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Recent developments in the use of calcium antagonists in myocardial protection
Pharmacological
Research,
251
Vol. 31. No. 3/4,1995
RECENT DEVELOPMENTS IN THE USE OF CALCIUM MYOCARDIAL PROTECTION G. GAVIRAGHI,
D. MICHELI
ANTAGONISTS
IN
and D. G. TRIST
Glaxo Research Laboratories, Via Fleming 4,37135 Verona, Italy Accepted 23 December I994 For more than two decades calcium antagonists (CEBs) have been widely used for the treatment of myocardial ischaemia (angina pectoris). Amongst the classes of CEBs, the 1,4dihydropyridines (DHPs), like nifedipine, have been used for this indication because of their haemodynamic and electrophysiological properties. The ability of nifedipine to reduce afterload and to induce coronary vasodilation, as well as to increase collateral blood supply, has supported its extensive use in the treatment of angina pectoris. However, its short duration of action also provokes reflex tachycardia, which often limits its beneficial effect and may actually precipitate pain. The newer DHPs, such as amlodipine and lacidipine, are endowed with slow onset and long duration of vasodilatory activity; they are able to reduce coronary resistance with little or no effect on heart rate. The more lipophilic DHP, lacidipine, shows also a pronounced vascular protection, on both smooth muscle and endothelium, and is able to reduce the formation of atheroma plaque in animal models at therapeutic doses. This protective activity might be explained in terms of both the effective CEB activity of lacidipine together with antioxidant properties that this DHP has shown. KEY WORDS:dihydropyridines,
lacidipine, antioxidant, vascular protection.
INTRODUCTION The concentration of calcium ions in tissue cytoplasm is normally maintained at a low level (nanomolar range). Upon depolarisation this rapidly increases (micromolar range) which causes a number of physiological consequences, particularly for the cardiovascular system. In cardiac muscle there is an increase in impulse generation in the sinus and A-V nodes, together with contraction of the myocardium. In smooth muscle the intracellular calcium concentration maintains vascular tone in coronary arteries and peripheral resistance vessels. Calcium entry blockers (CEBs) are a heterogeneous group of compounds, of namely dihydropyridines basically three classes, (nifedipine), aryl alkylamines (verapamil) and benzothiazepines (diltiazem), which all bind to plasma membrane voltage-operated channels (VOCs) of the Ltype. The consequence of which is to reduce the transport of calcium through these channels causing smooth muscles to relax and both negative inotropic and chronotropic effects on the heart are observed [ 11.
Based on a lecture given at the Joint Meeting of the Italian and British Pharmacologiial Societies in Rome, September 1993. Correspondence to: Dr G. Gaviraghi, Glaxo Research Laboratories, Via Fleming 4.37 135 Verona, Italy. 1043-6618/95/030251-04/$08.00/0
It is now generally accepted that sudden and maintained blockage of the coronary artery is the event which triggers a cascade of biochemical consequences which ends with cellular necrosis of the myocardium. The formation of thrombi and atherosclerotic plaque rupture is a common cause of how blood supply is reduced. This eventually leads to an increase in cytoplasmic calcium which in turn activates lytic enzymes leading to cell death [2]. The imbalance between oxygen supply and demand to the heart can also be temporary. In this case the outcome is not related to necrosis, but to impairment of the contractile function leading to what has been described as ‘stunned myocardium’ [3]. Transient reversible ischaemia, followed by reperfusion, can result in an increase in oxygen radicals through a number of different mechanisms. These include increased activity of xanthine oxidase, activation of neutrophils, activation of arachidonic acid metabolism, derangement of mitochondrial electron transport and autooxidation of catecholamines. Liberation of free radicals can induce dysfunction of cellular organelles, which can lead to calcium overload and problems of myocardial contraction [4]. CEBs have been shown experimentally to be able to reduce ischaemia-induced damage by their ability to prevent calcium overload [5]. However, not all CEBs exhibit the same haemodynamic and electrophysiological properties. In particular, there are 01995
The Italian Pharmacological
Society
Pharmacological Research, Vol. 31, No. 3/4,1995
252
LACIDIPINE
Fig. 1.
