TlPS - December 1988 IVol. 91

Henry Eiiiott

Apart from cigarette smoking, hypertension and hyperlipidaemia are major risk factors for atherosclerosis and coronary heart disease. However, ~-udre~o~e~tor ff~tago~~st~, given tv redzrce b!ood pressrfre, may have a~ adverse effect on lipid profiles - a s~oa~~i~g of ufze risk facfvr for u~oth~r! In contrast, antihyperfensive c+adrenoceptor antagvnists have potentially beneficial effects on ti;oid metabolism. Henry Elliatt analyses the complex adrenergic control of lipid metabolism and focuses OR the benefits leg. reduced ~ncide~~~ of atherasclervsis, reduced risk of coronary heart disease) that might be gained from cfinical use of ff~-adre~ocepfor antagoffisfs in u~tihyperfensi~e t~zerapy.

j3-Adrenaceptar antagonist drugs have been used for many years to control hypertension but, to date, they have failed to produce any convincing beneficial impact an the morbidity and mortality from coronary heart disease. There is however evidence that the risks af coronary heart disease can be sig- nificantly reduced by effective treatment of hyperIipidaemia’,*.

In contrast, there is aiso evi- dence that certain types of fi-adrenaceptar antagonist drugs can adversely affect plasma lipid profiles, p~s~mab~y by interfering with the adrenergic regulatory mechanisms involved in lipa- protein metabolism. It is possible, therefore, that the beneficial effect of improving one major risk factor by lowerlt?g blond pressure is aff- set by the adverse effect of warsen- ing another major risk factor by increasing plasma lipids. Thus, the ideal antihypertensive drug would be one that also improves the plasma lipid profile. Of the currently available drugs, only the orI-adrenaceptor antagonists appear to have this potential.

Lipids and plaque formation The principal lipids in humans

are cholesterol, which is an essen- tial constituent of cell membranes, and triglyceride, which is the main transport and storage form. Lipids

are transported in blood in protein complexes and these lipoprotein particles are classified according to their hydrated density which is related to the relative amounts of triglyceride and chaIester;tl. Low- density iipoproteins (LDLf and high-density lipoproteins (HDL) are rich in cholesterol; very-low- density lipoproteins (VLDL) and chylomicrons are rich in trigly- ceride (Fig, 1).

!n re!atian to the development of atherosclerosis and coronary heart disease, it is important to recog- nize the different roles that LDL and HDL have in lipid metabol- ism, LI)L, which is involved in the transport of cholesterol to the peri- pheral tissues, is potent~a!~~ atherogenic, whereas HDL, which is involved in the transport of

439

cholesterol fl;rm the periphery to

the liver (i.e. ‘reverse’ cholesterol transport), is potentially anti- atherogenic.

Because they act to remove (modified) LDL and VLDL/chylo- micron remnants from plasma, macrophages are integrally in- voived in the process of athero- genesis and are major cellular constituents in athe~sclerot~c plaques. LDL, chemically modi- iied (tr.g. uxidizedj tj reaction with arterial endothelial cells, is taken vp by low affinity binding sites on the macrophage (Fig. 2) and, via the ‘scavenger’ pathway, becomes internalized to be de- graded to free cholesterol and then to cholesterol ester. Because there is no negative feedback control for this system, there is progressive accumulation of cholesterol ester within the macraphage which eventually dies and releases its contents allowing deposition of lipid in the atherosclerotic plaque.

LDt and VLDL cholesteroI The plasma levels of LDL are

governed by its endogenaus rate of production from precursor VLDL and by the rate of its uptake into peripheral tissues and into the liver. Thus, mechanisms which in- fluence VLDL production, includ- ing adrenergic activity, will also influence LDL production.

The rate of hepatic synthesis of VLDL is influenced by many fac- tors: by chylamicran and VLDL remnants; by free fatty acids; by circulating levels of glucose, glu- case metabalites, insulin and glu- cagan; and by the activity of the adrenergic nervous system. Tri- glyceride-rich particles (VLDL and the diet-derived chylomicrans) are

-RICH LIPOPROTEINS I

LDL dified LDL LDL

Fig. 2. Uptake of cholesterol from plasma into macrophages.

cleared from plasma by the activity of lipoprotein lipase which causes release of fatty acids which can then be taken up by adipose tis- sues (for storage) and by skeletal muscle (as an energy source). Some of the released fatty acids are also taken up by the liver for re-proces- sing (Fig. 3). Although lipoprotein lipase is located on vascular endo- thelial cells it is transported there following its synthesis in skeletal muscle and adipose tissue.

