437s
Clinical Science (1981) 61,437~439s
P-Receptor-blocking agents may reverse or prevent
diuretic-induced increases in serum low-density
lipoprotein cholesterol
A. M E I E R , H . S C H I F F L , P . WEIDMA",
R. M O R D A S I N I , W. R I E S E N
C. BACHMANN
AND
Medizinische Poliklinik. Institute f o r Protein Research and Department of Clinical Chemistry, University of Berne,
Switzerland
Summary
Introduction
1. The effect of treatment with a thiazide-like
diuretic alone or combined with a P-adrenoceptor blocker on serum lipoproteins was investigated in 35 patients with essential hypertension.
2. In group I (18 patients), serum low-density
lipoprotein cholesterol was increased (P< 0.001)
during monotherapy with chlorthalidone (100
mglday) but not during combined chlorthalidone-/?-blocker therapy.
3. This tendency was similar in subgroups
studied with an inverse sequence of drug administration. In subgroup I, (1 1 men), a 22% increase
(P< 0.01) in low-density lipoprotein cholesterol
after 6 weeks of chlorthalidone was reversed after
use of a P-blocker as well as chlorthalidone; in
subgroup I, (five men, two post-menopausal
women), low-density lipoprotein cholesterol was
increased by 41% (P< 0.05) above placebo
values 6 weeks after withdrawal of the p-blocker
from combination therapy.
4. In group I1 (18 men), low-density lipoprotein cholesterol was increased by 13% (P<
0.025) after 4 weeks of monotherapy with
clopamide (5 mglday) but restored to control
levels 4 weeks after addition of pindolol (10
mglday).
5. No significant changes occurred during any
treatment phase in high-density lipoprotein cholesterol.
6. Certain Preceptor blocking agents may
prevent or reverse diuretic-induced increases in
serum low-density lipoprotein cholesterol.
Lipoproteins are important correlates of coronary heart disease. In patients with hypertension
effective blood pressure control with drug therapy
has markedly improved cardiovascular prognosis, although with limited beneficial effect on
the incidence of coronary heart disease [ l , 21.
Whether or not an effect of antihypertensive
agents on lipoprotein metabolism influences the
course of coronary heart disease is at present
unclear. Short- or long-term treatment with
diuretics may be associated with increases in a
lipoprotein with atherogenic potential, namely the
low-density lipoprotein (LDL) cholesterol fraction [3-71. On the other hand, it was suggested
that b-blockers may decrease serum high-density
lipoprotein (HDL) cholesterol [81. Since combination treatment with a diuretic and a &blocker is
a common therapeutic approach in the management of hypertension, the present investigation
was undertaken to assess possible interactions
between these two classes of drugs in their effect
on lipoprotein metabolism.
Key words: chlorthalidone, clopamide, diuretics,
lipoproteins, pindolol, propranolol, P-receptor
blockade.
Correspondence: Professor Peter Weidmann,
Medizinische Universitatspoliklinik, Freiburgstrasse 3,
3010 Bern, Switzerland.
Subjects and methods
Thirty-five patients with benign essential hypertension were studied. Age ranged from 18 to 62
years (mean 44 f. SEM 3 years). Three protocols
were followed. Protocol 1 (11 men, group IA)
included a 4-week placebo phase, followed by 6
weeks of treatment with chlorthalidone, 100
mg/day, and an additional 6 weeks of combination therapy with chlorthalidone (100 mglday)
and a /?-receptor-blocking agent (propranolol,
120 to 480 mglday, in nine patients; atenolol,
100 mglday, in two patients). In protocol 2 (five
men and two postmenopausal women, group IB),
initial combination therapy (mean duration
14 f 3 weeks) with chlorthalidone (100 mglday)
A . Meier et al.
438s
and a D-blocker (propranolol, 120 or 160
mglday, in four cases; atenolol, 100 mglday in
two cases; slow-release oxprenolol, 320 mglday,
in one case) was followed by 6 weeks of therapy
with chlorthalidone (100 mglday) and concluded
with a 4-week placebo phase. Protocol 3 (17 men,
group 11) contained a 4-week placebo phase,
followed by 4 weeks of monotherapy with
clopamide (5 mg/day) and an additional 4 weeks
of combination therapy with clopamide (5 mg/
day) and pindolol (10 mg/day). At the end of the
placebo, diuretic and combination treatment
phases, the following measurements were made
after an overnight fast: serum lipoprotein fractions (by sequential ultracentrifugation), cholesterol, triglycerides, apoprotein B, glucose,
insulin, sodium and potassium levels, body
weight, blood pressure, pulse rate and plasma and
blood volumes (groups I, and 11), as previously
reported [51.
