Calcium Antagonists as Cardioprotective Edward D. Frohlich,
The potential role that caklum antagonists play toward enhancing cardioprotection is d&cussed, while recognizing that they are much more heterogeneous than other classes of antihypertensive or antianginal agents. Similaritii and differences between the mechanisms of action and clinical effects of individual drugs are discussed. ~theseistheaMl~ofsomeofthemtoreduce left ventricular hypertrophy rapidly while simuttaneousiy and uniquely increasing right ventricular wall thickness. Although the clInical importance of this as a potential cardioprotective effect is undetermined, the renal protectfve effect of some calcium antagonists is discussed in detail. (Am J Cardiil1992;70:7 I-9 I)
From the Alton Ochsner Medical Foundation, New Orleans, Louisiana. Address for reprints: Edward D. Frohlich, MD, Alton Ochsner Medical Foundation, 1516 Jefferson Highway, New Orleans, Louisiana 70121.
Agents
MD
T
he pharmacologic effects of the calcium antagonists were first characterized by Fleckenstein’ in 1958. In describing the effects of verapamil, Fleckenstein noted reduction of arterial pressure, a negative myocardial inotropic effect, and a slowing of heart rate. These properties suggested that the compound was a P-adrenergic receptor blocker until further studies elucidated a new class of agents, the calcium antag0nists.l The calcium antagonists were initially introduced in the United States for the treatment of angina pectoris and supraventricular tachycardia. Later, they were approved for the treatment of hypertension-another resemblance to the l3blockers. Although these agents are effective in the treatment of coronary artery disease and hypertension, other cardioprotective effects of these agents, through their antiatherosclerotic actions, have been reported in experimental animal models. The calcium antagonists, a growing class of compounds, are extremely heterogeneous. Members of this class that are now available or under clinical investigation in the United States are listed in Table I. These agents are far more heterogeneous than the other classes of antihypertensive agents; this is related to their structural and chemical properties as well as to their pharmacologic and physiologic characteristics. The first 3 compounds in this class that were introduced, verapamil, diltiazem, and nifedipine, have been most extensively investigated with respect to their antihypertensive and antianginal properties. However, not every calcium antagonist reduces arterial pressure; nimodipine, for example, is used for patients with cerebral bleeding and does not reduce pressure. The calcium antagonists act by inhibiting the entrance of calcium ions (Ca’+) into cells and reducing intracellular Ca2+ availability. At least 4 types of calcium channel receptors are known to exist at the cell membrane; calcium antagonism is thought to be achieved principally through the inhibition of the L (slow, or long acting) channel and through inhibition of release of Ca2+ from intracellular stores in the sarcoplasmic reticulum, mitochondria, and from binding to proteins (including calmodulin). 1,2Each of these mechanisms proA SYMPOSIUM:
CARDIOPROTECTION
7I
hemodynamic changes originally reported in humans.6 Thus, the diminished efferent arteriolar resistance allows glomerular hydrostatic pressure Amlodipine Nicardipine to diminish. By reducing glomerular hydrostatic Clentiazem Nifedipine Diltiazem Nisoldipine pressure, diltiazem may be able to protect the Felodipine Nimodipine kidney from the glomerular hyperfiltration and Gallopamil Nltrendipine glomerulosclerosis that complicates essential hyperlsradipine Verapamil tension.7 More recently, we have augmented these clinical hemodynamic findings by demonstrating their vides the means of calcium antagonism and thereby a reduced state of contractility of the cardiac or effects on the heart.8 We found that, although the vascular myocyte. Further, the calcium antagonists calcium antagonists rapidly diminish left ventricumay operate through inhibition of > 1 calcium lar (LV) mass in rat and humans,4-6 they simultachannel or other receptor or through the Ca*+ neously increase right ventricular wall thickness.8 release mechanism. Nifedipine, for example, also In this recent echocardiographic study comparing 6 calcium antagonists and 3 angiotensin-converting operates at the a-adrenergic receptor in addition enzyme (ACE) inhibitors, all 9 agents reduced LV to its action at its calcium channel receptor. mass, posterior wall thickness, and septal wall The different effects and related