AMLODIPINE
The structures of lacidipine and amlodipine,
marked differences between nifedipine, verapamil and diltiazem as anti-ischaemic agents [6]. This review focuses on the 1,4_dihydropyridines since a major clinical indication for nifedipine remains angina pectoris and the newer second generation DHPs offer some potential advantages over nifedipine.
DHPS AND CARDIOPROTECTION The overall effect of DHPs on the ischaemic myocardium is positive. There are three contributing mechanisms through which a DHP like nifedipine acts. First, nifedipine is a potent coronary vasodilator. This makes the compound especially effective when myocardial ischaemia is due to coronary vasospasm or vasoconstriction. This also applies when spasm is involved by organic stenosis or by exercise. Second, due to the reduction of afterload, following peripheral vasodilation, there is an energy sparing effect on the myocardium. The vascular selectivity of nifedipine means that there is no direct effect on the heart (e.g. no negative inotropism) [7]. The short duration of action of this DHP seems to cause a reflex tachycardia that increases to some extent oxygen consumption [S]. Thus, the beneficial action of nifedipine on energy sparing depends on the ratio of afterload reduction to positive chronotropism. Third, an increase in collateral blood flow can favour a better redistribution of oxygen supply to the ischaemic area. However, the where this redistribution actually ‘steel effect’, reduces the perfusion to the affected area, can worsen acute ischaemic episodes.
SECOND GENERATION DHPS The drawbacks shown by nifedipine seem to be, more or less, shared by those DHPs with quick onset of activity and short duration (e.g. nifedipine, nisoldipine, isradipine and felodipine). Recently, a second generation of DHPs have been described
two long-acting
1,4_dihydropyridines.
which exhibit a slower onset and long duration of action. They can be further classified into two groups: the neutral, highly lipophilic molecules, such as lacidipine (logP=5.4), and the ionizable ones, such as amlodipine (Fig. 1). Although, under depolarizing conditions, both compounds in vitro show similar kinetics, in vivo they probably achieve their long duration of action through different mechanisms. This is accomplished for amlodipine by virtue of a long plasma half-life of -37 h. Lacidipine achieves the same goal through a high partition into the membrane, probably concentrating itself in the proximate lipid adjacent to the VOC. Owing to its slow washout lacidipine remains continuously available to interact with the inactivated form of the VOC. This hypothesis is supported by a number of experimental observations, both in model membrane systems and in vascular tissue under different polarising conditions [9, lo]. In man, the slow onset of action of lacidipine, after a single oral administration in the treatment of hypertension, minimised the reflex tachycardia [ Ill. The high partition of lacidipine into the membrane may well contribute to the vascular and organ protective properties exhibited by this DHP in experimental models.
LACIDIPINE AND VASCULAR PROTECTION Vascular protection, including that of the coronary arteries, has been shown in isolated tissues and in animal models of experimental hypertension and of atheroma. In the salt-loaded Dahl-S rat lacidipine has been shown to protect those organs at risk (e.g. brain, heart and eyes) together with a clear vascular protection of the affected tissue arteries. These effects, together with prevention of mortality, were seen with doses (0.3-1.0 mg kg-‘, p.o.) that did not sustain a 24-h blood pressure reduction after a single administration [12]. These observations can be reproduced using other DHPs, but only with high doses that significantly reduce blood pressure [ 131.