Results
Results are given in Table 1. In group I,
LDL-cholesterol was increased ( P < 0.001)
above placebo values during monotherapy with
chlorthalidone, but not during combination
therapy with a ,&blocker. This tendency was
similar in subgroups studied with an inverse
sequence of drug administration. In group I, a
22% increase ( P < 0.01) of LDL-cholesterol
during chlorthalidone monotherapy was reversed
after addition of a P-blocker to chlorthalidone,
and in group I, a 41% increase ( P < 0.05) of
LDL-cholesterol occurred after withdrawal of the
P-blocker from combination treatment. Findings
were comparable in group 11, where addition of
pindolol to clopamide reversed a 13% increase
( P < 0.025) of LDL-cholesterol occurring during
clopamide monotherapy. No significant changes
were noted during any treatment phase in
HDL-cholesterol (Table l), apoprotein B, serum
glucose, insulin or plasma volume.
Discussion
Serum LDL-cholesterol was significantly increased during monotherapy with chlorthalidone
(group I) or clopamide (group 11). However, no
such trend was observed during combination
therapy with these diuretics and a Padrenoceptor
blocker (in group I most often propranolol, in
group I1 always pindolol). Moreover, this tendency
was similar in subgroups studied with an inverse
sequence of drug administration. Our findings
indicate that the b-blocker reversed an increase in
LDL-cholesterol when added to previous diuretic
monotherapy (group I, or 11) or prevented such
TABLE1. Values obtained during placebo conditions, diuretic monotherapy and diuretic-P-adrenoceptor blocker combination
treatment
Means f SEM are shown. LDL, low-density lipoprotein; HDL, high-density lipoprotein; P, placebo; D, diuretic; B, P-blocker.
*P < 0.05; **P < 0.025;t P < 0.01; t t P < 0.001 vs placebo.
Group I
(all)
n = 18
Cholesterol (mmol/l)
P
D
D-B
Triglycerides (g/l)
P
D
D-B
P
D
D-B
P
D
D-B
P
D
D-B
P
D
D-B
P
D
D-B
LDL-cholesterol (mmolll)
HDL-cholesterol (mmolll)
Body weight (kg)
Mean blood pressure, supine (mmHg)
Pulse. supine (beatshin)
5.60 f 0.26
5.73 f 0.15
5.68 f 0.23
1.28 f 0.12
1.36 +0.10
1.37 f 0.11
2.76 f 0.18
3.55 f 0 . 2 6 t t
2.86 f 0.23
1.31 f 0.07
1.23 f 0.07
1.15 f 0.07
78.4 f 2 4
76.7 f 2 . 4 t t
77.5 f 2.5
I26 f 3
112 f 2 t t
109 f 3 t t
71f3
71 2 3
60 f 2 t t
Group I,
n= II
5.73 f 0.39
5.78 f 0.21
5.84 k 0.31
1.35 ? 0.19
1.42f 0.13
1.42f 0.12
2.86 f 0.28
3.44 f 0.36t
2.94 f 0.23
1.44+0.10
I .26 f 0.07
1.26 f 0.07
76.3 f 2.8
74.5 f 2.5t
75.1 f 2.6
I30 f 3
Ill 3tt
109 f 3 t t
73 f 4
72 f 3
59 f 3 t t
+
Group I,
n=7
5.42 f 0.31
5.63 f 0.23
5.44 f 0.31
1.19 f0.10
1.25 f 0.I7
1.29 f 0.21
2.60 f 0.21
3.68f 0.28'
2.76f 0.50
1.1OfO.10
1.15 f 0 . 1 3
1.00 f 0.13
82.2 f 5 . I
80.8 f 5.1*
82.1 f 5.2
120 f 6
113f3
109 f 6
68 f 2
70 f 3
62 f 3*
Group I I
I ? = 17
6.15 f 0.26
6.60 f 0.42
6.21 f 0.31
1.28 f 0.11
1.4450.16
1.41 2 0 . 2 0
3.94 f 0.23
4.47 f 0.31**
3.73 f 0.23
I .05f 0.02
1.13 f 0.05
1.05 f 0.05
82.1 f 3.7
81.4 f 3.7
82.6 f 3.9
117 f 2
109 f 2'
106 f 2**
74 f 2
74 f 1
72 f 2
Lipoproteins in diuretic-P-blocker therapy
an increase when given simultaneously with
chlorthalidone (group IB).
