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Combination Therapy: The Comprehensive Management Of Vulnerable Hypertensive Patients

Combination of ACE Inhibitors and Calcium Antagonists: A Logical Approach

Ruschitzka, Frank T.; Noll, Georg; Lüscher, Thomas F.

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Journal of Cardiovascular Pharmacology: Volume 31 - Issue - p S5-S16
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Although management of coronary atherosclerosis has centered on treating symptoms, symptom control alone has little effect on outcome. Therefore, modern cardiovascular therapies focus on risk factor intervention, such as reversing endothelial dysfunction, to influence the natural course of established coronary artery disease and/or to prevent the disease at an earlier stage.

Impairment of endothelial function leading to enhanced vasoconstriction, increased platelet vessel wall interaction, adherence of monocytes, and migration and proliferation of vascular smooth muscle is crucially involved in the pathophysiology of coronary artery disease (1,2). Endothelial cells are strategically located between the circulating blood and the vascular smooth muscle and release many vasoactive substances, that regulate function of vascular smooth muscle and trafficking blood cells (Fig. 1)(2). Vasodilatory mediators, such as nitric oxide (NO) and prostacyclin, are particularly important because they also possess thromboresistant and antiatherogenic properties by preventing platelet aggregation and cell adhesion (3,4). Furthermore, there is compelling evidence for NO as an antiproliferative principle (5). These effects are counterbalanced by endothelium-derived vasoconstrictors, such as angiotensin II (Ang II) and the 21-amino-acid peptide endothelin-1 (ET-1), both of which are potent vasoconstrictors with proliferative properties (6,7). This review discusses the effects of calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors on endothelium and vascular smooth-muscle function, with particular emphasis on the effects of NO, ET-1, and Ang II.

FIG. 1
FIG. 1:
Local vascular effects of ACE inhibitors and calcium antagonists. Whereas ACE inhibitors inactivate the formation of angiotensin I (AI) into angiotensin II (AII) as well as the inactivation of bradykinin (Bk) on endothelial cells, Ca2+ antagonists primarily interfere with Ca2+ influx at the level of vascular smooth muscle. AT, angiotensin receptor; cAMP, cyclic 3′, 5′-adenosine monophosphate; cGMP, cyclic 3′, 5′-guanasine monophosphate; CYC, cyclo-oxygenase; ECE, endothelin-converting enzyme; ET, endothelin; Gi, Gi protein; L-arg, L-arginine; NO, nitric oxide; NOS, nitric oxide synthase; PGI2, prostacyclin.


Three classes of calcium antagonists have been delineated: (a) heart rate-limiting phenylalkylamines (verapamil, gallopamil), (b) dihydropyridines of the first generation (nifedipine) and long-acting dihydropyridines of the second generation (e.g., felodipine, isradipine, amlodipine), and (c) diltiazem-like calcium antagonists (i.e., benzothiazepine type). The new calcium antagonist mibefradil activates both voltage-operated (L-type) and T-type Ca2+ channels and cannot be assigned to one of the former classes of the drugs. All the other calcium antagonists interfere with different parts of the voltage-operated Ca2+ channels, thereby decreasing influx of extracellular Ca2+ into cells, particularly vascular smooth-muscle cells. Intracellular Ca2+ is involved in a variety of intracellular processes, serving as an important signaling mechanism. In the context of coronary artery disease (CAD), increases in intracellular Ca2+ are involved in platelet activation, vasoconstriction and proliferation of vascular smooth-muscle cells (8), and release of vasoactive substances by endothelial cells (9,10).

Calcium antagonists and endothelium-dependent relaxations

The vascular endothelium synthesizes NO from its precursor, L-arginine, by a family of NO synthases, a constitutional, calcium-dependent form (cNOS) and an inducible, Ca2+-independent form (iNOS) (11-13). NO is released under both basal and stimulated conditions by a variety of humoral substances and by mechanical forces such as shear stress and blood flow. Its release can be competitively inhibited by L-arginine analogues (for review see ref. 14). The formation of NO is associated with increases in intracellular Ca2+ in endothelial cells (11,12), although calcium antagonists may in theory reduce the activity of Ca2+-dependent cNOS by blocking Ca2+ influx into endothelial cells (Fig. 1).

