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Atherosclerosis and thrombosis. Old and new drugs
ELSEVIER
Archives of Gerontology and Geriatrics 20 (1995) 43-48
ARCHIVES OF GERONTOLOGY AND GERIATRICS
Atherosclerosis and thrombosis. Old and new drugs Rodolfo Paoletti, Flavia Bruno*, Susanna Colli Institute of Pharmacological Sciences, University of Milan, via Balzaretti, 9, 20133 Milan, Italy Received 26 May 1994; revision received 15 September 1994; accepted 19 September 1994 Almtract
Thanks to the increasing knowledge of the pathogenesis of atherosclerosis, much effort has been made in the last years to develop new drugs aimed at controlling risk factors correlated with the disease as well as to investigate more deeply their mechanism of action. In particular, this brief review will describe some new aspects of the mechanism of action of drugs widely used in the control of risk factors like hyperlipemia, hypertension and blood viscosity. Among drugs active on plasma lipid profile, HMG-CoA reductase inhibitor are, at present, under study for their promising activity in the modulation of the interaction between the cells of the arterial wall and circulating blood elements. Indeed, these compounds have been found to control the proliferation of smooth muscle cells and other events related to the formation of atheroma. As far as antithrombotic drugs are concerned, the efficacy of low doses of aspirin has emerged by recent clinical trials. The successful use of low doses of aspirin has been possible following the comprehension of the mechanism by which this compound inhibits TXAdependent platelet function, thus allowing a dose-dependent dissociation of the antithromboric activity from other undesirable effects. Also for calcium antagonist an antiatherogenic effect which deserves further investigations has been recently clarified. Indeed it has been demonstrated that calcium antagonists have a protective effect against vascular lesions because they inhibit smooth muscle cell proliferation, lipid uptake by macrophages and the production of collagen and elastin. Another class of drugs which represents a new approach in the control of some risk factors is represented by n-3 fatty acids. Besides their activity on triglycerides, these compounds exert a positive effect on hemostatic and thromboembolic event, by reducing platelet aggregation and blood viscosity. Also for those molecules which appear to exert promising antiatherosclerotic and antithrombotic action, further studies will define their exact mechanism of action. Keywords: Atherosclerosis; Thrombosis; HMG-CoA reductase Inhibitors; Calcium antagonist; n-3 fatty acids * Corresponding author, Tel.: + 39 2 20488316, + 39 2 20488219; Fax: + 39 2 29404961. 0167-4943/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSD! 0167-4943(94)00604-6
44
R. Paoletti et a l . / Arch. Gerontol. Geriatr. 20 (1995) 43-48
1. Introduction
An increasing knowledge of the pathogenesis of the atherosclerotic process has led to an understanding of the importance of risk factors correlated with this disease. Atherosclerosis is a multifactorial disease involving risk factors such as hypercholesterolemia, hypertension, diabetes and smoking, circulating blood elements (platelets and leukocytes) and cells of the arterial wall (endothelial and smooth muscle cells). For this reason, pharmacological intervention must be aimed not only at control of plasma lipids and arterial pressure but also towards the use of drugs with effects on the function and biochemistry of blood cells and on cells of the arterial wall. Clinical experience indicates that the use of drugs which interfere with the synthesis of thromboxane in the platelet, in particular aspirin, reduces the incidence of thrombotic risks in patients affected by cardiovascular diseases, such as unstable angina or transient ischaemic attacks. On the basis of these clinical findings, prevention of cardiovascular disease can be effected with drugs which modulate the reactions of circulating blood elements with cells of the arterial wall. Among drugs acting on risk factors that are promising under this profile, we find calcium antagonists and HMGCoA reductase inhibitors, which can act directly on the cells of the arterial wall and on circulating blood elements. Indeed they can inhibit proliferation of smooth muscle cells and other events related to the formation of the atheroma. Subsequent pharmacological studies indicate that n-3 fatty acids may give protection against the incidence and progression of cardiovascular diseases via actions on lipid metabolism, arterial pressure, blood viscosity, platelet aggregation and fibrinogen levels. 2. Aspirin It is almost a century since the introduction of acetylsalicyclic acid (aspirin) for human therapy but it was only in the last 50 years, thanks to the studies of Sir J.R. Vane, at the Royal College of Surgeons in London, B. Samuelsson, at the Karolinska Institute in Stockholm and P.W. Majerus, at the Washington University in St. Louis 0Cane, 1971; Hamberg et al., 1975; Roth et al., 1975), that the mechanism of action through which aspirin inhibits platelet aggregation was elucidated. The last 10 years have been dedicated to the development of low-dose aspirin as an antithrombotic agent (Patrono et al., 1980). Much evidence indicates that there is a very close relationship between the clinical effects of aspirin and reduced levels of thromboxane in platelets: (a) (b)
(c)
thromboxane levels are elevated when there are high risk factors (Patrono et al., 1980, 1992). the biosynthesis of this product of arachidonate metabolism is sometimes increased in acute ischaemic syndromes, both in coronary and cerebral circulation (Patrono et al., 1980). aspirin administered at doses of 30-1500 mg/day exerts antithrombotic effects.
