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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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Abstract

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.

CALCIUM ANTAGONISTS

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).

ACE INHIBITORS

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.

INTERACTION OF CALCIUM ANTAGONISTS AND ACE INHIBITORS IN CLINICAL CONDITIONS

Hypertension

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.

CONCLUSION

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).

REFERENCES

1. Lüscher TF, Vanhoutte PM. The endothelium modulator of cardiovascular function. Boca Raton, FL: CRC Press, 1990.
2. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-9.
3. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-6.
4. Radomski MW, Palmer RM, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987;92:639-46.
5. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774-7.
6. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-5.
7. Yanagisawa M, Inoue A, Ishikawa T, et al. Primary structure, synthesis, and biological activity of rat endothelin, an endothelium-derived vasoconstrictor peptide. Proc Natl Acad Sci USA 1988;85:6964-7.
8. Cauvin C, Tejerina M, Hwang O, Kai-Yamamoto M, van Breemen C. The effects of Ca2+-antagonists on isolated rat and rabbit mesenteric resistance vessels. What determines the sensitivity of agonist-activated vessels to Ca2+-antagonists? Ann NY Acad Sci 1988;S22:338-50.
9. Busse R, Lamontagne D. Endothelium-derived bradykinin is responsible for the increase in calcium produced by angiotensin-converting enzyme inhibitors in human endothelial cells. Naunyn Schmiedebergs Arch Pharmacol 1991;344:126-9.
10. Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990;85:587-90.
11. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988;333:664-6.
12. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351:714-8.
13. Radomski MW, Palmer RM, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA 1990;87:10043-7.
14. Lüscher TF: Endothelium-derived nitric oxide: the endogenous nitrovasodilator in the human cardiovascular system. Eur Heart J 1991;12:2-11.
15. Küng CF, Tschudi MR, Noll G, Clozel JP, Lüscher TF. Differential effects of the calcium-antagonist mibefradil in epicardial and intramyocardial coronary arteries. J Cardiovasc Pharmacol 1995;26:312-8.
16. Takase H, Moreau P, Küng CF, Nava E, Lüscher TF. Antihypertensive therapy prevents endothelial dysfunction in chronic nitric oxide deficiency. Hypertension 1996;27:25-31.
17. Rapoport RM, Draznin MB, Murad F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature 1983;306:174-6.
18. Tschudi MR, Criscione L, Novosel D, Pfeiffer K, Lüscher TF. Antihypertensive therapy augments endothelium-dependent relaxations in coronary arteries of spontaneously hypertensive rats. Circulation 1994;89:2212-8.
19. Henry PD, Bentley KI. Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine. J Clin Invest 1981;68:1366-9.
20. Taddei S, Virdis A, Mattei P, Salvetti A. Vasodilatation to acetylcholine in primary and secondary forms of hypertension. Hypertension 1993;21:929-33.
21. Lüscher TF, Boulanger CM, Dohi Y, Yang ZH. Endotheliumderived contracting factors. Hypertension 1992;19:117-30.
22. Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta. Inhibition of endothelium-derived nitric oxide. J Clin Invest 1990;85:587-90.
23. Kiowski W, Lüscher TF, Linder L, Bühler FR. Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor. Circulation 1991;83:469-75.
24. Seo B, Oemar BS, Siebenmann R, von Segesser L, Lüscher TF. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994;89:1203-8.
25. Goerre S, Wenk M, Bärtsch P, et al. Endothelin-1 in pulmonary hypertension associated with high altitude. Circulation 1994;90:359-64.
26. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor [see Comments]. Nature 1990;348:730-2.
27. Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor [see Comments]. Nature 1990;348:732-5.
28. Vane J. Endothelins come home to roost [News; Comment]. Nature 1990;348:973-5.
29. Seo BG, Oemar BS, Siebenmann R, von Segesser L, Lüscher TF. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994;89:1203-8.