Pharmacological
5 3 m ;
Research, Vol. 31, No. 314.1995
253
240 220 200 180 180 140 120 100 80 80 40 20 0 0
4
2
8
8
10
Time (min)
Fig. 2. The effect of lacidipine (10m8M, 0) and nifedipine (10m8M, 0) on the increase in coronary perfusion pressure (percentage variation) in isolated rabbit heart induced by endothelin-1 (lo-” M, 0). Endothelin was added at time 0 after pretreatment for 1 h with the DHP. The results are expressed as the mean+ss from six experiments.
all show some antioxidant activity and lacidipine seems to be one of the most potent [ 141. Oxidative challenge to cells and tissues (e.g. with H202) induces an increase in intracellular calcium. The application of DHPs can counteract this increase and thus stabilize the intracellular calcium concentration [ 151. Experimentally it is possible to induce a myocardial dysfunction in the isolated Langendorff rabbit heart by means of electrolysis of the perfusion buffer to generate free radicals. The passage of a 20mA current for 1 min produced a significant increase in diastolic pressure and in coronary perfusion pressure. In the first case, this is thought to be indicative of an impaired relaxation due to calcium overload, and in the second case, suggestive of coronary spasm. These effects are thought to be indicative of functional damage induced by reactive oxygen species in the buffer [ 161. Application of lacidipine (lo-’ M), as seen with a variety of radical scavengers and antioxidants, antagonised both the increases in diastolic pressure (Fig. 3) and coronary perfusion pressure.
LACIDIPINE
0
10
20
30
Time (min)
Fig. 3. The effect of lacidipine (lo-* M, 0) on electrolysisinduced myocardial dysfunction in the Langendorff-perfused rabbit heart (0) caused by passing a 20 mA current for 1 min through the perfusion buffer. Lacidipine was added 1 h prior to the electrolysis. The ordinate represents the increase in diastolic pressure (percentage variation). Each point represents the mean with SE from six different experiments.
Endothelin-1 is an extremely potent vasoconstrictor, which is probably released during ischaemic conditions. This release can precipitate further myocardial ischaemia by causing a potent coronary spasm. In the isolated Langendorff perfused rabbit heart nifedipine (lo-* M) was not able to modify an increase in coronary perfusion pressure due to endothelin-1. However, lacidipine, at the same concentration ( 10e8 M) was able to antagonise the effect of endothelin-1 (Fig. 2). The difference between the two DHPs in this and other models might be explicable in terms of the high partition of lacidipine into the membrane together with an antioxidant activity. DHPs
AND ATHEROSCLEROSIS
Coronary artery atherosclerosis is considered an important, if not essential, common background on which acute stimuli (e.g. thrombosis and vasospasm) act to precipitate an ischaemic episode. Atherosclerotic lesions are the result of complex and convergent biochemical pathways involving hypercholesterolaemia and oxidation of low density lipoproteins. CEBs have been reported to be effective in reducing lesions in rabbit models of experimental atherosclerosis 1171. However, with the exception of isradipine, all require doses that are higher than are achievable in therapy [18]. In vitro lacidipine is able to reduce cell proliferation induced by cholesterol at very low concentrations (-lo-‘* M) [ 191. This observation is supported in vivo in rabbits and hamsters, both fed on high cholesterol diets. Lacidipine, at a dose that can be considered from the achieved plasma level to be equivalent to that used therapeutically (e.g. 3 mg kg-‘), reduced carotid intimal hyperplasia in rabbits [20] and protected from damage both the endothelium and smooth muscle of the aorta in hamsters [21].
CONCLUSIONS DHPs potentially should be of benefit in myocardial ischaemia because of their haemodynamic and electrophysiological properties. In particular, the newer second generation compounds (such as lacidipine) have advantages of decreasing after load with no rebound increase in heart rate, which could be
Pharmacological Research, Vol. 31, No. 3/4,1995
254
of benefit
in angina
pectoris
(effort
angina,
variant
angina). In addition, lacidipine has been shown to be protective in animal models associated with hypertension and atherosclerosis. Importantly, the effect does not appear to be simply explicable in terms of blood pressure reduction, but might be due to other
properties like antioxidant activity realisable because of its high partition into the plasma membrane. This is suggestive that at therapeutic doses coronary artery disease might be reduced. The usefulness of DHPs in acute myocardial infarction, as well as in the secondary prevention of infarction, is difficult to assess in that it is now seen as essential that other properties such as negative inotropic and antiarrhythmic actions are present. DHPs, including the newer ones, do not possess such
properties, however, a combination of P-blocker and DHP could be the rational choice of treatment for these indications.
antagonists
in myocardial
ischemia.