R. Paoletti et al./ Arch. Gerontol. Geriatr. 20 (1995) 43-48
45
It is interesting to note, from several clinical studies (Lewis et al., 1983; Cairns. et al., 1985; Lichtlen et al., 1990; Force et al., 1991; The Dutch Tia Trial Study Group, 1991), that the antithrombotic efficacy of the drug is not dose-dependent, whereas the incidence of side-effects is related to the dosage as well as the duration of the treatment. The explanation of this phenomenon is that the mechanism of action of aspirin is related to the acetylation of a single amino acid residue (Serine at position 529: Ser-529 ) in the polypeptide chain of the enzyme PGG/H synthetase. This acetylation causes inhibition of the cyclooxygenase activity, which differs according to the type of cells involved. In the platelet this effect is irreversible. The specific mechanism of action of aspirin in inhibiting TXA-dependent platelet function allows a dose-dependent dissociation of the antithrombotic effects from undesirable gastrointestinal symptoms. 3. HMG-CoA reductase inhibitors Thrombotic disorders are among the complications of hyperlipoproteinemias, both as a consequence of progressive alterations of the arterial wall and of changes in platelet reactivity. On this basis, it is of interest to evaluate the effects on some mechanisms involved in thrombus formation and in the initiation and progression of atheroma. Recently HMG-CoA reductase inhibitors have been demonstrated to reduce cholesterol ester accumulation in macrophages cultured 'in vitro' from monocytes isolated from human blood (Kempen et al., 1991). Indeed, these cells can accumulate large amounts of cholesterol esters following exposure to modified lipoproteins. Both chemically and naturally modified lipoproteins, for example those mildly oxidized by contact with the endothelium, can induce lipid accumulation in macrophages (Henriksen et al., 1981). The described effect is mediated by the presence of the 'scavenger receptor' on macrophages, which, besides its activity in lipoprotein internalization, plays a role in the proliferative capacity of the cell (Yui et al., 1993). This latter event may represent the 'primum movens' in progression of the atherosclerotic plaque. Given these considerations, HMG-CoA reductase inhibitors can be considered, in addition to their capacity to lower plasma cholesterol levels, as drugs which can control the capacity of the monocyte/macrophage to initiate and participate in an atherothrombotic event. This novel aspect of the mechanism of action of HMG-CoA reductase inhibitors has only been demonstrated with an 'in vitro' approach and thus the impact of this phenomenon requires confirmation by 'in vivo' studies. 4. Calcium antagonists Thanks to new studies investigating the importance of the arterial wall in the progression of atheroma, we can consider calcium antagonists as a new class of antiatherogenic agents. This class of drugs has been studied in a variety of experimental models including
46
R. Paoletti et al./Arch. Gerontol. Geriatr. 20 (1995) 43-48
the cholesterol-fed rabbit. These drugs have been shown to influence several processes with a role in the development of atherosclerotic lesions, including inhibition of smooth muscle cell migration and proliferation. Recently, much effort has been made to evaluate the direct effect of these drugs on the arterial wall and their inhibitory effect on the progression of new lesions, in animals and in man (Loscalzo, 1990; Blankenhorn, 1991; Schmitz et al., 1991). In particular, several studies on the cholesterol-fed rabbit (Jackson et al., 1989; Sowers, 1990) demonstrate that calcium antagonists have a protective effect against vascular lesions because they can inhibit smooth muscle cell migration and proliferation, lipid uptake by macrophages and the production of collagen and elastin. Thus, these drugs normalize parameters involved in progression of atherosclerosis. The antiatherogenic effects of calcium antagonists necessitate further research. It has been demonstrated that the mechanism of action of calcium antagonists is linked to their capacity to inhibit calcium uptake at the cellular level. In fact, molecules that facilitate the entry of calcium in the cell are able to increase intracellular cholesterol and cellular proliferation. Thus, for these drugs new possibilities in the future are related to their effects on the formation and progression of the atherosclerotic plaque.