mechanisms of thickness; but only the calcium antagonists (all 6) the various calcium antagonists are responsible for increased right ventricular wall thickness. These considerable variability in their clinical actions. Thus, understanding the differences in their dilat- findings strongly suggest that both classes of antihying effects in various blood vessels and the heart is pertensive drugs have similar systemic hemodycritical to understanding the multiplicity of their namic effects, but they act through different nonhemodynamic mechanisms on the mass of the 2 cardiovascular and renal protective effects. ventricles. The first report concerning the hemodynamic The mechanism for the independent risk of effects of the calcium antagonist nifedipine in hypertensive patients was by Olivari et a1.3They increased cardiovascular morbidity and mortality reported that after 3 weeks of treatment, mean that is associated with LV hypertrophy is not yet arterial pressure was reduced through a decrease known.9 In all likelihood, hemodynamic and also in total peripheral resistance. Similar systemic nonhemodynamic factors contribute in the development and reversal of hypertrophy. All antihypertenhemodynamic effects have been reported for diltiazem,4 verapamil,5 and other calcium antagonists. sive agents will reduce cardiac mass if they are used Following their intravenous administration, all 3 long enough, but only certain classes of these drugs agents are associated with a reflexive increase in rapidly reduce LV mass with short-term therapy.lO heart rate, cardiac output, and myocardial contrac- This most likely reflects their nonhemodynamic tility accompanied by increased circulating levels of actions. It is not known yet why these antihypernorepinephrine. 4,5 Variable systemic effects on tensive drugs have differing effects on cardiac heart rate and cardiac output may be seen with mass. The calcium antagonists reduce arterial presmore prolonged therapy. Reduction in arterial pressure has not been related to expanded intravas- sure by decreasing arteriolar smooth muscle tone. This is achieved by decreasing the availability of cular (plasma) volume or alterations in the reninintracellular calcium ions for muscle contraction. angiotensin-aldosterone system.3-s Despite this seeming similarity in the systemic The persistent decrease in arterial pressure is hemodynamic effects of these agents, their renal achieved by a reduction in total peripheral vascular hemodynamic effects are more variable. Although resistance, which is shared by all the major vascular all 3 agents (nifedipine, diltiazem, and verapamil) territories. Only certain calcium antagonists inmaintain glomerular filtration rate and reduce crease renal blood flow and this is not accomparenal vascular resistance,s5 only diltiazem de- nied by increased glomerular hydrostatic pressure creases the renal filtration fraction.4,6 This is and filtration rate, a genuine renal protective achieved through efferent as well as afferent glomer- effect. Although calcium antagonists reduce LV ular arteriolar dilation, thereby reducing intraglomass, they do so through mechanisms that seem to merular hydrostatic pressure.6 Using micropunc- be distinct from other antihypertensive drugs. ture techniques in the spontaneously hypertensive Studies concerned with the LV mass-reducing rat, we have confirmed the calculated intrarenal effects of calcium antagonists are ongoing but no TABLE I List of Calcium Antagonists in Clinical Study and Practice in the United States
8 I
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
DECEMBER
21, 1992
study has yet demonstrated reversal of the risk associated with LV hypertrophy. Current experience suggests that certain subsets of patients with essential hypertension can derive particular benefit from calcium antagonist therapy. Black or older hypertensive patients, and those with volumedependent hypertension and lowered plasma renin activity in particular, may benefit from the calcium antagonists. Other patients who may benefit from treatment with these agents include patients with angina pectoris who are not fully responsive to B blocker therapy and patients with bilateral renal arterial disease (or unilateral disease with a solitary kidney) in whom the ACE inhibitors are contraindicated. Finally, the calcium antagonists may also be the appropriate therapy for those patients who have experienced metabolic alterations with other classes of antihypertensive therapy. Clearly, additional studies are necessary to demonstrate their additional cardiovascular and renal protective effects.