Am J Cardiol
1987; 59: 75B-83B. 9. Herbette LG, Gaviraghi
G, Tulenko TN, Mason RP. Molecular interaction between lacidipine and biological membranes. J Hypertens 1993; ll(Supp1. 1): S13-19. 10. Giacometti A, Micheli D, Gaviraghi G, Trist DG. Quantification of the calcium antagonism of lacidipine by kinetic analysis. J Pharmacol Exptl Ther 1994; 269: 424-9.
11. Heber ME, Broadhurst PA, Bridgen GS, Raftery EB. Effectiveness of the once-daily calcium antagonist, lacidipine, in controlling 24-hour ambulatory blood pressure. Am J Cardiol 1990; 66: 1228-32. 12. Cristofori P, Terron A, Micheli D, Berolini G, Gaviraghi G, Carpi C. Vascular protection of lacidipine in salt-loaded Dahl-S rats at nonsustained antihypertensive doses. J Cardiovasc Pharmacol 1991; 7(Snppl. 4): S75-86. 13. Fleckenstein A, Fleckenstein-Grtin G, Frey M, Zom J. Future directions in the use of calcium antagonists. Am JCardiol1987; 57: 177B-187B. 14. van Amsterdam FTh, Roveri A, Maiorino M, Ratti E, Ursini F. Lacidipine: a dihydropyridine calcium antagonist with antioxidant activity. Free Rad Biol Med 1992; 12: 183-7.
15. Roveri A, Coassin M, Maiorino M, Zamburlini A, van Amsterdam FTh, Ratti E, Ursini F. Effect of hydrogen peroxide in smooth muscle cells. Arch Biochem Biophys 1992; 297: 265-70.
REFERENCES 1. Triggle DJ. Calcium channel drugs: antagonists and activators. ISI Atlas Pharmacol 1987; 1: 319-24. 2. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9. 3. Pate1 B, Kloner RA, Przyklenk K, Braunwald E. Postischemic myocardial “stunning”: A clinically relevant phenomenon. Ann Intern Med 1988; 108: 626-8. 4. Maza SR, Frishman WH. Therapeutic options to minimize free radical damage and thrombogenicity in ischemic/reperfused myocardium. Curric Cardiol 1987; 114: 1206-15. 5. Watts JA, Koch CD, LaNoue
KF. Effects of Ca” antagonism on energy metabolism: Ca” and heart function after ischemia. Am J Physiol 1980; 238: H909-16. 6. Pearle DL. Calcium antagonists in acute myocardial infarction. Am J Cardiol 1988; 61: 22B-25B. channel antagonists, part I: 7. Opie LH. Calcium fundamental properties: mechanisms, classification, site of action. Cardiovasc Drugs Ther 1987; 1: 41 l-30. 8. Nayler WG, Panagiopoulos S, Elz JS, Sturrock WJ. Fundamental mechanisms of action of calcium
16. Jackson CV, Mickelson JK, Stringer K, Rao PS, myocardial Lucchesi BR. Electrolysis-induced dysfunction. J Pharmacol Meth 1986; 15: 305-20. 17. Henry PD, Bentley KI. Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine. J Clin Invest 1981; 68: 1366-9. 18. Paoletti R, Bemini F. A new generation of calcium antagonists and their role in atherosclerosis. Am J Cardiol 1990; 66: 28H-3 1H. 19. Herbette LG, Mason PE, Gaviraghi G, Tulenko TN, Mason RP. The molecular basis for lacidipine’s unique pharmacokinetics: optimal hydrophobicity results in membrane interactions that may facilitate the treatment of atherosclerosis. J Cardiovasc Pharmacol 1994; 23(Suppl. 5): S16-25.
