- Email: [email protected]
Introduction: New aspects of calcium antagonism in cardiovascular disease
American Founded
JULY
Introduction: antagonism Kevin O’Malley,
1991
Volume
Journal
122,
Number
1, Part
2
New aspects of calcium in cardiovascular disease
MD Dublin,
Ireland
During the past decade, calcium antagonists have become firmly established as an effective and welltolerated treatment for arterial hypertension and in the management of chronic stable angina. Although three classes of calcium antagonists exist, research has focused mainly on the dihydropyridines such as nicardipine, which have vascular selectivity, a property that is distinctly advantageous in the treatment of arterial hypertension. Calcium antagonists may also play a role in the prevention of sudden cardiac death, which has been linked with left ventricular hypertrophy. Recent research into the effects of dihydropyridine calcium antagonists in patients with essential hypertension and evidence of left ventricular hypertrophy has shown that, in addition, to lowering blood pressure, this class of drug reduces left ventricular mass. Moreover, this is accomplished without any adverse effects on left ventricular systolic function. In addition, the dihydropyridines have favorable effects on cardiac, renal, and cerebral functions, which combined with their rapid action, make this type of calcium antagonist promising in the treatment of hypertensive emergencies, in which prompt lowering of the blood pressure is required in some circumstances. Compared with other drugs of its class, the calcium antagonist nicardipine may offer the advantage of being able to protect and preserve tissue perfusion. Current interest is turning towards additional beneficial effects of calcium antagonists other than their antihypertensive activity. In particular, the effects of calcium antagonists on the structural changes that occur in the cardiac and vascular smooth muscle of patients with cardiovascular disease and their ability to stabilize platelets, rendering them less sus4/O/29136
Heart
in 1925
ceptible to activation, have been the subjects of much research and discussion. It has been known for some time that hypertension alters the structure of the peripheral vasculature: the arterial wails thicken and the lumen is reduced. Not all antihypertensive drugs are effective in inducing regression of these changes, but it is generally agreed that angiotensin-converting enzyme inhibitors, calcium antagonists, and p-blockers have some favorable effects. However, as Dr. Schachter points out in his article on drug-induced modification of vascular structure, this area of research still requires much work to identify the optimal therapy. Dr. Amenta from “La Sapienza” University in Rome, Italy, presents his results from investigations of the effect of nicardipine on vascular hypertrophy in rats. His studies indicate that nicardipine is able to prevent cardiac and vascular changes induced by hypertension in rats. In addition, he showed that nicardipine was more active at the level of the coronary and pulmonary branches, confirming results of other investigators who have demonstrated the drug’s selectivity for the coronary vascular beds. Platelet hyperactivation has been linked to stress and cardiovascular disease for some time. It is hypothesized that platelets from hypertensive persons are hyperactivated in response to increased concentrations of epinephrine, although the exact mechanism by which this effect is produced is as yet unknown. In migraine sufferers nicardipine has demonstrated an ability to stabilize platelets, making them less susceptible to activation. Calcium antagonists have also shown promise in the treatment of Raynaud phenomenon. A French multicenter trial of nicardipine in patients with primary Raynaud phenomenon showed that nicardipine significantly reduced the number of crises experienced by patients and reduced the level of disability.
307
O’Malley
American
However, further trials are necessary in this condition before any conclusive recommendations can be made. As research uncovers the full spectrum of activity of calcium antagonists, it is rapidly becoming apparent that this class of drug has an important place in cardiovascular therapy, not only in the treatment of hypertension and angina, but also for the long-term beneficial effects on the vasculature and other mechanisms involved in the development of cardiovascular disease.
Calcium
antagonists:
July 1991 Heart Journal
This supplement brings together papers presented during a one-day symposium held in Stockholm, Sweden, as part of the XIIth Congress of the European Society of Cardiology in September 1990. During the meeting the latest research and some of the more recently discovered aspects of calcium antagonists were discussed, focusing in particular on one of the newer members of this class, nicardipine.