5. Fatty acids (n-3) Data obtained from epidemiological and clinical trials in humans and animals indicate that n-3 fatty acids may confer protection against the incidence and progression of cardiovascular diseases and reduce the frequency of recurrence of coronary stenosis. Despite intensive studies, the complete range of physiological, biochemical and molecular mechanisms underlying the activity of these fatty acids is not completely understood. Besides the effect that n-3 fatty acids exert on lipid metabolism (Harris, 1989), they are known to possess beneficial antiaggregatory and vasodilatory properties (Dyerberg and Bang, 1979; Fox and Di Corletto, 1988; Endres et al., 1989). Furthermore, n-3 fatty acids have been shown to have a positive effect on hemostatic and thromboembolic processes, by reducing blood viscosity, platelet aggregation and fibrinogen levels. The broad range of activities of n-3 fatty acids can be, at least in part, explained by the profound alterations that their intake determines in cell membrane composition (Von Schacky et al., 1985), thus justifying the ubiquity of their effects. At present, there is great interest in the mechanisms by which these fatty acids affect the behaviour of cells involved in thrombus formation, e.g. platelets, leukocytes and endothelial cells. In particular, their capacity to reduce the synthesis of vasoconstrictive and proinflammatory lipid mediators and cytokines, thus diminishing their potentially injurious actions, has been extensively investigated. In parallel, preliminary evidence indicates a reduced production of the atherogenic platelet-derived growth factor (PDGF), by monocytes of subjects receiving increased dietary n-3 fatty acids (Kaminsky et al., 1993). It is worth mentioning that PDGF is considered one of the most potent stimuli for proliferation of smooth muscle cells. Most recently, mechanisms and effects of dietary n-3 fatty acids were investigated
R. Paoletti et al./ Arch. Gerontol. Geriatr. 20 (1995) 43-48
47
in b a b o o n s . I n this study, following d i e t a r y n-3 fatty acid a d m i n i s t r a t i o n , vascular tissue was f o u n d to be less t h r o m b o g e n i c . M o r e o v e r , the f o r m a t i o n o f vascular lesions after c a r o t i d e n d a r t e r e c t o m y was c o m p l e t e l y inhibited ( H a r k e r et al., 1993). Also, for n-3 fatty acids which a p p e a r to exert p r o m i s i n g antiatherosclerotic a n d a n t i t h r o m b o t i c effects, further studies will define their exact m e c h a n i s m o f action a n d the d u r a t i o n o f their activity.