20. Soma MR, Parolini C, Donetti E, Galli C, Paoletti R, Fumagalli R. Lacidipine: in vivo effects on intimal carotid thickening in hypercholesterolaemic rabbits. Br J Pharmacol 1994; lll(Supp1.): 21P. 21. Cristofori P, Micheli D, Lanzoni A, Spagnolo D, Tarter G, Pastorino AM, Sbarbati A, Accordini C, Osculati F, Ratti E, Gaviraghi G. Antiatherosclerotic activity of lacidipine in cholesterol-fed hamsters. Br J Pharmacol 1994; lll(supp1.): 270P.
Research,
251
Vol. 31. No. 3/4,1995
RECENT DEVELOPMENTS IN THE USE OF CALCIUM MYOCARDIAL PROTECTION G. GAVIRAGHI,
D. MICHELI
ANTAGONISTS
IN
and D. G. TRIST
Glaxo Research Laboratories, Via Fleming 4,37135 Verona, Italy Accepted 23 December I994 For more than two decades calcium antagonists (CEBs) have been widely used for the treatment of myocardial ischaemia (angina pectoris). Amongst the classes of CEBs, the 1,4dihydropyridines (DHPs), like nifedipine, have been used for this indication because of their haemodynamic and electrophysiological properties. The ability of nifedipine to reduce afterload and to induce coronary vasodilation, as well as to increase collateral blood supply, has supported its extensive use in the treatment of angina pectoris. However, its short duration of action also provokes reflex tachycardia, which often limits its beneficial effect and may actually precipitate pain. The newer DHPs, such as amlodipine and lacidipine, are endowed with slow onset and long duration of vasodilatory activity; they are able to reduce coronary resistance with little or no effect on heart rate. The more lipophilic DHP, lacidipine, shows also a pronounced vascular protection, on both smooth muscle and endothelium, and is able to reduce the formation of atheroma plaque in animal models at therapeutic doses. This protective activity might be explained in terms of both the effective CEB activity of lacidipine together with antioxidant properties that this DHP has shown. KEY WORDS:dihydropyridines,
lacidipine, antioxidant, vascular protection.
INTRODUCTION The concentration of calcium ions in tissue cytoplasm is normally maintained at a low level (nanomolar range). Upon depolarisation this rapidly increases (micromolar range) which causes a number of physiological consequences, particularly for the cardiovascular system. In cardiac muscle there is an increase in impulse generation in the sinus and A-V nodes, together with contraction of the myocardium. In smooth muscle the intracellular calcium concentration maintains vascular tone in coronary arteries and peripheral resistance vessels. Calcium entry blockers (CEBs) are a heterogeneous group of compounds, of namely dihydropyridines basically three classes, (nifedipine), aryl alkylamines (verapamil) and benzothiazepines (diltiazem), which all bind to plasma membrane voltage-operated channels (VOCs) of the Ltype. The consequence of which is to reduce the transport of calcium through these channels causing smooth muscles to relax and both negative inotropic and chronotropic effects on the heart are observed [ 11.
Based on a lecture given at the Joint Meeting of the Italian and British Pharmacologiial Societies in Rome, September 1993. Correspondence to: Dr G. Gaviraghi, Glaxo Research Laboratories, Via Fleming 4.37 135 Verona, Italy. 1043-6618/95/030251-04/$08.00/0
It is now generally accepted that sudden and maintained blockage of the coronary artery is the event which triggers a cascade of biochemical consequences which ends with cellular necrosis of the myocardium. The formation of thrombi and atherosclerotic plaque rupture is a common cause of how blood supply is reduced. This eventually leads to an increase in cytoplasmic calcium which in turn activates lytic enzymes leading to cell death [2]. The imbalance between oxygen supply and demand to the heart can also be temporary. In this case the outcome is not related to necrosis, but to impairment of the contractile function leading to what has been described as ‘stunned myocardium’ [3]. Transient reversible ischaemia, followed by reperfusion, can result in an increase in oxygen radicals through a number of different mechanisms. These include increased activity of xanthine oxidase, activation of neutrophils, activation of arachidonic acid metabolism, derangement of mitochondrial electron transport and autooxidation of catecholamines. Liberation of free radicals can induce dysfunction of cellular organelles, which can lead to calcium overload and problems of myocardial contraction [4]. CEBs have been shown experimentally to be able to reduce ischaemia-induced damage by their ability to prevent calcium overload [5]. However, not all CEBs exhibit the same haemodynamic and electrophysiological properties. In particular, there are 01995
The Italian Pharmacological
Society
Pharmacological Research, Vol. 31, No. 3/4,1995
252
LACIDIPINE
Fig. 1.