NO exerts its effects via guanylyl cyclase, leading to increases in intracellular cGMP concentrations (15). cGMP lowers intracellular Ca2+ (most likely by increasing Ca2+ efflux and re-uptake of Ca2+ into intracellular stores and dephosphorylation of myosin light chains). Calcium antagonism facilitates the effects of NO at the level of vascular smooth-muscle cells in epicardial but not intramyocardial vessels (15). Moreover, long-term but not short-term therapy with verapamil improves blunted endothelium-dependent relaxations in NO-deficient hypertensive rats (16,17). In spontaneously hypertensive rats (SHR) and hypercholesterolemic rabbits, chronic therapy with nifedipine or isradipine ameliorates impaired endothelium-dependent relaxations to acetylcholine (18,19).

Calcium antagonists and endothelin

Endothelins have been implicated in the pathogenesis of several mainly cardiovascular disorders in view of their powerful vasoconstrictor and growth-promoting properties (20). The three members of the family, ET-1, ET-2, and ET-3, are produced in a variety of tissues, where they act as modulators of vasomotor tone, cell proliferation, and hormone production (21). Each ET isoform is a product of separate genes that code for a precursor protein mRNA. The expression of mRNA and the release of the peptide are stimulated by thrombin, transforming growth factor β1 (TGF-β1), interleukin-1 (IL-1), epinephrine, Ang II, arginine vasopressin, calcium ionophore, and phorbol ester (Fig. 1)(6,22). ET-1 causes vasodilatation at lower and marked and sustained contractions at higher concentrations (23,24), which in the heart eventually lead to ischemia, arrhythmias, and death. Intramyocardial vessels are more sensitive to the vasoconstrictor effects of ET-1 than epicardial coronary arteries, suggesting that the peptide is particularly important in the regulation of flow.

The production of ET-1 in endothelial cells (e.g., porcine aorta) is associated with an increase in intracellular Ca2+(Fig. 1)(10). The calcium inophore A23187, which increases intracellular calcium levels in endothelial cells, is a very potent stimulator of ET-1 production (10). However, calcium antagonists do not alter ET production in vitro or in vivo. Indeed, therapy with nifedipine does not modulate increased plasma endothelin levels in high-altitude healthy mountaineers (25).

ET-1 interacts with specific receptors on vascular smooth muscle (i.e., ETA and ETB receptors) (26-29) mediating vasoconstriction and proliferation (30). In endothelial cells, the peptide activates ETB receptors that are linked to the formation of NO and prostacyclin (Fig. 1)(27,28,31). In certain blood vessels, such as porcine coronary artery, ET receptors on vascular smooth muscle are linked to voltage-operated Ca2+ channels via Gi proteins (32). This may explain why calcium antagonists reduce ET-induced vasoconstriction in these vessels and are similarly effective in human coronary artery (33). In human internal mammary artery, the contractile effects induced by ET are mediated via cascade activation of phospholipase C, diacylglycerol, and ultimately formation of inositol triphosphate, which in turn releases Ca2+ from the sarcoplasmic reticulum, thus increasing cytosolic Ca2+(34-36). Accordingly, calcium antagonists fail to prevent ET-induced contractions in the human internal mammary artery (34). Interestingly, calcium antagonists are able to reverse ET-induced contractions in veins. This is most likely related to the fact that ET lowers the membrane potential of venous vascular smooth-muscle cells and thereby opens voltage-operated Ca2+ channels (37). Furthermore, ET-1 potentiates contractions of other vasoconstrictors, such as serotonin and norepinephrine, even at subthreshold concentrations, i.e., concentrations that do not induce any contractile response in themselves (Fig. 2)(38). These indirect potentiating effects of ET are due to an increased Ca2+ sensitivity of vascular smooth-muscle cells under the conditions described above and are therefore prevented by pretreatment with calcium antagonists of the dihydropyridine type (38).