References Blankenhorn, D.H. (1991): Blood lipids and human atherosclerosis regression: the angiographic evidence. Cuff. Opin. Lipidol., 2, 2324-2329. Cairns, J.A., Gent, M., Singer, J., Finnie, K.S., Froggatt, G.M., Holder, D.A., Jablonsk, G., Kostuk, W.J., Melendez, L. and Myers, M.G. (1985): Aspirin, sulfinpyrazone, or both in unstable angina: resuits of a Canadian Muiticenter Trial. N. Engl. J. Med., 313, 1369-1375. Dyerberg, J. and Bang, H.O. (1979): Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet, 2, 433-435. Endres, S., Ghorbani, R., Kelly, V.E., Georgilis, K., Lonnemann, G., van der Meer, J.W., Cannon, J.G., Rogers, T.S., Klempner, M.S., Weber, P.C., Schaefer, E.J., Wolf, S.M. and Dinarello, C.A. (1989): The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N. Engi. J. Med., 320, 265-271. Force, T., Miliani, R., Hibberd, P., Lorenz, R., Vedelhov, W., Leaf, A. and Weber, P. (1991): Aspirininduced decline in prostacyclin production in patients with coronary artery disease is due to decreased endoperoxide shift. Circulation, 84, 2286-2293. Fox, P.L. and Di Corleto, P.E. (1988): Fish oils inhibit endothelial cell production of platelet-derived growth factor-like protein. Science, 241,453-456. Hamber8, M., Svensson, J. and Samuelsson, B. (1975): Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Natl, Acad. Sci. USA, 72, 2294-2298. Harker, L.A., Kelly, A.B., Hanson, S.R., Krupski, W., Bass, A., Osterud, B., Fitzgerald, G,A., Goodnight, S.H. and Connor, W.E. (1993): Interruption of vascular thrombons formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in non-human primates. Circulation, 87~ 1017-1029. Harris, W.S. (1989): Fish oil and plasma lipid and lipoprotein metabolism in humans: A critical review. J. Lipid. Res., 30, 785-807. Henriksen, T., Mahoney, E.M. and Steinberg, D. (1981): Enhanced macrophage degradation of low density lipoprntein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density iipoproteins. Proc. Natl. Acad. Sci. USA, 78, 6499-6503. Jackson, C.L., Bush, R.C. and Bowyer, D.E. (1989): Mechanism of antiatherogenic action of calcium antagnnists. Atherosclerosis, 80, 17-26. Kaminski, J.E., Jendraschak, E., Kiefl, R. and yon Schacky, C. (1993): Dietary ~03fatty acids lower levels of platelet derived growth factor mRNA in mononuclear cells. Blood, 81, 1871-1879. Kempen, H.J.M., Vermeer, M., de Wit, E. and Havekes, L.M. (1991): Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages. Arterioscler. Thromb., 11, 146-153. Lewis, H.D. Jr, Davis, J.W., Archibald, D.G., Steinke, W., Smitherm, T.E., Doherty, J.E., Schnaper, H.W., Lewinter, M.M., Linares, E. and Pouget, J.M. (1983): Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results o f a Veterans Administration Cooperative Study. N. Engl. J. Med., 309, 396-403. Lichtlen, P.R., Hugenboitz, P.G., Rafflenbleu, W., Hecker, H., Jost, S. and Deckers, J.W. (1990): Retarclarion of angiographic progression of coronary artery disease by nifedipine. Results of the International Trial on Antiatherosclerotic Therapy (INTACT). Lancet, 335, 1109-1113. Loscalzo, J. (1990): Regression of coronary athernsclerosis. N. Engi. J. Med., 323, 1337-1339. Patrono, C., Ciabattoni, G., Pinca, E., Pugiiese, F., Castrncci, G., De Salvo, A., Satta, M.A. and Peskar, B.A. (1980): Low-dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb. Res., 17, 317-327.
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Patrono, C., Davi', G. and Ciabattoni, G. (1992): Thromboxane biosynthesis and metabolism in relation to cardiovascular risk factors. Trends Cardiovasc. Med., 2, 15-20. Roth, G.J., Stanford, N. and Majerus, P.W. (1975): Acetylation of prostaglandin synthetase by aspirin. Proc. Natl. Acad. Sci. USA, 72, 3073-3076. Schmitz, G., Hankovitz, J. and Kovacs, E.M. (1991): Cellular processes in atherogenesis: potential targets of calcium channel blockers. Atherosclerosis, 88, 109-132. Sowers, J.R. (1990): Calcium channel blockers and atherosclerosis. Am. J. Kidney Dis., XVI, 3-9. The Dutch TIA Trial Study Group (1991): A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischen~c attack or minor ischemic stroke. N. Engl. J. Med., 325, 1261-1266. Vane, J.R. (1971): Inhibition of prostaglandins as a mechanism of action for aspirin-like drugs. Nature, 231,232-235. Von Schacky, C., Fischer, S. and Weber, P.C. (1985): Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function and eicosanoid formation in humans. J. Clin. Invest., 76, 1626-1631. Yui, S., Sasaki, T., Miyazaki, A., Horiuchi, S. and Yamazaki, M. (1993): Induction of routine macrophage growth by modified LDLs. Arterioscler. Thromb., 13, 331-337.
