor effect in the conscious rat and related
both to concurrent plasma All concentrations. Nine female
Wistar rats were infused intravenously, first with 5% glucose for
3 days, then All 20 ng min-I kg-I at 2·4 rnl/day for 7 days and
finally glucose for 3 days. Nine control rats received glucose
throughout. All raised mean arterial pressure (MAP) progressively to an average 49·7 mmHg higher on day 7 than
during the control glucose period (P < 0·001). MAP in control
rats did not change significantly. Plasma angiotensin II levels
during the progressive rise were six times those of control rats.
In contrast, the pressor response to an hourly infusion of All at
270 ng min- I kg-I, raising plasma levels to 32 times those of
control, was on average 45·3 ± 3 mmHg. Thus a small but
sustained rise in plasma All concentration raises MAP by more
than a large rapid rise. Because changes of plasma All
concentration during prolonged infusion were closer to the
physiological range of All, this suggests that the slow pressor
effect of All may be more important than the direct vasoconstrictor effect in long-term regulation of MAP. Sodium
balance, water and food intakes were not altered by prolonged
infusion of All. Thus the thresholds for electrolyte and
dipsogenic effects of All are higher than that of the slow pressor
response, suggesting greater importance for the latter.
80. INTRA-ARTERIAL
BLOOD
PRESSURE
CARDIOVASCULAR RESPONSES IN BLACK
WHITE HYPERTENSIVE SUBJECTS
AND
AND
D. B. ROWLANDS, R. D. S. WATSON, T. J. STALLARD, J. DE
GIOVANNI AND W. A. LITTLER
Department of Cardiovascular Medicine, East Birmingham
Hospital, Birmingham 89 SST, U.K.
The common occurrence of complications, particularly stroke.
in black hypertensive subjects may reflect increased susceptibility to the effects of hypertension compared with white
subjects. We have investigated black and white hypertensive
subjects who were free of clinical evidence of target organ
damage and compared responses to tests selected to reflect the
severity of vascular damage.
lntra-arterial blood pressure and variability (expressed as
standard deviation of the mean) were measured under standardized conditions in hospital in nine West Indian essential
hypertensive patients (mean age 43 years, casual blood pressure
158/103 mmHg) and compared with values in white patients
matched for age, sex, casual blood pressure and socio-economic
status; baroreflex sensitivity and pressor and heart rate
responses to cold and sub-maximal bicycle exercise were also
measured.
Mean systolic and diastolic pressures and variability (± SD)
were not significantly different during waking (black: 138 ± 15/
89 ± 13; white 146 ± 17/93 ± 13 mmHg) or during sleep
(black: 117 ± 12/75 ± 9; white: 125 ± 13/78 ± ll mmHg.
Mean baroreflex sensitivity in blacks (9·0 ms/mmHg) was
similar to that in whites (7·5 ms/mmlIg); similarly, there were
no significant differences in the heart rate or pressor responses
to cold and bicycle exercise.
These observations suggest that black and white hypertensive subjects have similar cardiovascular responses to pressor
stimuli and provide no evidence to support the hypothesis that
there are racial differences in susceptibility to the effects of
hypertension.
8\. ACUTE
AND
LONG-TERM
ACTIONS
OF
PRAZOSIN
IN
THE
RABBIT:
EXPERIMENTAL
OBSERVATlONS OF THE FIRST DOSE EFFECT
C. A. HAMILTON AND J. L. REID
University of Glasgow Department of Materia Medica, Stobhill
Hospital, Glasgow G21 3UW, Scotland, U'K,
Prazosin, an a, adrenoceptor antagonist, is widely used in the
treatment of hypertension. Although it may cause severe
postural hypotension and syncope after the first dose, tolerance
usually develops during the first days or weeks of therapy
(Graham et al., 1976, British MedicalJournal, ii, 1293-1294).