FIG. 2
FIG. 2:
Potentiating effects of low concentrations of ET-1 on serotonin-induced contractions. In the human internal mammary artery, pretreatment with subthreshold and low concentrations of ET-1 increases contractile responses evoked by serotonin (3 × 10−8 M). From ref. 38, by permission of the American Heart Association.

Several studies have suggested that small vessels are more dependent on the influx of extracellular Ca2+ than larger vessels (8,38). Therefore, in the human forearm circulation, intra-arterial but not oral application of verapamil or nifedipine prevents contractions induced by intra-arterially infused ET-1 (Fig. 3)(23). It remains to be determined if clinically used oral dosages of verapamil or nifedipine are effective in inhibiting the vasoconstrictor effect of endogenously formed ET. Further studies are required to clarify the potential usefulness of calcium antagonists in clinical disease states associated with increased ET production.

FIG. 3
FIG. 3:
Effects of ET-1 in the human forearm circulation in the presence and absence of the Ca2+ antagonists verapamil and nifedipine. The results of two series of experiments with the two Ca2+ antagonists have been pooled because similar results were obtained. The change in forearm blood vascular resistance is given. Both nifedipine and verapamil fully prevented the decrease in forearm vascular resistance occurring with higher concentrations of ET and en mass the vasodilator effects of the peptide. From ref. 23, by permission of the American Heart Association.

Calcium antagonists and atherosclerosis

In damaged blood vessels or those with functionally altered endothelial cells, platelets adhere rapidly. Platelets are an important source of platelet-derived growth factor (PDGF), a potent mitogen (2). In cultured smooth-muscle cells derived from human coronary arteries, platelet-derived growth factor (PDGF) induces marked proliferative responses, with a half-maximal concentration of 0.1-0.5 ng/ml (Fig. 4)(39). The effect of PDGF involves activation of tyrosine kinase and autophosphorylation of PDGF receptors (39,40). However, at clinically therapeutic concentrations, verapamil inhibits PDGF-induced proliferative responses in human coronary vascular smooth-muscle cells (Fig. 4)(39). In contrast, proliferative responses induced by pulsatile stretch are unaffected by verapamil or nifedipine. This indicates that mechanical forces, such as pulsatile stretch, and receptor-operated growth factors, such as PDGF, mediate their effects via distinct mechanisms. Tyrosine kinase, S6 kinase, and mitogen-activating protein (MAP) kinase are not affected by calcium antagonists, suggesting that they interact at different intracellular signal transduction mechanisms (39).

FIG. 4
FIG. 4:
The effects of Ca2+ antagonists on proliferative responses of human coronary vascular smooth-muscle cells in culture. Increasing concentrations of verapamil markedly decreased the [3H]thymidine incorporation of human vascular smooth-muscle cells held in culture stimulated with platelet-derived growth factors (PDGF; 1 ng/ml). *p < 0.05. From ref. 39, by permission of the American Heart Association.

In cholesterol-fed rabbits several classes of calcium antagonists inhibit the atherosclerotic process in vivo (19). In three large angiographic trials, chronic therapy with nifedipine or nicardipine was shown to reduce the development of new lesions in the coronary circulation without affecting already existing stenoses (41-43). These clinical studies have confirmed that calcium antagonists exert antiatherogenic properties, although less pronounced compared to lipid-lowering therapy (44-46). However, the clinical relevance of these findings in terms of reducing morbidity and mortality in patients with CAD is yet to be established and has recently been disputed. In particular, the dihydropyridines are reported to increase risk for MI (47) and to raise mortality after MI (48). Therefore, there is no place for dihydropyridines in secondary prevention of MI and they should not be recommended as first-choice therapy in hypertension and CAD until new trial evidence (49) is provided. Heart rate-limiting Ca2+-channel blockers, such as verapamil and diltiazem, are useful alternatives in patients with impaired left ventricular function or heart failure and contraindications to β-blocker treatment. The DAVIT II trial suggests that, at least in patients with normal left ventricular function after MI, verapamil benefits outcome (50). Similar results have been obtained with diltiazem, albeit in a subgroup analysis (51).