REFERENCES l. Fleckenstein A. Calcium Antagonism in Heart and Smooth Muscle. New York: John Wiley & Sons,1983. 2. Slish DF, Schultz D, Schwartz A. Molecular biology of the calcium antagonist receptor. Hyprtm-tin 1992;19:1%24. 3. Olivari MT, Bartonelli C, Polese A, Fiorentini C, Morazzi P, Guazzi MD. Treatment of hypertensionwith nifedipine, a calcium antagonisticagent. Circulation 1980;59:10561062. 4. Amodeo C, Kobrin I, Venture HO, Messerli FH, Frohlich ED. Immediate and short-term hemodynamiceffects of diltiazem in patients with hypertension. Circularton 1986;73:106113. 5. Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Cardiovascular effects of verapamil in patients with essentialhypertension.Circulation 198257: 1030-1036. 6. Isshigi T, Amodeo C, Messedi FH, Pegram BL, FrohIich ED. Diltiazem maintains renal vasodilation without hyperfiltration in hypertension. Studies in essential hypertensiveman and the spontaneouslyhypertensive rat. Cardiovasc Drugs Ther 1987;1:345-348. 7. FrohIich ED. Correction of physiological alterations of hypertension.Cardiovast Dnrgs Ther 1987;1:35!&366. 8. Aristizabal D, Frohlich ED, McLoughlm M, Messexli FH. Disparate stmctural effects of left and right ventricles by angiotensin converting enzyme inhibitors (ACE) and calcium antagonists (Ca ANT) (abstr). Hyptemion 1991;18(3):26. 9. Frohlich ED. Left ventricular hypertrophy: An independent factor of risk. In: Frohlich ED, ed. Preventive Aspects of Coronary Heart Disease. Philadelphia: FA Davis, 1990~85-94. 10. Froblich ED. The heart in hypertension: A 1991 ovewiew. Hlpaension 1991;18(3):62-68.
A SYMPOSIUM:
CARDIOPROTECTION
9 I
The potential role that caklum antagonists play toward enhancing cardioprotection is d&cussed, while recognizing that they are much more heterogeneous than other classes of antihypertensive or antianginal agents. Similaritii and differences between the mechanisms of action and clinical effects of individual drugs are discussed. ~theseistheaMl~ofsomeofthemtoreduce left ventricular hypertrophy rapidly while simuttaneousiy and uniquely increasing right ventricular wall thickness. Although the clInical importance of this as a potential cardioprotective effect is undetermined, the renal protectfve effect of some calcium antagonists is discussed in detail. (Am J Cardiil1992;70:7 I-9 I)
From the Alton Ochsner Medical Foundation, New Orleans, Louisiana. Address for reprints: Edward D. Frohlich, MD, Alton Ochsner Medical Foundation, 1516 Jefferson Highway, New Orleans, Louisiana 70121.
