1 4 ~
Medical Research Society
approximately 4 h earlier. Following base-line measurements dose-response curves were obtained using four
dose levels of isoprenaline in the range 0.005-0.04
pg kgg' min-' or dobutamine in the dose 1.25-10
mg kg-' min-'. The haemodynamic measurements were
repeated after 5 min at each dose. Isoprenaline and
dobutamine infusions were separated by an interval of 30
min. The base-line values of cardiac output, heart rate
and arterial pressure were similar irrespective of which
drug was given first (Table 1).
TABLE
1. Control ualues (meanfSEM)
Cardiac
output
(I/min)
Isoprenaline
Dobutamine
3.24 k 0.27
3.23 f 0.15
Heart rate Mean arterial
(min- ')
pressure
(mmHg)
101.8 k 8.04
99.3c! 7.30
84.4 k 4 0
8 5 . 8 k 2.4
Isoprenaline and dobutamine produced a dose depsndent increase of cardiac output. Isoprenaline doses of
0.005 and 0.02 pg kg-' min-' seemed equipotent with
dobutamine doses of 2.5 and 5.0 pg kg-' min-' respectively. Both drugs produced a dose dependent
increase of heart rate, but in the low dosage range
dobutamine caused a greater increase than isoprenaline,
at doses which were equipotent with respect to cardiac
output. A greater effect on mean arterial pressure was
produced by isoprenaline at low doses but no further
increase occurred as the dosage was raised. Dobutamine,
however, caused a steady dose dependent elevation of
mean arterial pressure. The study has confirmed the
positive inotropic effect of dobutamine. However, in
post-operative surgical patients with a low cardiac output
the increase in heart rate with dobutamine at low dosage
was greater than that with isoprenaline.
30. THE SPECIFICITY OF 8-ADRENOCEPTORS
FOR THE RELEASE O F RENIN I N MAN
ROY DAVIES,D. M. GEDDES,J. D. H. SLATER,R. C.
WIGGINS
and N. N. PAYNE
Institute of Clinical Research, The Middlesex Hospital
Medical School, London, W.l
Renin secretion, as indexed by a rise of plasma renin
activity (PRA), is increased by stimuli which excite the
sympathetic nervous system (Vander, 1965, American
Journal of Physiology, 209,659). We have shown that the
effect of orthostasis in man is attenuated by racemic propranolol but not by (+)-propranolol (Tobert et al., 1973,
Clinical Science, 44,291), thus showing that the inhibition
of renin release is a specific 8-adrenoceptor effect unrelated to the potent membrane-stabilizing effect of
propranolol. More recently we have shown in man
(Davies et al., 1974, Ciba Symposium Proceedings, in
press) that another 8-antagonist, oxprenolol, which has
much greater intrinsic sympathomimetic activity, is also
potent in attenuating the rise of PRA in response to
orthostasis.
In 1967 Lands (Nature, 214, 597) proposed a subdivision of 8-adrenoceptors into those pertinent to
cardiac function (8-1 receptors) and those pertinent to the
receptors in bronchial and arteriolar musculature (8-2
receptors).
Because the renin-secreting cells are peripheral rather
than central, 8-2 receptors would seem particularly
relevant. Indeed, the studies of Webber and his colleagues
in rabbits and those of Amery and his colleagues in man
(Webber et a/., 1974, Journal of Clinical Investigation, 54,
1413; Amery et al., 1974, New England Journal of Medicine, 290, 284) claim, by indirect evidence, that renin
release is 8-2 mediated.
We have tested this idea directly by comparing the
effect of salbutamol, a 8-2 agonist, with negligible 8-1
activity, with that of isoprenaline, which, by dafinition,
promotes mainly 8-1 activity. If renin release in man is
provoked by stimulating 8-2 adrenoceptors, then salbutamol should be an unequivocal stimulant. If, on the
other hand, 8-1 adrenoceptors are the mediators of renin
release, then, in appropriate dosage with comparable
effects on the mean arterial pressure, salbutamol should
be ineffective.