The endothelium is crucially involved in the activation of the renin-angiotensin system (RAS) because ACE is located on endothelial cell membranes and transforms the biologically inactive Ang I into Ang II (52). Depending on the vascular tissue, non-ACE peptidases may also contribute to the conversion of Ang I (53). Both a circulating and a vascular RAS exist. Ang II, the active compound of the RAS has been reported to contribute to the pathogenesis of different forms of hypertension by producing potent vasoconstriction and inducing salt and water reabsorption (54). Moreover, Ang II evokes proliferation and migration of vascular smooth-muscle cells predominantly via Ang I receptors (55-59). Several other angiotensin receptors have been characterized (60). Interestingly, in coronary endothelial cells, the antiproliferative effects of the Ang II receptor offset the growth-promoting effects mediated by the Ang I receptor (61). Intensive research has focused on developing drugs, such as ACE inhibitors, renin inhibitors, and Ang II receptor antagonists, that interfere with the RAS at different levels. ACE inhibitors reduce blood pressure not only in renin-dependent models of hypertension but also in those less clearly related to the RAS, such as the SHR and essential hypertension in humans. The antihypertensive effect of ACE inhibitors has been mainly attributed to diminished formation of Ang II in both plasma and tissue and an accumulation of vasodilator kinins, because ACE catalyzes both the conversion of Ang I into Ang II and the degradation of bradykinin and related peptides (Fig. 1)(54,62).

ACE and endothelium-derived relaxing factors

The endothelium synthesizes and releases several vasoactive substances. Among the best characterized and probably the most important is NO, previously known as endothelium-derived relaxing factor (1). Because of its vasodilatory, antiaggregatory, and antiproliferative properties, loss of endothelial NO could contribute to the development of overt cardiovascular disease.

The response to bradykinin, an endothelium-dependent vasodilator acting via the L-arginine pathway, is profoundly affected by ACE inhibition (63-66). ACE and the endothelial cell kininase II responsible for the degradation of bradykinin are identical enzymes. It is of interest that endothelial cells can produce and release bradykinin locally, particularly in response to flow and shear stress (9,67,68). Locally released bradykinin may then activate β2-bradykinin receptors on endothelial cells and activate the endothelial L-arginine-NO pathway as well as other endothelium-derived relaxing factors, such as the putative hyperpolarizing factor (69). In human coronary artery, ACE inhibitors increase endothelium-dependent relaxations to bradykinin. In the presence of low concentrations of bradykinin, ACE inhibitors cause endothelin-dependent relaxations (70). Similarly, in the perfused porcine eye ACE inhibitors markedly enhance the increase in ophthalmic flow induced by bradykinin (70). These differences in effectiveness of ACE inhibitors indicate a heterogeneity of ACE activity or expression in different vascular beds. In contrast to enalapril or captopril, a highly tissue-selective ACE inhibitor, quinaprilat, increases forearm blood flow in the human circulation, most likely by activating the L-arginine-NO pathway (71). It is still a matter of debate if ACE inhibitors induce prolongation of the half-life of bradykinin and/or directly stimulate NO release, because it is questionable whether there is sufficient bradykinin concentration in the endothelium to permit this effect (72). In addition, other endothelium-derived substances, such as endothelium-derived hyperpolarizing factor (EDHF), might be involved in the vasoactive properties of ACE inhibitors via an effect of the β2 receptor.