The mechanism by which P-blockers prevented
or reversed diuretic-induced increases in serum
LDL-cholesterol in our patients is at present
unclear. Haemodilution or major changes in
carbohydrate metabolism cannot be causal factors, since plasma volume and serum insulin or
glucose concentrations were not significantly
changed after short-term diuretic treatment in our
previous studies [3-61 or throughout both treatment periods in the present investigation. A
P-adrenoceptor specific influence could play a
role. Thiazide-like diuretics, by inhibiting phosphodiesterase [91 and/or by causing mild activation of the sympathetic nervous system [41,
may increase cyclic AMP, thereby stimulating
lipolysis in fat tissue [ 101. Conversely, p-adrenoceptor blockade which blunts the effects of
noradrenaline is known to inhibit adenylate
cyclase, thereby reducing the activity of hormone
sensitive lipase [ 111.
Our data indicate the need for further, longterm investigations of the pathogenic relevance of
diuretic-induced changes in lipoprotein metabolism and a possible beneficial influence of
concomitant treatment with a Padrenoceptor
blocker.
Acknowledgments
This work was supported by the Swiss National
Science Foundation. Miss I. Bollinger, Mrs G.
Haueter, Miss R. Mosimann, Miss E. Schlumpf
and Miss I. Schmied provided technical assistance.
15
439s
References
I l l HAMILTON,M., THOMPSON, E.N. & WISNIEWSKI,
T.K.M.
(1974) The role of blood pressure control in preventing
complications of hypertension. Lancet, i, 235-238.
THERAPEUTIC
TRIALIN MILD HYPERTENSION
121 AUSTRALIAN
(1980) Report by the management committee. Lancet, i,
I26 I- 1267.
G., WEIDMANN,
P., PEHEIM,E.,
131 GLUCK,Z.,BAUMGARTNER,
BACHMANN,
C., MORDASINI,
R., FLAMMER,J. & KEUSCH,G.
(1978) Increased ratio between serum L?- and /%lipoproteins
during diuretic therapy: an adverse effect? Clinical Science, 55
(Suppl. 5). 325s-328s.
141 GLUCK, Z.,WEIDMANN,P., MORDASINI,R., PEHEIM,E.,
BACHMANN,
C., KEUSCH,G. & RIESEN,W. (1979) Einfluss
einer Diuretikatherapie auf die Serumlipoproteine: ein unerwiinschter Effekt? Schweizerkche Medizinische Wochenschrifr, 109,104-108.
151 GLUCK,Z.,WEIDMANN,
P., MORDASINI,R., BACHMANN,
C.,
RIESEN,W., PEHEIM,E., KEUSCH,G. & MEIER, A. (1980)
Increased serum low-density lipoprotein cholesterol in men
treated short-term with the diuretic chlorthalidone. Melabolism, 29.240-245.
161 WEIDMANN, P., MEIER, A., MORDASMI, R., RIESEN,W.,
BACHMANN, C. & PEHEIM,E. (1981) Diuretic treatment and
serum lipoproteins: effects of tienilic acid and indapamide.
Klinische Wochenschrift, 59,343-346.
A.I., STEELE,B.W., SCHNAPER,H.W., FITZ, A.E.,
171 GOLDMAN,
FROHLICH,E.D. & PERRY,H.M.(1980) Serum lipoprotein
levels during chlorthalidone therapy. Journal of the American
Medical Association, 244, 1691-1695.
I81 LEREN, P., Foss, P.O., HELGELAND,A., HJERMANN,I.,
HOLME, 1. & LUND-LARSEN,
P.G. (1980) Effect of propranolol and prazosin on blood lipids. The Oslo Study. Lancet,
ii, 4-6.
191 SEN~T, G., LOSERT, W., SCHULTZ, G., S i n , R. &
BARTELHEIMER,
H.K. (1966) Ursache der Storungen im
Kohlenhydratstoffwechsel unter dem Einfluss sulfonamidierter
Diuretika. Naunyn-Schmiedeberg’s Archives of Pharmacology
and Experimental Pathology, 255,369-382.
J. (1972)effects of catecholamines on metaI101 HIMMS-HAGEN,
bolism. In: Handbook of Experimental Pharmacalagy,
Catechalamines, vol. 33, pp. 363-462. Ed. Blaschko, H. &
Muscholl, E. Springer, Berlin-Heidelberg-New York.
1111 ASHMORE,J., CARR, L. & LOVE, W. (1963) Lipolysis in
adipose tissue: effect of dichloroisoproterenol and related
compounds. Journal of Pharmacology and Experimental
Therapeutics, 140,182-192.