LDL, derived from the catabol- ism of VLDL in plasma, is removed from p!asma into the liver and the peripheral tissues via two path- ways. The most important path- way (70%) is the high affinity LDL receptor pathway (also termed apoprotein B/E receptor pathway) (Fig. 4); the low affinity pathway is a non-receptor-mediated ‘scaven- ger’ pathway.

HDL cholesfero1 ED!_ is respor.sible for remov-

ing excess cholesterol from peri- pheral tissues and transporting it to the liver. Surface fragments, mainly phospholipids derived from the action, of lipoprotein lipase on triglyceride-rich parti- cles, are integrated into the HDL particles and are able directly to take up unesterified cholesterol from the cells. The enzyme leci- thin-cholesterol acyl transferase (LCAT) is then responsible for conveiting unesterified choles- terol into cholesterol ester which passes to the core of the HDL particle and allows further choles- terc! to be taken into the outer layers (Fig. 4). HDL thus transports cholesterol to the liver where a

second tvpe of triglyceride lipase, hepatic iipase, acts to release un- esterified cholesterol into the liver (Fig. 5).

Adrenergic control mechanisms The adrenergic nervous system

has an important but complex regulatory influence on lipid and lipoprotein metabolism, and also on intermediate metabolism and glucose homeostasis. It is not sur- prising, therefore, that adrenergic agonist and antagonist drugs may alter plasma lipid profiles, either directly or indirectly. The sites of potential influence include:

cholesterol synthesis

TlPS - December 1988 [Vol. 91

intermediary metabolism LDL receptor pathway lipases and other enzymes macrophages.

Enzymes involved in cholesterol metabolism

Recently attention has focused on the role of the adr’energic ner- vous system in the r,l:gulation of the activity of key enzymes in- volved in cholesterol metabolism, primarily in the liver, particularly the rate-limiting enzyme of en- dogenous cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase). Also involved is acyl CoA : choles- terol acyl transferase (ACAT) which is the rate-limiting enzyme for intracellular cholesterol esteri- Zcation.

The hepatic activity of HMG CoA reductase can be stimulated in

vivo in rabbits by fi-adrenoceptor agonists, and there is some evi- dence that these drug: ma! also increase the activity of hepatic ACAT3. There is no corresponding experimental evidence with (Y- adrenoceptor drugs but, if the adrenergic control of the activity of HMG CoA reductase is analogous to that of the peripherai circula- tion, it is possible that blockade of a-adrenoceptor mechanisms per- mits unopposed activity of fl- adrenocelptor mechanisms. If so, p- adrenoceptor antagonist drugs might reduce the activity of these enzymes whereas a-adrenoceptor

Chylomicron or VLDL

Chylomicron remnant

or VLDL remnant

a ,-adrenoceptor antagon

(LPLI stimulates

Fig. 3. Location and activity of lipoprotein /ipase.

- Surface fragment

TIP5 - December 1988 Wol. 91

LPL produces svface fragm which pick up unesterified choleeteroi from the ccl

TISS

Fig. 4. HDL production and LDL removal.

antagonist drugs might permit their unopposed activity. Xow- ever, the role of p- and ar-adreno- ceptor antagonists in regulating the activity . these enzymes in humans has not yet been assessed.

Effects of intermediary metabolism

Glucose homeostasis - The adrenergic nervous system can in- directly influence lipid metabol- ism via its effects on insulin secre- tion and glucose homeostasis.

cx-Adrenoceptor antagonists, particularly arz-antagonists, have been shown to enhance insulin secretion4p5. There are several mechanisms by which insulin it- self can lead to a reduction in circulating triglyceride levels: by decreasing the mobilization of free fatty acids”; by enhancing the acti- vity of lipoprotein lipase ; and by reducing the hepatic production of VLDL”s9:

The role of fl-adrenoceptors on the regulation of insulin secretion is less well defined although dim- inished insulin secretion has been demonstrated with p- adrenoceptor antagonism50”. Dim- inished levels of insulin tend to enhance fatty acid mobilization”, promote VLDL production by the liver12 and, again independently of the activity of the adrenergic ner- vous system itself, inhibit lipopro- tein lipase activity13. Thus, the overa!l impact of a @-adrenoceptor antagonist-induced reduction in insulin is to reduce the break- down of circulating triglycerides and thus promote hyper-triglycer- idaemia.