Another mechanism by which an ACE inhibitor could ameliorate endothelial function is through modulation of superoxide O2-production. In experimental models of cardiovascular disease, increased vascular superoxide generation impairs endothelium-dependent vascular relaxation via inactivation of NO. In contrast to norepinephrine-treated rats, vascular superoxide anion production is doubled and associated with blunted endothelium-dependent relaxation to acetylcholine in rats that were made hypertensive with Ang II (72). Interestingly, the activity of vascular NADH/NADPH oxidases, which are an important source of superoxide anions, is increased by Ang II in vitro and in vivo (73). Even subthreshold concentrations of Ang II that do not cause blood pressure elevation are shown to double NADH activity and superoxide production (72), so that an ACE inhibitor could attenuate superoxide generation in different models of hypertension that are not related to Ang II.

In summary, there is mounting evidence that the RAS and the L-arginine-NO pathway are closely interconnected. Modulation of NO generation and degradation by bradykinin and superoxide anions, respectively, may contribute to the beneficial effects of ACE inhibitors in patients after MI, congestive heart failure, and renal disease.

Angiotensin and endothelin-1

Ang II increases the expression of ET mRNA in endothelial cells in culture (Fig. 5)(74,75). In addition, Ang II exerts similar effects in endothelial cells obtained from the rat mesenteric microcirculation (74,76). This is in line with published data demonstrating that chronic Ang II infusion potently increases ET-1 tissue levels (Fig. 6)(77). In a model of hypertension induced by chronic Ang II infusion, long-term treatment with an orally active, selective ETA receptor antagonist, LU135252, blunts the Ang II-induced blood pressure increase. Concomitantly, ET-dependent relaxations to acetylcholine and impaired contractions to ET-1 and norepinephrine were improved. Thus, ETA receptor antagonism partially, prevents Ang II-induced hypertension and endothelial dysfunction in the rat (78).

FIG. 5
FIG. 5:
Northern blot analysis of ET gene expression using a cDNA probe in cultured porcine aortic endothelial cells. Within 4 h, angiotensin II, transforming growth factor β-1 (TGFβ1), and thrombin increase ET messenger RNA. From ref. 10.
FIG. 6
FIG. 6:
Chronic angiotensin II infusion potently increases ET-1 tissue levels. Concentration of ET-1 in small mesenteric arteries of Wistar-Kyoto rats after 2 weeks of treatment with either angiotensin II (Ang II), the ETA receptor antagonist LU135252, or a combination of both (n=7-9). *p < 0.001 vs. control; p < 0.05 vs. Ang II alone. From ref. 77, by permission of the American Heart Association.

Expression of ET in response to Ang II may further enhance the vasoconstrictor effects of Ang II. In perfused mesenteric resistance arteries of the SHR, perfusion with Ang II per se causes only a transient contraction. However, after vessel tone has returned to baseline, the concentration-response curve to norepinephrine is significantly shifted to the left (76). This effect of Ang II is endothelium-dependent and can be inhibited by an inhibitor of the ET-converting enzymes, such as phosphoramidone. Therefore, it appears that Ang II stimulates the local vascular production of ET and thereby enhances vasoconstrictor responses to norepinephrine (see above).

Chronic effects of ACE inhibitors on endothelial function

Chronic therapy with ACE inhibitors augments bradykinin-induced stimulation of the L-arginine-NO pathway (Fig. 1) and formation of EDHF, i.e., a factor inducing vascular smooth-muscle relaxation independent of NO and prostacyclin generation that is of particular importance in smaller vessels (79). This may keep the blood vessel wall in a continuous state of vasodilatation, thereby improving blood flow and lowering peripheral vascular resistance and blood pressure. Long-term administration of ACE inhibitors may contribute to the antithrombotic properties of the endothelium, because platelets possess Ang II receptors and bradykinin potentiates NO-mediated inhibition of platelet aggregation and adhesion (4). ACE inhibitors also ameliorate the endogenous fibrinolysis system by preventing Ang II-induced increase of PAI-1 activity and bradykinin-mediated stimulation of tPA secretion (80,81). Furthermore, Ang II induces smooth-muscle migration and hypertrophic growth, accompanied by induction of the expression of growth-related proto-oncogenes (82) and synthesis of autocrine growth factors (83). Indirect effects of ACE inhibitors may also be important for the regulation of vascular growth, because NO has been implicated as an antiproliferative (5) and antimigratory agent (57).