We have investigated pharmacokinetic and dynamic explanations of the 'first dose effect' of prazosin in an animal
model. Male white New Zealand rabbits received 6 mg of
prazosin hydrochloride daily in their drinking water for 3-21
days. Neither plasma renin activity nor body weight was
affected by prazosin treatment. Steady-state blood prazosin
levels measured by high-performance liquid chromatography
(Yee, Rubin & Meffin, 1979, Journal of Chromatography, 172,
313-318) were similar in animals treated with prazosin for 3 or
21 days (21 ± 19 and 28 ± 14 ng/ml), suggesting that prazosin
clearance and metabolism are unaltered during short-term and
long-term treatment. After a single intravenous injection of
prazosin (0·05 mg/kg) when plasma levels were similar
(22 ± II ng/ml) mean arterial pressure (MAP) fell from 84 ± 7
to 68 ± 7 mmHg (P < 0·01). However, tolerance developed
with longer-term treatment, when similar plasma levels were
associated with MAP of 76 ± 6 and 88 ± 12 mmHg at 3 and 21
days respectively. Pressor responses to intravenous phenylephrine (an al agonist) and noradrenaline (mixed al and a,
agonist), which were reduced after acute intravenous prazosin,
increased during long-term treatment (rise in MAP after 100 pg
of phenylephrine 70 ± 17, 42 ± 12, 51 ± 9, 64 ± 18 mmHg
respectively in untreated, acute prazosin and 3 and 21 days
pretreatment). However, radioligand-binding studies in which
['H [prazosin or ['H [clonidine was used as specific ligand
revealed no changes in the maximum number of prazosin- or
c1inidine-binding sites or their dissociation constant in the heart.
spleen, forebrain or hindbrain.
Thus prazosin tolerance is observed during chronic treatment.
The
compensatory
mechanisms developed during chronic
Medical Research Society
prazosin therapy were related to the postsynaptic Q, adrenoceptors but did not appear to be mediated by alteration in
receptor binding and may involve other mechanisms in
excitation-contraction coupling.
82. PLASMA CATECHOLAMINE CONCENTRATIONS
IN MOTHER AND INFANT AT BIRTH
G. C. INGLIS, M. J. WHITTLE", A. I. WILSON" AND S. G. BALL
MRC Blood Pressure Unit, Western Infirmary, and "Queen
Mother's Maternity Hospital, Glasgow, Scotland, U.K.
The foetal sympathoadrenal system is probably important
during labour and delivery. However, little is known of the levels
of catecholamines, particularly the ratio of noradrenaline
(NAD) to adrenaline (AD) in the human foetus at birth. This
largely reflects problems in obtaining adequate amounts of
blood for assay, and the difficulty distinguishing NAD and AD
with relatively insensitive fluorimetric methods (Lagercrantz &
Bistoletti, 1973, Paediatric Research, 11, 889; Nakai &
Yamada, 1978, Journal ofPerinatal Medicine, 6,39).
We have employed a modification of the radioenzymatic
method of Da Prada & Zurcher (1976, Life Sciences, 19, 1161),
to measure NAD and AD in blood sampled from the umbilical
arteries (UA) and umbilical vein (UV) of the foetus, and from a
peripheral vein of the mother (MV) at delivery. Thirteen infants
and mothers were studied, classified into two groups according
to mode of delivery. Group A comprised five uncomplicated
standard vertex deliveries and group B, eight elective caesarean
sections. The mean maternal NAD level for group A was
I· 7 ± 0·4 nmol/I (mean ± SEM) and was not significantly
different from the mean maternal NAD level, 1·3 ± 0·2 nrnol/l,
in group B.
Group A mean plasma NAD concentrations were
215·4 ± 181·9 nmol/l (range 4·6-577·5 nmol/I) for UA
samples and 35·7 ± 21·1 nmol/I (range 2·3-105·4 nmol/I for
UV samples.
Group B mean plasma NAD concentrations were
31·5 ± 17·3 nmol/I (range 2·4-130·4 nmol/I) for UA samples
and 3·1 ± 1·0 nmol/I (range 1·0-8·8 nmol/l) for UV samples.
The mean UA noradrenaline level for both groups, 86·7 ± 55·9
nmol/l, was significantly greater (P < 0·0 I) than the mean UV
noradrenaline level, 15·6 ± 8·8 nmol/l.
Plasma AD concentrations were measured in five cases. The
mean UA value was 2·4 ± 0·6 nmol/l, UV value 0·3 ± 0·1
nmol/l and MV value 0·4 ± 0·1 nmol/l, The mean NAD: AD
ratios in the MV, UA and UV samples were 3: I; 9: I and 7: 1.
Maternal NAD and AD levels, in spite of the stress of childbirth,
are within our normal range of values for recumbant adults
(NAD ~ 5·5 nmol/l; AD ~ 1·0 nmol/l). The mean concentrations of UA and UV noradrenaline in elective caesarean sections
were less than those found in normal deliveries but, in this small
group, the differences were not statistically significant. UA
catecholamine levels are greater than the UV levels, as
previously observed by Saarikowski [1975, Acta Physiologica
Scandinavica, 93 (Suppl. 421)]. The high concentrations of
NAD compared with adrenaline found in UA samples suggest
that this is the predominant catecholamine in the foetus.