Fatty acid synthesis - There ia evidence to suggest that the fi- adrenoceptor stimulant action of catecholamines inhibits fatty acid synthesis and utilization and thereby reduces the production and secretion of triglyceride and VLDL. Thus, fi-adrenoceptor antag- onists may lead to an increase in VLDL whereas o-adrenoceptor antagonists will promote a reduc- tion in VLDLr4.

441

clinical studies that treatment with al-adrenoceptor antagonists is as- sociated with small reductions in LDL.

Effects on enzymes Lipoprotein lipase - The en-

zyme lipoprotein lipase, which is involved in the catabolism of trigiyceride-rich lipoproteins in the circulation, has been widely studied. There is evidence to suggest that its activity is under adrenergic control although it has not been established whether this reflects increased synthe- sis or an alteration in the local activity or concentration. Thus, fi- adrenoceptor stimulation increases lipoprotein lipase activity whereas or-adrenoceptor stimulation de- creases its activity (Fig. 3). These effects lead respectively to an in- crease or decrease in the rate of breakdown of circulating trigly- cerides’7*‘8. Thus, P-adrenoceptor antagonists may promote in- creased plasma triglyceride levels, whereas o-adrenergic antagonists may facilitate a reduction in plas- ma triglyceride levels. Evidence of this differential effect on lipo- protein lipase activity has been reported in several human studies, particularly those involving pro- pranolol and prazosin”-*‘.

LDL receptor pathway In in-vitro studies of cultured

human fibroblasts, adrenaline decreases the activity of the LDL receptor pathway whereas dox- azosin (an or-adrenoceptor antag- onist, see Fig. 2) increases LDL receptor activity’5,‘6. In theory, increased activity of the LDL receptor pathway should lead to reduced plasma levels of LDL cholesterol. There is evidence from

Impairment of the activity of lipoprotein lipase also indirectly interferes with the interconversion of HDL3 and HDLZ subfractionsz2 and this may be a contributory mechanism for the reductions in HDL2 cholesterol reported with fi- adrenoceptor antagonist drugs”3*24.

Hepatic lipase, LCAT and chol- esteyl ester hydrolase - There is only limited information about the adrenergic control of these

PLASMA LCAT

Fig. 5. Cholesfdrol uptake and VLDL synfhesis in liver cells.

442

e~,~ymes which are particularly important in ‘reverse’ cholesterol transport. For example, P-adreno- ceptor antagonism has been shown to decrease the activity of LCAT”5,‘6 and of cholesteryl ester hydrolase (leading to impaired HDL cholesterol uptake)27. 60th these effects might contribute to the decrease in HDL reported in clinical studies with P-adrenocep- tar antagonist drugs. Correspond- ingly, these drugs may inhibit hepatic lipase activity and thereby interfere with the uptake of HDL cholesterol into the liver, whereas arz-adrenoceptor antagonists may promote this (Fig. 5).

Apoli~p#tein A-l is the prin- cipai component form (70%) of HDL and, along with LCAT, it is responsible for removing choles- terol from macrophages (and other tissue cells). Clearly, deficiency of apo A-l will lead to impaired chol- esterol removal and thus promote the development of atherosclero- sis. There is some evidence from clinical studies that at-adreno- ceptor antagonism with prazosin stimulates the formation of apo A-l (Refs 28 and 29, whereas p- adrenoceptor antagonism was as- sociated with reduced levels3”; it might therefore be expected that treatment with aI-adrenoceptor antagonists would enhance chol- esterol removal from peripheral tissues.

There is thus much evidence to illustrate the possible sites of influ- ence of rhe adrenergic nervous system on plasma lipid levels and on lipoprotein metabolism. Studies with adrenoc~ptor antag- onists indicate that g- and p- adrenoceptor antagonists have opposite effects - a,-adrenoceptot antagonists appear to promote potentially beneficial lipid changes. However, the picture is complex, the details of the mech-

anisms involved remain obscure, ~orroburative evidence from human studies is limited and the impact on atherosclerosis and coronary heart riised~ remains to be established.