AMLODIPINE
The structures of lacidipine and amlodipine,
marked differences between nifedipine, verapamil and diltiazem as anti-ischaemic agents [6]. This review focuses on the 1,4_dihydropyridines since a major clinical indication for nifedipine remains angina pectoris and the newer second generation DHPs offer some potential advantages over nifedipine.
DHPS AND CARDIOPROTECTION The overall effect of DHPs on the ischaemic myocardium is positive. There are three contributing mechanisms through which a DHP like nifedipine acts. First, nifedipine is a potent coronary vasodilator. This makes the compound especially effective when myocardial ischaemia is due to coronary vasospasm or vasoconstriction. This also applies when spasm is involved by organic stenosis or by exercise. Second, due to the reduction of afterload, following peripheral vasodilation, there is an energy sparing effect on the myocardium. The vascular selectivity of nifedipine means that there is no direct effect on the heart (e.g. no negative inotropism) [7]. The short duration of action of this DHP seems to cause a reflex tachycardia that increases to some extent oxygen consumption [S]. Thus, the beneficial action of nifedipine on energy sparing depends on the ratio of afterload reduction to positive chronotropism. Third, an increase in collateral blood flow can favour a better redistribution of oxygen supply to the ischaemic area. However, the where this redistribution actually ‘steel effect’, reduces the perfusion to the affected area, can worsen acute ischaemic episodes.
SECOND GENERATION DHPS The drawbacks shown by nifedipine seem to be, more or less, shared by those DHPs with quick onset of activity and short duration (e.g. nifedipine, nisoldipine, isradipine and felodipine). Recently, a second generation of DHPs have been described
two long-acting
1,4_dihydropyridines.
which exhibit a slower onset and long duration of action. They can be further classified into two groups: the neutral, highly lipophilic molecules, such as lacidipine (logP=5.4), and the ionizable ones, such as amlodipine (Fig. 1). Although, under depolarizing conditions, both compounds in vitro show similar kinetics, in vivo they probably achieve their long duration of action through different mechanisms. This is accomplished for amlodipine by virtue of a long plasma half-life of -37 h. Lacidipine achieves the same goal through a high partition into the membrane, probably concentrating itself in the proximate lipid adjacent to the VOC. Owing to its slow washout lacidipine remains continuously available to interact with the inactivated form of the VOC. This hypothesis is supported by a number of experimental observations, both in model membrane systems and in vascular tissue under different polarising conditions [9, lo]. In man, the slow onset of action of lacidipine, after a single oral administration in the treatment of hypertension, minimised the reflex tachycardia [ Ill. The high partition of lacidipine into the membrane may well contribute to the vascular and organ protective properties exhibited by this DHP in experimental models.
LACIDIPINE AND VASCULAR PROTECTION Vascular protection, including that of the coronary arteries, has been shown in isolated tissues and in animal models of experimental hypertension and of atheroma. In the salt-loaded Dahl-S rat lacidipine has been shown to protect those organs at risk (e.g. brain, heart and eyes) together with a clear vascular protection of the affected tissue arteries. These effects, together with prevention of mortality, were seen with doses (0.3-1.0 mg kg-‘, p.o.) that did not sustain a 24-h blood pressure reduction after a single administration [12]. These observations can be reproduced using other DHPs, but only with high doses that significantly reduce blood pressure [ 131.