83. HYPORENINAEMIC HYPOALDOSTERONISM: A
DISORDER OF
RENAL TUBULAR CHLORIDE
REABSORPTION
P. L. PADFIELD, R. J. GREKIN AND M. G. NICHOLLS
University of Michigan, Division of Internal Medicine. Ann
Arbor, Michigan, U.sA.
To test the hypothesis (Grekin, Nicholls & Padfield, 1979,
Lancet, l, 1116-1118) that the biochemical abnormalities found
in hyporeninaemic hypoaldosteronism are due to excessive
reabsorption of chloride (and hence sodium and potassium) at
the thick ascending limb of Henle's loop (TALH) a patient was
25p
studied before and during long-term therapy with an agent
(frusemide) known to block chloride transport at TALH.
A 54 year old male diabetic patient with hypertension and
intermittent hyperkalaemia was found to have low-normal
plasma renin activity, 1·3 mg h- I mr ' (0-2·5), plasma
angiotensin II, 16 ng/l (8-25) and plasma aldosterone, 4·3 ng/dl
(4-15), which responded sluggishly to 3 days of sodium
depletion, 3·0 ng h- I ml" (3·0-34), 12 ng/l (18-55) and 10
ng/dl (10-41) respectively: normal ranges shown in parentheses.
A markedly increased pressor response to infused angiotensin II
(152/100 mmHg to 170/116 mmHg at 2 ng min-I kg:', with a
further increase to 198/134 mmHg at 4 ng min-I kg:") was
suggestive of a volume-expanded state. After 2 months of
therapy with increasing doses of frusemide (to 480 mg/day)
blood pressure fell to 132/88 mmHg. PRA (9·2 ng min-I kg"),
angiotensin II (43 ng/l) and aldosterone (I I ng/dl) were
increased into or above the normal range with a normal
response to acute sodium depletion (19 ng h- I ml", 77 ng/l and
32 ng/dl respectively). The dose-response curve of blood
pressure against circulating angiotensin II during an angiotensin infusion was shifted to the right, approximating to that
seen in sodium-replete normal subjects. These data favour
volume expansion rather than a structural renal defect as the
cause of renin suppression in this syndrome.
The biochemical features of hyporeninaemic hypoaldosteronism are the opposite of those seen in Bartter's syndrome, a
condition associated with impaired chloride transport across
TALH, and thus the correction of these abnormalities with
frusemide provides circumstantial evidence in support of our
original hypothesis (Grekin et al., 1979).
84. CLINICAL TRIAL OF DIFFERENT DOSES OF IJII IN
TREATMENT OF THYROTOXICOSIS: 10 YEAR
FOLLOW-UP
C. A. HARDISTY, R. N. SMITH, A. J. BETHELL AND D. S.
MUNRO
Department of Medicine, Clinical Sciences Centre, Northern
General Hospital, Sheffield S5 7AU, U.K.
In 1960, a prospective clinical trial was undertaken to clarify the
effects of different doses of IJII in the treatment of thyrotoxicosis on the production of hypothyroidism (initiated by the
late Professor G. M. Wilson). Three irradiation doses were used
calculated to administer 14000, 7000 or 3500 rad doses to the
thyroid. After 3 months, carbimazole was used to control
persistent thyrotoxic symptoms and continued for 2 year
courses unless the patient became euthyroid or hypothyroid.
The early results from this trial have been published (Smith &
Wilson, 1967, British Medical Journal, i, 129-132).
Only 26 patients were actually given 14000 rad doses
because an unacceptably high level of hypothyroidism (20%)
occurred within a year, reaching 35% at 5 years and 50% by 10
years. However, none of this group required further radioiodine.
The 7000 rad dose was administered to 319 patients and 309
were given 3500 rad doses. At 5 years, 10% of the 3500 rad
dose group were hypothyroid compared with 20% after 7000
rads; at 10 years the corresponding figures were 25% and 40%
respectively. Up to 8 years, there was little difference between
the two doses in the rate at which patients became euthyroid.
Thereafter, the number of euthyroid patients diminished to 60%
in the 7000 rad dose group but increased to 72% in the 3500 rad
group owing to differences in the incidence of hypothyroidism.
Persistent hyperthyroidism was more frequent in the 3500 rad
group so that 30% still required antithyroid drugs at 5 years
compared with 10% after the 7000 rad dose. In addition, further
IlII was required at least twice as frequently after a failure of
drug therapy in the lower dosage group.
On balance, 3500 rads produced the best overall results but
this group needed longer periods of antithyroid drugs during
their slower response to IlII therapy.