Archives of Gerontology and Geriatrics 20 (1995) 43-48
ARCHIVES OF GERONTOLOGY AND GERIATRICS
Atherosclerosis and thrombosis. Old and new drugs Rodolfo Paoletti, Flavia Bruno*, Susanna Colli Institute of Pharmacological Sciences, University of Milan, via Balzaretti, 9, 20133 Milan, Italy Received 26 May 1994; revision received 15 September 1994; accepted 19 September 1994 Almtract
Thanks to the increasing knowledge of the pathogenesis of atherosclerosis, much effort has been made in the last years to develop new drugs aimed at controlling risk factors correlated with the disease as well as to investigate more deeply their mechanism of action. In particular, this brief review will describe some new aspects of the mechanism of action of drugs widely used in the control of risk factors like hyperlipemia, hypertension and blood viscosity. Among drugs active on plasma lipid profile, HMG-CoA reductase inhibitor are, at present, under study for their promising activity in the modulation of the interaction between the cells of the arterial wall and circulating blood elements. Indeed, these compounds have been found to control the proliferation of smooth muscle cells and other events related to the formation of atheroma. As far as antithrombotic drugs are concerned, the efficacy of low doses of aspirin has emerged by recent clinical trials. The successful use of low doses of aspirin has been possible following the comprehension of the mechanism by which this compound inhibits TXAdependent platelet function, thus allowing a dose-dependent dissociation of the antithromboric activity from other undesirable effects. Also for calcium antagonist an antiatherogenic effect which deserves further investigations has been recently clarified. Indeed it has been demonstrated that calcium antagonists have a protective effect against vascular lesions because they inhibit smooth muscle cell proliferation, lipid uptake by macrophages and the production of collagen and elastin. Another class of drugs which represents a new approach in the control of some risk factors is represented by n-3 fatty acids. Besides their activity on triglycerides, these compounds exert a positive effect on hemostatic and thromboembolic event, by reducing platelet aggregation and blood viscosity. Also for those molecules which appear to exert promising antiatherosclerotic and antithrombotic action, further studies will define their exact mechanism of action. Keywords: Atherosclerosis; Thrombosis; HMG-CoA reductase Inhibitors; Calcium antagonist; n-3 fatty acids * Corresponding author, Tel.: + 39 2 20488316, + 39 2 20488219; Fax: + 39 2 29404961. 0167-4943/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSD! 0167-4943(94)00604-6
44
R. Paoletti et a l . / Arch. Gerontol. Geriatr. 20 (1995) 43-48
1. Introduction
An increasing knowledge of the pathogenesis of the atherosclerotic process has led to an understanding of the importance of risk factors correlated with this disease. Atherosclerosis is a multifactorial disease involving risk factors such as hypercholesterolemia, hypertension, diabetes and smoking, circulating blood elements (platelets and leukocytes) and cells of the arterial wall (endothelial and smooth muscle cells). For this reason, pharmacological intervention must be aimed not only at control of plasma lipids and arterial pressure but also towards the use of drugs with effects on the function and biochemistry of blood cells and on cells of the arterial wall. Clinical experience indicates that the use of drugs which interfere with the synthesis of thromboxane in the platelet, in particular aspirin, reduces the incidence of thrombotic risks in patients affected by cardiovascular diseases, such as unstable angina or transient ischaemic attacks. On the basis of these clinical findings, prevention of cardiovascular disease can be effected with drugs which modulate the reactions of circulating blood elements with cells of the arterial wall. Among drugs acting on risk factors that are promising under this profile, we find calcium antagonists and HMGCoA reductase inhibitors, which can act directly on the cells of the arterial wall and on circulating blood elements. Indeed they can inhibit proliferation of smooth muscle cells and other events related to the formation of the atheroma. Subsequent pharmacological studies indicate that n-3 fatty acids may give protection against the incidence and progression of cardiovascular diseases via actions on lipid metabolism, arterial pressure, blood viscosity, platelet aggregation and fibrinogen levels. 