Pharmacological
5 3 m ;
Research, Vol. 31, No. 314.1995
253
240 220 200 180 180 140 120 100 80 80 40 20 0 0
4
2
8
8
10
Time (min)
Fig. 2. The effect of lacidipine (10m8M, 0) and nifedipine (10m8M, 0) on the increase in coronary perfusion pressure (percentage variation) in isolated rabbit heart induced by endothelin-1 (lo-” M, 0). Endothelin was added at time 0 after pretreatment for 1 h with the DHP. The results are expressed as the mean+ss from six experiments.
all show some antioxidant activity and lacidipine seems to be one of the most potent [ 141. Oxidative challenge to cells and tissues (e.g. with H202) induces an increase in intracellular calcium. The application of DHPs can counteract this increase and thus stabilize the intracellular calcium concentration [ 151. Experimentally it is possible to induce a myocardial dysfunction in the isolated Langendorff rabbit heart by means of electrolysis of the perfusion buffer to generate free radicals. The passage of a 20mA current for 1 min produced a significant increase in diastolic pressure and in coronary perfusion pressure. In the first case, this is thought to be indicative of an impaired relaxation due to calcium overload, and in the second case, suggestive of coronary spasm. These effects are thought to be indicative of functional damage induced by reactive oxygen species in the buffer [ 161. Application of lacidipine (lo-’ M), as seen with a variety of radical scavengers and antioxidants, antagonised both the increases in diastolic pressure (Fig. 3) and coronary perfusion pressure.
LACIDIPINE
0
10
20
30
Time (min)
Fig. 3. The effect of lacidipine (lo-* M, 0) on electrolysisinduced myocardial dysfunction in the Langendorff-perfused rabbit heart (0) caused by passing a 20 mA current for 1 min through the perfusion buffer. Lacidipine was added 1 h prior to the electrolysis. The ordinate represents the increase in diastolic pressure (percentage variation). Each point represents the mean with SE from six different experiments.
Endothelin-1 is an extremely potent vasoconstrictor, which is probably released during ischaemic conditions. This release can precipitate further myocardial ischaemia by causing a potent coronary spasm. In the isolated Langendorff perfused rabbit heart nifedipine (lo-* M) was not able to modify an increase in coronary perfusion pressure due to endothelin-1. However, lacidipine, at the same concentration ( 10e8 M) was able to antagonise the effect of endothelin-1 (Fig. 2). The difference between the two DHPs in this and other models might be explicable in terms of the high partition of lacidipine into the membrane together with an antioxidant activity. DHPs
AND ATHEROSCLEROSIS
Coronary artery atherosclerosis is considered an important, if not essential, common background on which acute stimuli (e.g. thrombosis and vasospasm) act to precipitate an ischaemic episode. Atherosclerotic lesions are the result of complex and convergent biochemical pathways involving hypercholesterolaemia and oxidation of low density lipoproteins. CEBs have been reported to be effective in reducing lesions in rabbit models of experimental atherosclerosis 1171. However, with the exception of isradipine, all require doses that are higher than are achievable in therapy [18]. In vitro lacidipine is able to reduce cell proliferation induced by cholesterol at very low concentrations (-lo-‘* M) [ 191. This observation is supported in vivo in rabbits and hamsters, both fed on high cholesterol diets. Lacidipine, at a dose that can be considered from the achieved plasma level to be equivalent to that used therapeutically (e.g. 3 mg kg-‘), reduced carotid intimal hyperplasia in rabbits [20] and protected from damage both the endothelium and smooth muscle of the aorta in hamsters [21].
CONCLUSIONS DHPs potentially should be of benefit in myocardial ischaemia because of their haemodynamic and electrophysiological properties. In particular, the newer second generation compounds (such as lacidipine) have advantages of decreasing after load with no rebound increase in heart rate, which could be
Pharmacological Research, Vol. 31, No. 3/4,1995
254
of benefit
in angina
pectoris
(effort
angina,
variant
angina). In addition, lacidipine has been shown to be protective in animal models associated with hypertension and atherosclerosis. Importantly, the effect does not appear to be simply explicable in terms of blood pressure reduction, but might be due to other
properties like antioxidant activity realisable because of its high partition into the plasma membrane. This is suggestive that at therapeutic doses coronary artery disease might be reduced. The usefulness of DHPs in acute myocardial infarction, as well as in the secondary prevention of infarction, is difficult to assess in that it is now seen as essential that other properties such as negative inotropic and antiarrhythmic actions are present. DHPs, including the newer ones, do not possess such
properties, however, a combination of P-blocker and DHP could be the rational choice of treatment for these indications.
antagonists
in myocardial
ischemia.
