Download Inhibition by Etomidate of Steroidogenesis by Isolated Bovine

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second scan a marked overall increase in rCBF
(up to 40% in the cortex and up to 70% in the
basal ganglia). This difference was highly
significant (p<O.OOl). NO increase of the rcmo2
was seen. The normal volunteers showed the same
pattern of response as the patients. I n Group B
no increase of rCBF occurred.
Conclusions: After L-Dopa administration a
marked increase of rCBF in all brain regions
occurs without a concomitant increase of the
oxygen utilisation. Domperidone, a peripheral
dopaminergic receptor antagonist, prevents this
effect, without affecting the positive clinical
influence of L-Dopa. These results indicate
that L-Dopa affects the rCBF via a direct effect
on the blood vessel wall and not indirect via a
primary increase in oxygen metabolism. Also the
rise in rCBF has no direct relation with the
clinical improvement of the patients.
1 9 9 EFFECT OF PROPRANOIDL ON SERUM FREE T4
AND FREE T3 IN HEALTHY SUBJECTS:
M.R.
WILKINS J.A. FRANKLYN K.L. WOODS
AND M.J. -ALL
Departments of Therapeutics and Medicine, The
Medical School, Edgbaston, Birmingham Bl5 2TH
Propranolol has been reported to increase
total serum thyroxine (T4) and reduce triiodothyronine (T3) concentrations in both hyperthyroid and euthyroid subjects (Faber, J.
Horm. Metab. Res. (1979) 11:34-36; Cooper D.S.
et al Am. J. Med. (1982) 73:86/-71). However,
only a very small proportion (<0.3%) of total
circulating T4 and T3 is in the unbound ('free')
and metabolically active form. We have studied
the effects of propranolol on 'free' T4 and
'free' T3 levels, measured by radioimmunoassay
(Amerlex kits), in a group of normal subjects.
=
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Eight healthy male volunteers received
propranolol 80mg b.d. from day 0 to day 14 and
then 1 2 h g b.d. from day 15 to day 21. Blood
was sampled regularly before, during and in the
week following treatment. There was a significant fall in 'free' T3 (mean basal 6.4 + SEM 0.3
to mean day (21) 5.2 + 0.2 pmol/l, P(OT05) and
rise in 'free' T4 (mean basal 19.8 2 0.9 to
mean day (22) 23.9 + 0.7 pmol/l, pC0.01).
Reverse T3 rose (mean basal 0.44 2 0.02 to mean
day (21) 0.61 2 0.03 nmol/l, p<O.Ol) and TBG
fell (mean basal 9.4 + 0.3 to mean day (22) 8.2
+ 0.4 4 1 , p<O.OOl).-
-
These changes support the hypothesis that
propranolol alters the peripheral deiodination of
T 4 to T3. The 18% fall in 'free' T3, not
previously demonstrated, may be biologically as
well as statistically significant.
200 INHIBITION BY ETOMIDATE OF STEROIDOGENESIS
BY ISOLATED BOVINE ADRENAL CELLS
C.J. KENYON, R. FRASER, C.E.
GRAPANO
A.F. LEVER
MRC Blood Pressure Unit, Western Infirmary, and
'Oept of Biochemistry, Royal Infirmary, Glasgow
.
Etomidate when used as a long-term sedative
has been associated with increased mortality
69 P
and low plasma cortisol levels in patients in
intensive care units.
We have investigated
the in vitro effects of this drug on the synthesis of corticosteroids and their precursors
to try and locate its site of action. Cells
were isolated from bovine adrenocortical tissue
by collagenass digestion.
Aliquots of cell
suspension (30.000 cells/mll were incubated in
medium 199 for Ih at 37OC with and without
10-8Pl ACTH and with various concentrations of
etomidate (0-625 ng/ml).
Etomidate at 25 nghl
blocked ACTH-stimulated cortisol synthesis
[ p (0.001); 625 ng/ml inhibited basal synthesis
Cells treated with the
by 30% ( p (0.01).
highest dose of etomidate produced at least 30%
less progesterone both basally and when stimulated with ACTH (p (0.001) indicating that
cholesterol cleavage activity is partially but
not completely inhibited. Both basal and ACTHstimulated deoxycorticosterone syntheses were
Corticosdoubled (p (0.0011 with 625 ng/ml.
terone output, although halved with etomidate
[p (0.051, was still twofold greater with ACTH
stimulation ( p (0.001). This latter observation, together with deoxycorticosterone data,
might indicate that 116-hydroxylase activity is
partially inhibited.
A combination of the
inhibition of cholesterol cleavage, Ilghydroxylation and possibly 17a-hydroxylation
may explain why cortisol synthesis is more
effectively inhibited than other steroids.
These results are consistent with the view
that etomidate directly inhibits steroid
synthesis not by interfering with the mechanism
of ACTH action but by blocking certain steroidogenic enzymes.
It may interfere with various
cytochrome P450-dependent reactions as has been
suggested for ketoconazole, an antimycotic drug
which structurally resembles etomidate (Loose
et al, 1983, J Clin Invest 71: 14951.
201PROLACTIN RESPONSE TO PERGOLIDE IN
CYCLICAL OEDEMA
J.B. YOUNG, A.M. BROWNJOHN, C. CHAPMAN AND
M.R. LEE
Renal Unit and Depts. of Medicine and Nuclear
Medicine, The General Infirmary, Leeds L S l 3EX
We have reported (Young et al. Br Med J 1983;
286: 1691-1693) abnormal regulation of prolactin (Prl) and other anterior pituitary hormones
in cyclical oedema suggesting a hypothalamic
disturbance may be present. Bromocriptine, a
dopamine agonist which suppresses Prl secretion
is known to be effective in some women with cyclical oedema and it is possible that the hypothalamic disturbance includes a reduction in
dopaminergic activity. Pergolide mesylate is
a new, potent and long acting dopamine agocist
and is a potentially effective treatment for
cyclical oedema. We have studied the acute effects of a single dose of this drug on plasma
Prl concentrations in 8 women with cyclical
oedema and 4 female controls.
Two patients (pts.) received 50 pgn pergolide
and plasma Prl was suppressed throughout a 27 h
study period but both pts. developed severe
hypotension and nausea. A further 6 pts. (mean
age 37.5 t 4 y) and 4 controls (mean age 26.5
t 2 y) received 10 I.LS~ pergolide and this dose