We have, therefore, compared the effects of a 3 rnin
intravenous infusion of isoprenaline into three normal
men with that of salbutamol in a dose ratio (isoprenaline
100 pg/salbutamol 1000 pg) which would show a similar
change of mean arterial pressure with both drugs (Gibson
et al., 1971, Postgraduate Medical Journal, Suppl. 47,4Q).
PRA, heart rate and blood pressure were measured at
3 min intervals for 18 min and then at 5 rnin intervals
for 30 min. PEL4 rose sharply following isoprenaline,
approximately doubling within 6-9 min. Salbutamol was
without effect on PRA, despite comparable haemodynamic changes.
These findings are consistent with the view that renin
release in man is mediated by 81 adrenoceptors.
31. THE PHYSIOLOGICAL SIGNIFICANCE OF
URINARY VASOPRESSIN AND ITS RELATIONSHIP TO PLASMA LEVELS IN MAN
J. D. H. SLATER,
MARYL. FORSLING
A. M. KHOKHAR,
and C. M. RAMAGE
Cobbold Laboratories and Department of Physiology, The
Middlesex Hospital Medical School, London, W. 1
Until recently, plasma or urine arginine vasopressin concentrations (AVP) have been measured by bioassay. This
is complex, laborious and relatively insensitive. Therefore
we have developed a radioimunoassay procedure for
the measurement of urine AVP. Since vasopressin is
destroyed and/or metabolized in the kidneys, a knowledge
of the relationship between plasma and urine AVP is
necessary for a physiological interpretation of the changes
of urine AVP.
Six healthy male volunteers were infused with 0.9%
saline at 4 ml/min for 4 h. Arginine vasopressin was
infused at 12.5,25 and 50 mU/min for 40 rnin at each rate
of infusion. Times plasma and urine samples were
assayed for vasopressin using bioassay (Forsling, 1974,
Medical Research Society
Journal of Physiology, 241, 3 ~ and
) radioimmunoassay
(Khokhar, Ramage & Slater, 1975, in press) respectively.
The results indicate that there is a good correlation
(r = 0.96, P< 0.001) between plasma AVP concentration
(range 2-40 mU/ml) and the urine AVP concentration
(range 5W500 pg/ml). A similar correlation (r = 0.93,
P< 0.001) is obtained when plasma AVP concentration is
plotted against the rate of renal excretion of AVP.
The mean increments of vasopressin excretion were
+2*3 and +4.2 when the rate of infusion was doubled
from 12.5 to 25 mU/min and quadrupled from 12.5 to 50
mU/min respectively. Similarly the mean increments in
the urine AVP concentration under these circumstances
were 2.3 and -!-4.4 respectively.
The relationship between AVP excretion and the urine
flow rate was studied by infusing 20% mannitol (5 ml/
min for 20 min) during constant infusion of AVP at 4
mU/min. Vasopressin excretion increased in two out of
three subjects studied. This increase was not progressive
and, despite a 200% increase in the mean urine flow rate,
the mean AVP excretion increased by 62% only.
The results indicate that, when the rate of urine flow is
relatively stable, measurements of AVP in urine reflect
plasma A W concentration.
Using this method we have studied sixteen healthy
male volunteers during water loading and after 18 h of
fluid deprivation. Mean values for the rate of renal AVP
excretion were 57 pg/min f 6 (SEM)following a water
load when free water clearance was 2.6k1.2 (SEM).
When the urinelplasma osmolality ratio exceeded unity
during fluid deprivation, free water reabsorption was
unchanged at 1.4 ml/min+0*08 (SEM), whatever the
urine osmolality, but renal AVP excretion rose 59% from
69 pg/min in the urine osmolality range of 400-800
mOsm/kg to 110 pg/min in the urine osmolality range of
800-1200 mOsm/kg. Assuming that the plasma AVP
concentration reflects the changes in the secretion of this
hormone, we suggest that the failure of AVP secretion to
cease when its effect on renal tubular water reabsorption
is maximal, is likely to be associated with other effects of
AVP within the physiological range.