Am J Cardiol
1987; 59: 75B-83B. 9. Herbette LG, Gaviraghi
G, Tulenko TN, Mason RP. Molecular interaction between lacidipine and biological membranes. J Hypertens 1993; ll(Supp1. 1): S13-19. 10. Giacometti A, Micheli D, Gaviraghi G, Trist DG. Quantification of the calcium antagonism of lacidipine by kinetic analysis. J Pharmacol Exptl Ther 1994; 269: 424-9.
11. Heber ME, Broadhurst PA, Bridgen GS, Raftery EB. Effectiveness of the once-daily calcium antagonist, lacidipine, in controlling 24-hour ambulatory blood pressure. Am J Cardiol 1990; 66: 1228-32. 12. Cristofori P, Terron A, Micheli D, Berolini G, Gaviraghi G, Carpi C. Vascular protection of lacidipine in salt-loaded Dahl-S rats at nonsustained antihypertensive doses. J Cardiovasc Pharmacol 1991; 7(Snppl. 4): S75-86. 13. Fleckenstein A, Fleckenstein-Grtin G, Frey M, Zom J. Future directions in the use of calcium antagonists. Am JCardiol1987; 57: 177B-187B. 14. van Amsterdam FTh, Roveri A, Maiorino M, Ratti E, Ursini F. Lacidipine: a dihydropyridine calcium antagonist with antioxidant activity. Free Rad Biol Med 1992; 12: 183-7.
15. Roveri A, Coassin M, Maiorino M, Zamburlini A, van Amsterdam FTh, Ratti E, Ursini F. Effect of hydrogen peroxide in smooth muscle cells. Arch Biochem Biophys 1992; 297: 265-70.
REFERENCES 1. Triggle DJ. Calcium channel drugs: antagonists and activators. ISI Atlas Pharmacol 1987; 1: 319-24. 2. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9. 3. Pate1 B, Kloner RA, Przyklenk K, Braunwald E. Postischemic myocardial “stunning”: A clinically relevant phenomenon. Ann Intern Med 1988; 108: 626-8. 4. Maza SR, Frishman WH. Therapeutic options to minimize free radical damage and thrombogenicity in ischemic/reperfused myocardium. Curric Cardiol 1987; 114: 1206-15. 5. Watts JA, Koch CD, LaNoue
KF. Effects of Ca” antagonism on energy metabolism: Ca” and heart function after ischemia. Am J Physiol 1980; 238: H909-16. 6. Pearle DL. Calcium antagonists in acute myocardial infarction. Am J Cardiol 1988; 61: 22B-25B. channel antagonists, part I: 7. Opie LH. Calcium fundamental properties: mechanisms, classification, site of action. Cardiovasc Drugs Ther 1987; 1: 41 l-30. 8. Nayler WG, Panagiopoulos S, Elz JS, Sturrock WJ. Fundamental mechanisms of action of calcium
16. Jackson CV, Mickelson JK, Stringer K, Rao PS, myocardial Lucchesi BR. Electrolysis-induced dysfunction. J Pharmacol Meth 1986; 15: 305-20. 17. Henry PD, Bentley KI. Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine. J Clin Invest 1981; 68: 1366-9. 18. Paoletti R, Bemini F. A new generation of calcium antagonists and their role in atherosclerosis. Am J Cardiol 1990; 66: 28H-3 1H. 19. Herbette LG, Mason PE, Gaviraghi G, Tulenko TN, Mason RP. The molecular basis for lacidipine’s unique pharmacokinetics: optimal hydrophobicity results in membrane interactions that may facilitate the treatment of atherosclerosis. J Cardiovasc Pharmacol 1994; 23(Suppl. 5): S16-25.
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