In experimental animals, chronic therapy with ACE inhibitors augments endothelium-dependent relaxations to bradykinin and to other agonists, such as acetylcholine. This effect can be demonstrated in the aorta of normotensive rats (84) and in mesenteric resistance arteries of SHR (85,86). Because this endothelial protective effect can be obtained with different ACE inhibitors, such as benazapril and trandolapril, it is likely to be a drug class effect. Combination of trandolapril with a calcium antagonist such as verapamil at low dosages is as effective as a high dose of trandolapril or verapamil alone (Fig. 7)(84). This may have important clinical implications because low-dose combination therapy with an ACE inhibitor and a calcium antagonist may provide vascular protective effects while concomitantly decreasing the risk for adverse effects.

FIG. 7
FIG. 7:
Effects of chronic therapy with verapamil or trandolapril alone or in combination on endothelium-dependent relaxations in the aorta of stroke-prone spontaneously hypertensive rats (SHR-SP). Relaxations to acetylcholine of aortas with endothelium of SHR-SP contracted with norepinephrine was diminished in the placebo-treated group compared with all other treatment groups. Most interestingly, antihypertensive therapy with a low-dose combination therapy of verapamil and trandolapril was as effective as high-dose monotherapy. Incubation with a thromboxane receptor antagonist (SQ30741) restored impaired endothelium-dependent relaxations, indicating an increase in release of NO relative to that of thromboxane (TXA2)/prostaglandin H2 (PGH2). From ref. 86.

Using quantitative angiography, investigators of the Trial on Reversing Endothelial Dysfunction (TREND) study showed that 6-month treatment with the highly tissue-specific ACE inhibitor quinaprilat ameliorates endothelium-dependent coronary vasomotion in normotensive patients with CAD (Fig. 8)(87). Paradoxical vasoconstriction to high doses of the prototypical endothelium-dependent vasoactive agent acetylcholine was substantially decreased (from 14.3 to 2.3% constriction at baseline and follow-up, respectively). Moreover, in comparison with placebo, twice as many patients in the ACE inhibitor-treated group exhibited dilatation to acetylcholine.

FIG. 8
FIG. 8:
TREND (Trial on Reversing Endothelial Dysfunction) study. Quantitative coronary angiography revealed that 6-month treatment with the ACE inhibitor quinaprilat ameliorates vascular function in normotensive patients with coronary artery disease. Net changes in the responses to acetylcholine of 10−6 mol/L and 10−4 mol/L in the placebo and quinalapril group were significant for all segments. Modified from ref. 87, by permission of the American Heart Association.

In contrast to experimental data obtained in the rat, the ACE inhibitors captopril, enalapril, and cilazapril were unable to improve or even normalize impaired endothelium-dependent vasodilatation in hypertensive patients (88). This lack of effect, which contrasts with experimental data, may be related to the duration of therapy, because these patients were treated for 2-5 months rather than for 6 months as in the TREND study. Although 8 weeks of treatment may be sufficient in the rat, a similar duration of treatment may be ineffective in humans, particularly after hypertension is fully established. Furthermore, in the clinical setting, hypertension is usually detected and treated at an advanced stage of disease, whereas in animal models treatment is usually started before hypertension develops. However, less pronounced lipophility and tissue selectivity of the ACE inhibitors used might also provide an explanation for the observed lack of effects of some ACE inhibitors used. Moreover, the involvement of second enzymes capable of processing Ang I to Ang II cannot be excluded.

Angiotensin and atherosclerosis

Vascular smooth-muscle cells express angiotensin receptors. In the media of an intact blood vessel wall, the acute effect of activation of these receptors is vasoconstriction (54). However, Ang II induces migration and proliferation via activation of Ang I receptors. The recently cloned Ang II receptor exerts antiproliferative effects, and its activation tends to counterbalance excessive proliferative effects of Ang II (61).