2. Aspirin It is almost a century since the introduction of acetylsalicyclic acid (aspirin) for human therapy but it was only in the last 50 years, thanks to the studies of Sir J.R. Vane, at the Royal College of Surgeons in London, B. Samuelsson, at the Karolinska Institute in Stockholm and P.W. Majerus, at the Washington University in St. Louis 0Cane, 1971; Hamberg et al., 1975; Roth et al., 1975), that the mechanism of action through which aspirin inhibits platelet aggregation was elucidated. The last 10 years have been dedicated to the development of low-dose aspirin as an antithrombotic agent (Patrono et al., 1980). Much evidence indicates that there is a very close relationship between the clinical effects of aspirin and reduced levels of thromboxane in platelets: (a) (b)
(c)
thromboxane levels are elevated when there are high risk factors (Patrono et al., 1980, 1992). the biosynthesis of this product of arachidonate metabolism is sometimes increased in acute ischaemic syndromes, both in coronary and cerebral circulation (Patrono et al., 1980). aspirin administered at doses of 30-1500 mg/day exerts antithrombotic effects.
R. Paoletti et al./ Arch. Gerontol. Geriatr. 20 (1995) 43-48
45
It is interesting to note, from several clinical studies (Lewis et al., 1983; Cairns. et al., 1985; Lichtlen et al., 1990; Force et al., 1991; The Dutch Tia Trial Study Group, 1991), that the antithrombotic efficacy of the drug is not dose-dependent, whereas the incidence of side-effects is related to the dosage as well as the duration of the treatment. The explanation of this phenomenon is that the mechanism of action of aspirin is related to the acetylation of a single amino acid residue (Serine at position 529: Ser-529 ) in the polypeptide chain of the enzyme PGG/H synthetase. This acetylation causes inhibition of the cyclooxygenase activity, which differs according to the type of cells involved. In the platelet this effect is irreversible. The specific mechanism of action of aspirin in inhibiting TXA-dependent platelet function allows a dose-dependent dissociation of the antithrombotic effects from undesirable gastrointestinal symptoms. 3. HMG-CoA reductase inhibitors Thrombotic disorders are among the complications of hyperlipoproteinemias, both as a consequence of progressive alterations of the arterial wall and of changes in platelet reactivity. On this basis, it is of interest to evaluate the effects on some mechanisms involved in thrombus formation and in the initiation and progression of atheroma. Recently HMG-CoA reductase inhibitors have been demonstrated to reduce cholesterol ester accumulation in macrophages cultured 'in vitro' from monocytes isolated from human blood (Kempen et al., 1991). Indeed, these cells can accumulate large amounts of cholesterol esters following exposure to modified lipoproteins. Both chemically and naturally modified lipoproteins, for example those mildly oxidized by contact with the endothelium, can induce lipid accumulation in macrophages (Henriksen et al., 1981). The described effect is mediated by the presence of the 'scavenger receptor' on macrophages, which, besides its activity in lipoprotein internalization, plays a role in the proliferative capacity of the cell (Yui et al., 1993). This latter event may represent the 'primum movens' in progression of the atherosclerotic plaque. Given these considerations, HMG-CoA reductase inhibitors can be considered, in addition to their capacity to lower plasma cholesterol levels, as drugs which can control the capacity of the monocyte/macrophage to initiate and participate in an atherothrombotic event. This novel aspect of the mechanism of action of HMG-CoA reductase inhibitors has only been demonstrated with an 'in vitro' approach and thus the impact of this phenomenon requires confirmation by 'in vivo' studies. 4. Calcium antagonists Thanks to new studies investigating the importance of the arterial wall in the progression of atheroma, we can consider calcium antagonists as a new class of antiatherogenic agents. This class of drugs has been studied in a variety of experimental models including