+
32. THE EFFECT OF DIETARY SODIUM ON
ANGIOTENSIN PRESSOR ACTIVITY: STUDIES
USING CONVERTING ENZYME INHIBITOR SQ
20881
H. THURSTON
Department of Medicine, f i e General Hospital, Gwendolen Road, Leicester LE5 4P W
The pressor responsiveness to angiotensin I1 and norepinephrine was examined in rats before and during
blockade of converting enzyme activity, using the nonapeptide SQ 20881. Responses to angiotensin I1 were
impaired by sodium deprivation but enhanced by sodium
loading or bilateral nephrectomy. During the period of
converting enzyme blockage a two-fold increase in
angiotensin 11pressor response was observed in the salt
restricted rats whereas only a small change occurred in
the salt loaded animals. Infusion of the inhibitor proH
1 5 ~
duced a profound fall in the blood pressure of the salt
depleted animals with a relatively minor fall in the
sodium loaded rats. Norepinephrine pressor responses
were slightly potentiated in the salt restricted group after
administration of SQ 20881 but no change occurred in the
salt loaded or nephrectomized animals. These observations support the view that the decrease of angiotensin 11
pressor activity found during salt deprivation is the result
of a prior occupancy of receptor sites by endogenous
hormone. Therefore postulation of a change in number
or affinity of receptors consequent to changes in sodium
balance need not be required to explain the phenomenon.
33. PRESSOR AND ALDOSTERONE RESPONSIVENESS TO ANGIOTENSIN I1 I N ANEPHRIC MAN
J. DEHENEFFE,
V. CUESTA, J. D. BRIGGS,J. J. BROWN,
A. F. LEVER,J. J. MORTONand J. I. S.
R. FRASER,
ROBERTSON
M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow
Five anephric patients received graded angiotensin 11
infusions before and after sodium depletion. Following a
control period, angiotensin I1 was infused intravenously
for 1 h each at 2,4 and 8 ng kg-' min-'. Arterial plasma
angiotensin 11,aldosteroneand electrolytes were measured
at the end of each period. Blood pressure was monitored
throughout. Sodium loss was achieved by 3 days of
dietary sodium restriction (10-15 mmol/day) combined
with sodium-depleting haemodialysis. In all cases, these
manoeuvres resulted in significant falls in weight (mean
1.3 kg, 2.4%); diastolic blood pressure (mean 26.1
mmHg) and plasma sodium (mean 7.0 mmol/l). No
significant changes in plasma potassium were observed.
Basal immunoreactive angiotensin I1 was detectable in
plasma in all cases (mean 24 pg/ml). Pre- and postdepletion plasma angiotensin 11 and aldosterone levels
were not signficantly different.
When increments in blood pressure were plotted
against the logarithm of circulating angiotensin 11, a
linear pattern was apparent in all cases. When the values
from the five subjects were combined, there was no
significant difference between the curves obtained before
and after sodium depletion. In three cases no significant
aldosterone response to infused angiotensin I1 was found
before sodium depletion. In the other two patients there
was a linear relationship when plasma aldosterone was
plotted against the logarithm of plasma angiotensin 11.
After sodium depletion, the aldosterone response to
angiotensin I1 was distinctly enhanced in four cases. The
fifth patient remained unresponsive.
After sodium depletion, a signiEcant correlation was
noted between the basal plasma aldosterone concentration and the changes induced by angiotensin 11infusion
(r = 0.63; P< 001).
The results suggest: (a) that sodium depletion per se
does not alter the pressor dose-response curve to angiotensin 11 in anephric man; (b) that, as in normal man,
sodium depletion sensitizes the adrenocortical zona
glomerulosa to angiotensin 11, but with qualitative and
quantitative differences in the anephric subjects.