Agents
MD
T
he pharmacologic effects of the calcium antagonists were first characterized by Fleckenstein’ in 1958. In describing the effects of verapamil, Fleckenstein noted reduction of arterial pressure, a negative myocardial inotropic effect, and a slowing of heart rate. These properties suggested that the compound was a P-adrenergic receptor blocker until further studies elucidated a new class of agents, the calcium antag0nists.l The calcium antagonists were initially introduced in the United States for the treatment of angina pectoris and supraventricular tachycardia. Later, they were approved for the treatment of hypertension-another resemblance to the l3blockers. Although these agents are effective in the treatment of coronary artery disease and hypertension, other cardioprotective effects of these agents, through their antiatherosclerotic actions, have been reported in experimental animal models. The calcium antagonists, a growing class of compounds, are extremely heterogeneous. Members of this class that are now available or under clinical investigation in the United States are listed in Table I. These agents are far more heterogeneous than the other classes of antihypertensive agents; this is related to their structural and chemical properties as well as to their pharmacologic and physiologic characteristics. The first 3 compounds in this class that were introduced, verapamil, diltiazem, and nifedipine, have been most extensively investigated with respect to their antihypertensive and antianginal properties. However, not every calcium antagonist reduces arterial pressure; nimodipine, for example, is used for patients with cerebral bleeding and does not reduce pressure. The calcium antagonists act by inhibiting the entrance of calcium ions (Ca’+) into cells and reducing intracellular Ca2+ availability. At least 4 types of calcium channel receptors are known to exist at the cell membrane; calcium antagonism is thought to be achieved principally through the inhibition of the L (slow, or long acting) channel and through inhibition of release of Ca2+ from intracellular stores in the sarcoplasmic reticulum, mitochondria, and from binding to proteins (including calmodulin). 1,2Each of these mechanisms proA SYMPOSIUM:
CARDIOPROTECTION
7I
hemodynamic changes originally reported in humans.6 Thus, the diminished efferent arteriolar resistance allows glomerular hydrostatic pressure Amlodipine Nicardipine to diminish. By reducing glomerular hydrostatic Clentiazem Nifedipine Diltiazem Nisoldipine pressure, diltiazem may be able to protect the Felodipine Nimodipine kidney from the glomerular hyperfiltration and Gallopamil Nltrendipine glomerulosclerosis that complicates essential hyperlsradipine Verapamil tension.7 More recently, we have augmented these clinical hemodynamic findings by demonstrating their vides the means of calcium antagonism and thereby a reduced state of contractility of the cardiac or effects on the heart.8 We found that, although the vascular myocyte. Further, the calcium antagonists calcium antagonists rapidly diminish left ventricumay operate through inhibition of > 1 calcium lar (LV) mass in rat and humans,4-6 they simultachannel or other receptor or through the Ca*+ neously increase right ventricular wall thickness.8 release mechanism. Nifedipine, for example, also In this recent echocardiographic study comparing 6 calcium antagonists and 3 angiotensin-converting operates at the a-adrenergic receptor in addition enzyme (ACE) inhibitors, all 9 agents reduced LV to its action at its calcium channel receptor. mass, posterior wall thickness, and septal wall The different effects and related mechanisms of thickness; but only the calcium antagonists (all 6) the various calcium antagonists are responsible for increased right ventricular wall thickness. These considerable variability in their clinical actions. Thus, understanding the differences in their dilat- findings strongly suggest that both classes of antihying effects in various blood vessels and the heart is pertensive drugs have similar systemic hemodycritical to understanding the multiplicity of their namic effects, but they act through different nonhemodynamic mechanisms on the mass of the 2 cardiovascular and renal protective effects. ventricles. The first report concerning the hemodynamic The mechanism for the independent risk of effects of the calcium antagonist nifedipine in hypertensive patients was by Olivari et a1.3They increased cardiovascular morbidity and mortality reported that after 3 weeks of treatment, mean that is associated with LV hypertrophy is not yet arterial pressure was reduced through a decrease known.9 In all likelihood, hemodynamic and also in total peripheral resistance. Similar systemic nonhemodynamic factors contribute in the development and reversal of hypertrophy. All antihypertenhemodynamic effects have been reported for diltiazem,4 verapamil,5 and other calcium antagonists. sive agents will reduce cardiac mass if they are used Following their intravenous administration, all 3 long enough, but only certain classes of these drugs agents are associated with a reflexive increase in rapidly reduce LV mass with short-term therapy.lO heart rate, cardiac output, and myocardial contrac- This most likely reflects their nonhemodynamic tility accompanied by increased circulating levels of actions. It is not known yet why these antihypernorepinephrine. 