46
R. Paoletti et al./Arch. Gerontol. Geriatr. 20 (1995) 43-48
the cholesterol-fed rabbit. These drugs have been shown to influence several processes with a role in the development of atherosclerotic lesions, including inhibition of smooth muscle cell migration and proliferation. Recently, much effort has been made to evaluate the direct effect of these drugs on the arterial wall and their inhibitory effect on the progression of new lesions, in animals and in man (Loscalzo, 1990; Blankenhorn, 1991; Schmitz et al., 1991). In particular, several studies on the cholesterol-fed rabbit (Jackson et al., 1989; Sowers, 1990) demonstrate that calcium antagonists have a protective effect against vascular lesions because they can inhibit smooth muscle cell migration and proliferation, lipid uptake by macrophages and the production of collagen and elastin. Thus, these drugs normalize parameters involved in progression of atherosclerosis. The antiatherogenic effects of calcium antagonists necessitate further research. It has been demonstrated that the mechanism of action of calcium antagonists is linked to their capacity to inhibit calcium uptake at the cellular level. In fact, molecules that facilitate the entry of calcium in the cell are able to increase intracellular cholesterol and cellular proliferation. Thus, for these drugs new possibilities in the future are related to their effects on the formation and progression of the atherosclerotic plaque.
5. Fatty acids (n-3) Data obtained from epidemiological and clinical trials in humans and animals indicate that n-3 fatty acids may confer protection against the incidence and progression of cardiovascular diseases and reduce the frequency of recurrence of coronary stenosis. Despite intensive studies, the complete range of physiological, biochemical and molecular mechanisms underlying the activity of these fatty acids is not completely understood. Besides the effect that n-3 fatty acids exert on lipid metabolism (Harris, 1989), they are known to possess beneficial antiaggregatory and vasodilatory properties (Dyerberg and Bang, 1979; Fox and Di Corletto, 1988; Endres et al., 1989). Furthermore, n-3 fatty acids have been shown to have a positive effect on hemostatic and thromboembolic processes, by reducing blood viscosity, platelet aggregation and fibrinogen levels. The broad range of activities of n-3 fatty acids can be, at least in part, explained by the profound alterations that their intake determines in cell membrane composition (Von Schacky et al., 1985), thus justifying the ubiquity of their effects. At present, there is great interest in the mechanisms by which these fatty acids affect the behaviour of cells involved in thrombus formation, e.g. platelets, leukocytes and endothelial cells. In particular, their capacity to reduce the synthesis of vasoconstrictive and proinflammatory lipid mediators and cytokines, thus diminishing their potentially injurious actions, has been extensively investigated. In parallel, preliminary evidence indicates a reduced production of the atherogenic platelet-derived growth factor (PDGF), by monocytes of subjects receiving increased dietary n-3 fatty acids (Kaminsky et al., 1993). It is worth mentioning that PDGF is considered one of the most potent stimuli for proliferation of smooth muscle cells. Most recently, mechanisms and effects of dietary n-3 fatty acids were investigated
R. Paoletti et al./ Arch. Gerontol. Geriatr. 20 (1995) 43-48
47
in b a b o o n s . I n this study, following d i e t a r y n-3 fatty acid a d m i n i s t r a t i o n , vascular tissue was f o u n d to be less t h r o m b o g e n i c . M o r e o v e r , the f o r m a t i o n o f vascular lesions after c a r o t i d e n d a r t e r e c t o m y was c o m p l e t e l y inhibited ( H a r k e r et al., 1993). Also, for n-3 fatty acids which a p p e a r to exert p r o m i s i n g antiatherosclerotic a n d a n t i t h r o m b o t i c effects, further studies will define their exact m e c h a n i s m o f action a n d the d u r a t i o n o f their activity.
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