An overview
Calcium antagonists reduce the influx of calcium ions through the calcium channels. This causes a reduction in myocardlal contractility or a fall in vascular resistance because of a lowering of vascular smooth muscle tone. Therefore, the net effect is a fall in blood pressure. The three major classes of calcium antagonists, the dihydropyridines, papaverine derivatives, and benzothiazepines, differ in molecular structure and their binding characteristics to the calcium channels. Furthermore, newer antagonists, particularly the dihydropyridines such as nlcardipine, have a high affinity for vascular tissue and are highly selective for vascular smooth muscle. These compounds atso have a favorable effect on hypertension mainly because of lowerlng of vascular resistance. In addition, they do not cause potentially negative metabolic effects on glucose or lipid levels and are generally well tolerated. Based on these findings, the Joint Natlonal Committee in the Unlted States and the World Health Organization/ International Society of Hypertension Committee on the Management of Mild Hypertension recommended the use of calcium antagonists as first-line treatment in hypertension. (AM HEART J lQ91;122:3OB-11.)
Lennart
Hansson, MD Gothenburg,
Sweden
Calcium ions are essential for the activation of contractile proteins in striated and smooth muscle cells,lm3 with the intracellular concentration of these ions determining the activity of the contractile apparatus.4l 5 Therefore, if influx of calcium ions from the extracellular to the intracellular space could be prevented or suppressed, this should result in reduced contractility. There are many ways by which the entry of calcium ions into cells through the so-called calcium channels can be reduced. Calcium antagonists are particularly interesting because their From the Department of Medicine, University of Gothenburg, &tra Hospital. Reprint requests: Lennart Hansson, MD, Department of Medicine, University of Gothenburg, Rostra Hospital, S-416 85 Gothenburg, Sweden. 4JQl29138
308
action provides a pharmacologic basis for the treatment of several cardiovascular disorders. There are three major classes of calcium antagonists, the dihydropyridines, the papaverine derivatives, and the benzothiazepines (Fig. 1). They differ not only in their molecular structure but also in their characteristics of binding to the calcium channels.6 In this context it should be mentioned that although there appear to be several different types of calcium channels in vascular muscle, as in other cells, only two types seem to be important under physiologic conditions7 The fact that different calcium antagonists have different affinities for myocardial cells compared with those for vascular smooth muscle cells is of great clinical importance. Studies have shown that the in vitro potency ratio for myocardial muscle affinity to
JULY
Introduction: antagonism Kevin O’Malley,
1991
Volume
Journal
122,
Number
1, Part
2
New aspects of calcium in cardiovascular disease
MD Dublin,
Ireland
During the past decade, calcium antagonists have become firmly established as an effective and welltolerated treatment for arterial hypertension and in the management of chronic stable angina. Although three classes of calcium antagonists exist, research has focused mainly on the dihydropyridines such as nicardipine, which have vascular selectivity, a property that is distinctly advantageous in the treatment of arterial hypertension. Calcium antagonists may also play a role in the prevention of sudden cardiac death, which has been linked with left ventricular hypertrophy. Recent research into the effects of dihydropyridine calcium antagonists in patients with essential hypertension and evidence of left ventricular hypertrophy has shown that, in addition, to lowering blood pressure, this class of drug reduces left ventricular mass. Moreover, this is accomplished without any adverse effects on left ventricular systolic function. In addition, the dihydropyridines have favorable effects on cardiac, renal, and cerebral functions, which combined with their rapid action, make this type of calcium antagonist promising in the treatment of hypertensive emergencies, in which prompt lowering of the blood pressure is required in some circumstances. Compared with other drugs of its class, the calcium antagonist nicardipine may offer the advantage of being able to protect and preserve tissue perfusion. Current interest is turning towards additional beneficial effects of calcium antagonists other than their antihypertensive activity. In particular, the effects of calcium antagonists on the structural changes that occur in the cardiac and vascular smooth muscle of patients with cardiovascular disease and their ability to stabilize platelets, rendering them less sus4/O/29136
Heart
in 1925
ceptible to activation, have been the subjects of much research and discussion. It has been known for some time that hypertension alters the structure of the peripheral vasculature: the arterial wails thicken and the lumen is reduced. Not all antihypertensive drugs are effective in inducing regression of these changes, but it is generally agreed that angiotensin-converting enzyme inhibitors, calcium antagonists, and p-blockers have some favorable effects. However, as Dr. Schachter points out in his article on drug-induced modification of vascular structure, this area of research still requires much work to identify the optimal therapy. Dr. Amenta from “La Sapienza” University in Rome, Italy, presents his results from investigations of the effect of nicardipine on vascular hypertrophy in rats. His studies indicate that nicardipine is able to prevent cardiac and vascular changes induced by hypertension in rats. In addition, he showed that nicardipine was more active at the level of the coronary and pulmonary branches, confirming results of other investigators who have demonstrated the drug’s selectivity for the coronary vascular beds. Platelet hyperactivation has been linked to stress and cardiovascular disease for some time. It is hypothesized that platelets from hypertensive persons are hyperactivated in response to increased concentrations of epinephrine, although the exact mechanism by which this effect is produced is as yet unknown. In migraine sufferers nicardipine has demonstrated an ability to stabilize platelets, making them less susceptible to activation. Calcium antagonists have also shown promise in the treatment of Raynaud phenomenon. A French multicenter trial of nicardipine in patients with primary Raynaud phenomenon showed that nicardipine significantly reduced the number of crises experienced by patients and reduced the level of disability.