Most interestingly, NO and Ang II interact with each other at the level of vascular smooth-muscle cells (Fig. 9). Migration induced by Ang II can be concentration-dependently inhibited by NO released from sodium nitroprusside or S-nitroso-acetylpenicillamine (SNAP). The effects of NO donors on angiotensin-induced migration are enhanced by superoxide dismutase (SOD, an enzyme that breaks down oxygen-derived free radicals and in turn increases the half-life of NO) and reduced by hemoglobin (a scavenger of NO). Because superoxide anions participate in the oxidation of lipoproteins and damage to membrane lipids, attenuation of vascular superoxide production may explain some of the favorable effects of ACE inhibitors (72). In addition, induction of NO synthase (iNOS) by IL-1β in vascular smooth muscle markedly depresses migratory responses (2).

FIG. 9
FIG. 9:
Regulation of the response to injury in the blood vessel wall. In injured blood vessels, platelets and monocytes adhere and invade the blood vessel wall. Vascular smooth-muscle cells start to proliferate and migrate into the intima, where they proliferate further. The mediators involved are indicated. AI, angiotensin I; AII, angiotensin II.

Experimental data strongly suggest that chronic therapy with ACE inhibitors reduces the development of atherosclerosis, at least in the hypercholesteremic rabbit (89,90). Similarly, in hypertensive rats cilazapril improves endothelial function and prevents monocyte adhesion (91). Whether or not ACE inhibitors are able to prevent atherosclerosis in humans is the subject of ongoing trials. The recently finished Quinalapril Ischemic Events Trial (QUIET) study unfortunately was not conclusive. Although there was a trend towards reduced events, no improvement of angiographically visible atherosclerosis was found except in a subgroup analysis in patients with hyperlipidemia (B. Pitt, personal communication, 1997).

Disappointingly, like many other drugs, including calcium antagonists, ACE inhibitors failed to reduce the incidence of restenosis after PTCA (92,93). The fact that the drugs were at least in part effective in animal models (94,95) may be related to species differences and differences in plaque biology of human atherosclerotic lesions and experimentally induced intimal hyperplasia. In any event, it is quite likely that in humans with CAD, a number of potent stimuli contribute to proliferative responses that lead to restenosis, whereas the experimental setting may be much more homogeneous and hence drugs interfering with only one mediator may be more effective. Moreover, in clinical trials the doses used were significantly lower than the doses used in animal models.



Once monotherapy has proved to be ineffective, combination treatment should be considered. Because blood pressure lowering is possible with more or less all anti-hypertensive drugs available, it may be advantageous to use drugs that embody vascular protective and lipid-lowering properties and interfere with different regulatory processes of the circulation. This may provide better hemodynamic and vascular protective effects. A further advantage of combination therapy would be a reduction in dosage and side effects.

Both ACE inhibitors and calcium antagonists are effective in lowering blood pressure in patients with essential hypertension (96). It is conceivable that a combination of these two drugs could be advantageous because they are interfering with different regulatory mechanisms. However, calcium antagonists are potent vasodilators. When infused into the human forearm circulation, calcium antagonists of any class can increase blood flow by a factor of 8-10 (23). In contrast, ACE inhibitors do not cause vasodilatation, with a few exceptions (68), whereas calcium antagonists do not interfere with the RAS, an important regulatory pathway in the circulation. Whereas calcium antagonists stimulate the sympathetic nervous system (97), ACE inhibitors reduce sympathetic activity by preventing the essential stimulating effects of Ang II on sympathetic outflow (98). As outlined above, in the blood vessel wall ACE inhibitors and calcium antagonists act synergistically, which may provide enhanced vascular protection.