4,5 Variable systemic effects on tensive drugs have differing effects on cardiac heart rate and cardiac output may be seen with mass. The calcium antagonists reduce arterial presmore prolonged therapy. Reduction in arterial pressure has not been related to expanded intravas- sure by decreasing arteriolar smooth muscle tone. This is achieved by decreasing the availability of cular (plasma) volume or alterations in the reninintracellular calcium ions for muscle contraction. angiotensin-aldosterone system.3-s Despite this seeming similarity in the systemic The persistent decrease in arterial pressure is hemodynamic effects of these agents, their renal achieved by a reduction in total peripheral vascular hemodynamic effects are more variable. Although resistance, which is shared by all the major vascular all 3 agents (nifedipine, diltiazem, and verapamil) territories. Only certain calcium antagonists inmaintain glomerular filtration rate and reduce crease renal blood flow and this is not accomparenal vascular resistance,s5 only diltiazem de- nied by increased glomerular hydrostatic pressure creases the renal filtration fraction.4,6 This is and filtration rate, a genuine renal protective achieved through efferent as well as afferent glomer- effect. Although calcium antagonists reduce LV ular arteriolar dilation, thereby reducing intraglomass, they do so through mechanisms that seem to merular hydrostatic pressure.6 Using micropunc- be distinct from other antihypertensive drugs. ture techniques in the spontaneously hypertensive Studies concerned with the LV mass-reducing rat, we have confirmed the calculated intrarenal effects of calcium antagonists are ongoing but no TABLE I List of Calcium Antagonists in Clinical Study and Practice in the United States
8 I
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
DECEMBER
21, 1992
study has yet demonstrated reversal of the risk associated with LV hypertrophy. Current experience suggests that certain subsets of patients with essential hypertension can derive particular benefit from calcium antagonist therapy. Black or older hypertensive patients, and those with volumedependent hypertension and lowered plasma renin activity in particular, may benefit from the calcium antagonists. Other patients who may benefit from treatment with these agents include patients with angina pectoris who are not fully responsive to B blocker therapy and patients with bilateral renal arterial disease (or unilateral disease with a solitary kidney) in whom the ACE inhibitors are contraindicated. Finally, the calcium antagonists may also be the appropriate therapy for those patients who have experienced metabolic alterations with other classes of antihypertensive therapy. Clearly, additional studies are necessary to demonstrate their additional cardiovascular and renal protective effects.
REFERENCES l. Fleckenstein A. Calcium Antagonism in Heart and Smooth Muscle. New York: John Wiley & Sons,1983. 2. Slish DF, Schultz D, Schwartz A. Molecular biology of the calcium antagonist receptor. Hyprtm-tin 1992;19:1%24. 3. Olivari MT, Bartonelli C, Polese A, Fiorentini C, Morazzi P, Guazzi MD. Treatment of hypertensionwith nifedipine, a calcium antagonisticagent. Circulation 1980;59:10561062. 4. Amodeo C, Kobrin I, Venture HO, Messerli FH, Frohlich ED. Immediate and short-term hemodynamiceffects of diltiazem in patients with hypertension. Circularton 1986;73:106113. 5. Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Cardiovascular effects of verapamil in patients with essentialhypertension.Circulation 198257: 1030-1036. 6. Isshigi T, Amodeo C, Messedi FH, Pegram BL, FrohIich ED. Diltiazem maintains renal vasodilation without hyperfiltration in hypertension. Studies in essential hypertensiveman and the spontaneouslyhypertensive rat. Cardiovasc Drugs Ther 1987;1:345-348. 7. FrohIich ED. Correction of physiological alterations of hypertension.Cardiovast Dnrgs Ther 1987;1:35!&366. 8. Aristizabal D, Frohlich ED, McLoughlm M, Messexli FH. Disparate stmctural effects of left and right ventricles by angiotensin converting enzyme inhibitors (ACE) and calcium antagonists (Ca ANT) (abstr). Hyptemion 1991;18(3):26. 9. Frohlich ED. Left ventricular hypertrophy: An independent factor of risk. In: Frohlich ED, ed. Preventive Aspects of Coronary Heart Disease. Philadelphia: FA Davis, 1990~85-94. 10. Froblich ED. The heart in hypertension: A 1991 ovewiew. Hlpaension 1991;18(3):62-68.
A SYMPOSIUM:
CARDIOPROTECTION
9 I