307
O’Malley
American
However, further trials are necessary in this condition before any conclusive recommendations can be made. As research uncovers the full spectrum of activity of calcium antagonists, it is rapidly becoming apparent that this class of drug has an important place in cardiovascular therapy, not only in the treatment of hypertension and angina, but also for the long-term beneficial effects on the vasculature and other mechanisms involved in the development of cardiovascular disease.
Calcium
antagonists:
July 1991 Heart Journal
This supplement brings together papers presented during a one-day symposium held in Stockholm, Sweden, as part of the XIIth Congress of the European Society of Cardiology in September 1990. During the meeting the latest research and some of the more recently discovered aspects of calcium antagonists were discussed, focusing in particular on one of the newer members of this class, nicardipine.
An overview
Calcium antagonists reduce the influx of calcium ions through the calcium channels. This causes a reduction in myocardlal contractility or a fall in vascular resistance because of a lowering of vascular smooth muscle tone. Therefore, the net effect is a fall in blood pressure. The three major classes of calcium antagonists, the dihydropyridines, papaverine derivatives, and benzothiazepines, differ in molecular structure and their binding characteristics to the calcium channels. Furthermore, newer antagonists, particularly the dihydropyridines such as nlcardipine, have a high affinity for vascular tissue and are highly selective for vascular smooth muscle. These compounds atso have a favorable effect on hypertension mainly because of lowerlng of vascular resistance. In addition, they do not cause potentially negative metabolic effects on glucose or lipid levels and are generally well tolerated. Based on these findings, the Joint Natlonal Committee in the Unlted States and the World Health Organization/ International Society of Hypertension Committee on the Management of Mild Hypertension recommended the use of calcium antagonists as first-line treatment in hypertension. (AM HEART J lQ91;122:3OB-11.)
Lennart
Hansson, MD Gothenburg,
Sweden
Calcium ions are essential for the activation of contractile proteins in striated and smooth muscle cells,lm3 with the intracellular concentration of these ions determining the activity of the contractile apparatus.4l 5 Therefore, if influx of calcium ions from the extracellular to the intracellular space could be prevented or suppressed, this should result in reduced contractility. There are many ways by which the entry of calcium ions into cells through the so-called calcium channels can be reduced. Calcium antagonists are particularly interesting because their From the Department of Medicine, University of Gothenburg, &tra Hospital. Reprint requests: Lennart Hansson, MD, Department of Medicine, University of Gothenburg, Rostra Hospital, S-416 85 Gothenburg, Sweden. 4JQl29138
308
action provides a pharmacologic basis for the treatment of several cardiovascular disorders. There are three major classes of calcium antagonists, the dihydropyridines, the papaverine derivatives, and the benzothiazepines (Fig. 1). They differ not only in their molecular structure but also in their characteristics of binding to the calcium channels.6 In this context it should be mentioned that although there appear to be several different types of calcium channels in vascular muscle, as in other cells, only two types seem to be important under physiologic conditions7 The fact that different calcium antagonists have different affinities for myocardial cells compared with those for vascular smooth muscle cells is of great clinical importance. Studies have shown that the in vitro potency ratio for myocardial muscle affinity to