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apoprotein C-I11 in such variants improves
their substrate efficiency with lipoprotein
lipase.
Triglyceride-rich lipoproteins (a< 1.006 g/.1)
were prepared by ultracentrifugation from serum
of four hypertriglyceridaemic subjects with the
variant phenotype; and from nine
hypertriglyceridaemic controls. Incubation with
neuraminidase (c. perfringens, sigma) for 5
to 30 minutes produced increasing desialylation
of lipoproteins. After washing they were
concentrated by ultrafiltration, analysed for
apoprotein C-I11 composition by gel
electrophoresis and subjected to a substrate
competition assay with purified lipoprotein
lipase.
The apo C-111-2 : apo C-111-1 ratio
of control was 0.66 0.28 (9) compared to
variant of 1.7 0.4 (4), p<O.OI.
During
incubation of variant lipoprotein with
neuraminidase for 0, 5 and'3O minutes the ratio
of the variant decreased from 1.5, 0.62 to 0.15.
Substrate competition assays of the variant
lipoproteins at these times were: 29 ?: 3
46 2 and 37 f 3 percent reduction in release
of fatty acid from a synthetictriolein d s i o n .
Thus when the majority of the C-I11 peptides
were desialylated the particle became a less
efficient substrate for the lipase.
'he data suggest that there may be an optimal
proportion of sialylated C-I11 apoproteins on
triglyceride-rich lipoproteins for effective
substrate interaction with lipoprotein lipase.
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compartmental analysis showed that 56% and 69%
of the lZ5I-LDL and I3'I-LDL-CHD respectively
were intravascular. The chief extravascular
site of accumulation of native LDL was the liver.
Uptake was mainly receptor-mediated. judging by
the difference between the amounts of LDL and
LDL-CHD present, calculated by dividing hepatic
'"I and '"I by their respective specific
activities in plasma. These results demonstrate
that PIB reduces plasma LDL by promoting
receptor-mediated catabolism, and suggest that
the liver is the main organ of LDL uptake after
PIB. These conclusions support the concept that
LDL receptors are present in the liver and bind
increased amounts of LDL in response to
measures which stimulate bile acid synthesis.
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EFFECTS OF PARTIAL ILEAL BYPASS ON RECEPTORMEDIATED LOW DENSITY LIPOPROTEIN CATABOLISM
F. SPENGEL, N.B. MYANT, R. DUFFIELD,
C. WOOD, AND G.R. THOMPSON
MRC Lipid Metabolism Unit and Dept of Surgery,
Royal Postgraduate Medical School,
Hammersmith Hospital, London W12 OHS
Recently we reported that the cholesterollowering effect of partial ileal bypass (PIB)
in patients with heterozygous familial hypercholesterolaemia (FH) was due to stimulation of
low density lipoprotein (LDL) catabolism, presumably secondary to the increase in bile acid
synthesis induced by that procedure (Spengel et
al, 1981, Europ.J.Clin.Invest., 1 1 , 11-30). To
investigate the mechanism of this effect we
measured the turnover of homologous 51-LDL and
311-LDLblocked with cyclohexanedione (CHD) in
3 Rhesus monkeys before and 6 weeks after PIB.
The fractional catabolic rate (FCR) of LDL via
the receptor pathway was calculated as the
difference between total ('"I-LDL)
and
receptor-independent ( 'I-LDL-CHD) rates of
turnover. On average serum cholesterol fell by
30% and FCR increased from 0.042 to 0.054 hr-'
post-operatively; the proportion of LDL catabolised via the receptor pathway increased 2-fold.
'
'
'
To ascertain the role of the liver one monkey
was re-studied 5 months after PIB. This animal
was sacrificed 4 days after injection of lZ5ILDL and 311-LDL-CHDand radioactivity was
measured in plasma and tissues. Multi-
'
19P
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EVIDENCE USING A NEW CONVERTING ENZYME INHIBITOR(MK421) FOR THE ROLE OF THE RENIN SYSTEM
IN NORMOTENSIVE SUBJECTS AND ITS PROBABLE
EFFECTIVENESS IN LOWERING HIGH BLOOD PRESSURE.
G.A.MACGREGOR,N.D.MARKANDU,J.BAYLISS,J.E.
ROULSMN, M.SQUIRES,J.J.MORTON* Department of
Medicine, Charing Cross Hospital Medical School,
London W6 8RF *MRC BP Unit, Glasgow.
Mechanisms maintaining blood pressure (BP) in
normotensive subjects may also maintain BP in
patients with essential hypertension. Studies
therefore with BP-lowering drugs in normotensive
subjects which can be carefully controlled may
reveal more about the mechanism of action of the
drugs as well as forming a profile of its probable effectiveness in patients with high BP. We
have given a new non-sulfhydryl containing angiotensin converting enzyme inhibitor(MK421) in a
single dose randomised double blind cross-over
study using 5 mg, 20 mg or matched placebo to 9
normotensive volunteers on a sodium intake of
150 mmol/day. BP(supine & upright) was measured
at -2, -1,0,&,2,4,6,24 hr and blood for measurement of plasma angiotensin 11, renin activity,
aldosterone and converting enzyme activity was
taken at 0,2,6,24hr after dosing. The subjects
pursued their normal activities during the day.
Placebo caused no significant change in BP or
any of the blood measurements. 5mg & 20 mg of
MK421 both caused significant falls in BP which
were maximum at 4 to 6 his (P <O.OO1)i(Average
supine BP fall at 4 hrs with 5mg = 9.9-3.2 mm Hg
(11.5% fall) and 2Omg = 8.5+1.0 mm Hg(9.596 fall).
There was no significant difference between the
BP fall with 5mg & 20mg at any time after dosing.
5mg & 2Omg both produced significant falls in
plasma angiotensin I1,plasma aldosterone and
converting enzyme activity and significant rises
in plasma renin activity(PRA).
Some of these
changes were greater or more prolonged with 2Omg
as compared to 5mg. The results confirm that
inhibition of converting enzyme in normotensive
man on a normal sodium intake produces a fall in
BP similar to that seen with captopril. They
suggest an important role for the renin system
in the maintenance of normal BP. The results
also suggest that this non-sulfhydryl containing
converting enzyme inhibitor will be an effective
BP-lowering drug in patients with high BP. 5mg
appears as a single dose to be as effective as
20mg.