References 1

2 Frick, H. M. et ai. (1987) N. Engl. I. Med. 317, 1237-1245

3 Devery, R., O’Donnell, L. and Tomkin, G. H. (1986) Biochim. Biophys. Acta 887, 173-181

4 Persson, 1. and Larsen, L. (1972) Acta Endocri&. 71, 331-337

5 Ahren, B., Lundquist, I. and Jarhult, J. (1984) Acla Endocrinof. 105, 78-82

6 Saudek, C. D. and Eder, H. A. (1979) Am. 1. Med. b6, &E-852

7 I’ykalisto, 0. J., Smith, I’. H. and Brun- zell, J. 0. (1975) f. Clin. Invesf. 56, l108-1117

8 Durrington, I’. N., Newton, R S., Wein- stein, D. 6. and Steinberg. D. (1982) J. Clin. Invest. 70, 63-73

9 Pullinger, C. R. and Gibbons, G. F. (1985) Biochim. Biophys. Acta 833,44-51

10 Robertson, R. P. and Porte. D., Jr (1973) Diabetes 22, 1-8

11 Srhlierf, G. and Dorow, E. (1973) 7. Clifl. Invest. 52, 732-740

I2 Wilcox, H. G., Dunn, G. D. and Heim- berg, M. (1975) Biochim. ~~~pkys. Arfa 398,39-54

13 Nikkila, E. A., Huttunen, J. K. and Enholm, C. (1977) Diabefes 26,11-21

14 DalI’AgIio, E., Chang, H. and Reaven, G. M. (1984) Am. /. Med. 76 (SuppI. 2A), 85-88

15 Maziere, J. C., Maziere, C.. Gardette, J., Mora, L. and I’olonoveki, J. (1983) Bio- cl!;,,. Biophys. Res. Commaa. 112, 795- 800

TfPS - December 2988 &W. 91

16 ?_eren,T. I’. (1985) Acfa. r~a~araJ. Toxi- cot. 56,269-2x?

17 Day, J. L., Metcatfe, 1, and Simpson, c. N. (1982) Dr. Med. 1. 284,1145-1148

18 Jansen, H. and Bagpen, M. C. A. (1987) 1, Cardiovasc. Dkarmacol. 10 (Suppl. 9). SIC-520

19 Tanaka, I<‘., Sakapuchi, S., Oshige, K., Niimura, T, and Kanehisg, T. (1976) Metabolism 25, 1071-1075

20 Schauer, I., Schauer, X, Ruhling, K. and Thielmann, K. (1980) Arfery 6,146150

21 Ferrera, L. A. et al. (1986) Am. 1. Med. 80 [SuppI. 2Af. 104-108

22 Patsch, J. R., Gotto, A.M., Jr, Oliver- wona, T. and Eisenberg, S. (1978) Pvoc. Natl Acad. Sci. USA 75,4519-4523

23 Murphy, M. B. &al. (1984) Br. Heart /. 51, 589-594

24 Lehtonen, A. and Mamiemi, J. (1984) Atherosclerosis 51,335-338

25 Lehtonen, A., Hietanen, E.. Mznfemi, 1.. Pellonen, P. and Niekanen, J. (1982) Br. I. CJin. Phnrtiiacot. 13 (Suppl. 2). 4455-448s

26 Goto, Y. (1984) Am. f, Med. 76 (Suppi. ZA), 72-78

27 Khoo, J. C., Drevon, C. A. and Steinberg, D. (1979) J. BiaJ. Chcm. 254, 17851787

28 Johnson, 8. F., Romero, L., Johnson, I. and Mawah, R. (1984) Am. I. Med. 76 (Suppl. 2A), 109-112

29 Gemma, G. et al. (19P2) j. Cardiooasc. Pharnfaccl. 4 (Suppl. 2), 5233-5237

30 Rouffy, J. and Jaillard, J. (1984) Am. 1.

1\ Med. 74,lOzilOS

The first issue of TiPS wus ptiblished in 1979. The 200th issue was published in December 2987. Leading researchers chose to write for this prestigious edition which y~~sents the most recent adva~~s in the science u~p~~co~o~ in its boldest sense. A complete perspective of pharmacology today and tomorrow is drawn by:

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