Acute myocardial infarction

The first trial using diltiazem in patients after acute MI showed disappointing results (99). The overall results were negative and the subgroup analysis showed a benefit only in patients without pulmonary congestion. Diltiazem increased mortality in patients with pulmonary congestion. Follow-up trials with verapamil also did not unequivocally indicate benefit but showed a trend toward reducing total and cardiovascular mortality. These beneficial effects were also confined to patients with normal ejection fractions (50). Most likely, the negative inotropic effects of verapamil outweigh its cardioprotective effects in patients with impaired left ventricular function.

ACE inhibitors are the most extensively studied drugs in patients after MI. A number of trials using captopril, enalapril, ramipril, lisinopril, and trandolapril have demonstrated an 18-25% reduction in total mortality (100-103). Furthermore, hospitalizations for CHF were markedly reduced, as was the incidence of acute coronary syndromes such as unstable angina pectoris and acute MI. ACE inhibitors are proven to be particularly beneficial (if not exclusively seen) in patients with impaired left ventricular function (left ventricular ejection fraction below 40%). It is possible that the inhibitory effects of ACE inhibitors on the sympathetic nervous system are crucial for these differences. Most interestingly, a Danish study provides evidence for a rationale for combining calcium antagonists and ACE inhibitors in the clinical setting, because additional treatment with verapamil further improved outcome in postinfarct patients (104). When added to an ACE inhibitor, verapamil significantly reduced cardiac event rates in post-acute MI patients with CHF.

Protection of kidney function

Impaired renal function is an important complication of hypertension, diabetes, and atherosclerotic vascular disease. Particularly in diabetes and hypertension, increased intraglomerular pressure plays a key role in the development of renal failure (105). Albumin excretion has been used as a surrogate marker to determine changes in early renal damage during therapy with calcium antagonists or ACE inhibitors (106,107). ACE inhibitors are particularly interesting in this context because they primarily lower efferent renal resistance and hence most effectively reduce intraglomerular pressure. Recently, ACE inhibitor treatment was shown to substantially reduce morbidity and mortality in patients with diabetic nephropathy (108) and in different causes of glomerulonephritis (109). However, calcium antagonists lower intraglomerular pressure by reducing perfusion pressure and both afferent and efferent renal resistance. Clinical trials have shown that albumin excretion is reduced with chronic therapy with an ACE inhibitor and a calcium antagonist, such as verapamil. Combination therapy appears to have an additive effect (110). Therefore, combination therapy with a calcium antagonist and an ACE inhibitor is a promising concept in patients with impaired renal function complicated by endothelial dysfunction, as in diabetes mellitus and/or advanced atherosclerosis.


Calcium antagonists and ACE inhibitors are well-established drugs in treatment of patients with cardiovascular disease. Whereas ACE inhibitors ameliorate the deleterious effect of Ang II by inhibiting the RAS and reducing sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Moreover, calcium antagonists are mainly involved in facilitating the effects of endothelium-derived relaxing factors and preventing those of endothelium-derived vasoconstrictors. They particularly affect mediators such as Ang II at the level of vascular smooth-muscle cells by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. ACE inhibitors increase the activity of the L-arginine-NO pathway through their effects on bradykinin, in addition to their inhibition of Ang II and subsequently superoxide formation. Calcium antagonists and ACE inhibitors both have potent antiproliferative, antimigratory, antithrombotic, and antiatherogenic properties and act synergistically in ameliorating endothelial dysfunction. Therefore, a combination of calcium antagonists and ACE inhibitors provides a straightforward approach for the benefit of our patients with cardiovascular disease.

Acknowledgments: Research was supported by grants from the Swiss National Research Foundation (No. 32-32562.91), the Sandoz Foundation, and Patria Insurances, and by a grant-in-aid from Knoll Pharmaceuticals AG, Ludwigshafen, Germany. Frank Ruschitzka is the recipient of a grant from the German Research Association (Deutsche Forschungsgemeinschaft Ru 612/1-1).


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Section Description

Proceedings of satellite symposium of the 8th European Meeting on Hypertension June 13, 1997; Milan, Italy


ACE inhibitors; Calcium antagonists; Angiotensin; Combination therapy; Resistance arteries

© Lippincott-Raven Publishers