30. Hirata Y, Takagi Y, Fukuda Y, Marumo F. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 1989;78:225-8.
31. Dohi Y, Lüscher TF. Endothelin in hypertensive resistance arteries. Intraluminal and extraluminal dysfunction. Hypertension 1991;18:543-9.
32. Goto K, Kasuya Y, Matsuki N, et al. Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca(2+) channel in vascular smooth muscle. Proc Natl Acad Sci USA 1989;86:3915-8.
33. Godfraind T, Mennig D, Morel N, Wibo M. Effect of endothelin-1 on calcium channel gating by agonists in vascular smooth muscle. J Cardiovasc Pharmacol 1989;13(suppl 5):S112-7.
34. Yang Z, Bauer E, von Segesser L, Stulz P, Turina M, Lüscher TF. Different mobilization of calcium in endothelin-1-induced contractions in human arteries and veins: effects of calcium antagonists. J Cardiovasc Pharmacol 1990;16:654-60.
35. Resink TJ, Scott-Burden T, Bühler FR. Endothelin stimulates phospholipase C in cultured vascular smooth muscle cells. Biochem Biophys Res Commun 1988;157:1360-8.
36. Wallnöfer A, Weir S, Ruegg U, Cauvin C. The mechanism of action of endothelin-1 as compared with other agonists in vascular smooth muscle. J Cardiovasc Pharmacol 1989;13(suppl 5):S23-31.
37. Miller VM, Komori K, Burnett JC Jr, Vanhoutte PM. Differential sensitivity to endothelin in canine arteries and veins. Am J Physiol 1989;257:H1127-31.
38. Yang ZH, Richard V, von Segesser L, et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm? Circulation 1990;82:188-95.
39. Yang Z, Noll G, Lüscher TF. Calcium antagonists differently inhibit proliferation of human coronary smooth muscle cells in response to pulsatile stretch and platelet-derived growth factor. Circulation 1993;88:832-6.
40. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203-12.
41. Loaldi A, Polese A, Montorsi P, De Cesare N, Fabbiocchi F, Ravagnani P, Guazzi MD. Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris. Am J Cardiol 1989;64:433-9.
42. Waters D, Lesperance J, Francetich M, et al. A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis. Circulation 1990;82:1940-53.
43. Lichtlen PR, Hugenholtz P, Rafflenbeul W, Jost S, Deckers JW. Retardation of angiographic progression of coronary artery disease by nifedipine. Lancet 1990;335:1109-13.
44. Brown BG, Zhao XQ, Sacco DE, Albers JJ. Arteriographic view of treatment to achieve regression of coronary atherosclerosis and to prevent plaque disruption and clinical cardiovascular events. Br Heart J 1993;69:S48-53.
45. Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). The MARS Research Group. Ann Intern Med 1993;119:969-76.
46. Dumont JM. Effect of cholesterol reduction by simvastatin on progression of coronary atherosclerosis: design, baseline characteristics, and progress of the Multicenter Anti-Atheroma Study (MAAS). Control Clin Trials 1993;14:209-28.
47. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-31.
48. Psaty BM, Hechbert SR, Koepsel TD. The risk of myocardial infarction associated with antihypertensive drug therapy. JAMA 1995;274:620-5.
49. Lubsen J, Poole-Wilson PA. ACTION: 30000 patient-years double-blind, placebo-controlled trial of nifedipine GITS in stable angina. Br J Clin Pharmacol 1997;88(suppl):23-6.
50. DAVIT-II. Secondary prevention with verapamil after myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction. Am J Cardiol 1990;66:33-40.
51. MDPIT. The effect of diltiazem on mortality and reinfarction after myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group. N Engl J Med 1988;319:385-92.
52. Sealey JE, Laragh HH. The renin angiotensin aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis. In: Laragh JH, Brenner BM, eds. Hypertension, pathophysiology, diagnosis and management, 1st. edition. New York: Raven Press, 1990:1287-317.
53. Okamura T, Okunishi H, Ayajiki K, Toda H. Conversion of angiotensin I to angiotensin II in dog isolated renal artery: role of two different angiotensin II-generating enzymes. J Cardiovasc Pharmacol 1990;15:353-9.
54. Dzau VJ. Short- and long-term determinants of cardiovascular function and therapy: contributions of circulating and tissue renin-angiotensin systems. J Cardiovasc Pharmacol 1989;14(suppl 4):S1-5.
55. Casscells W. Migration of smooth muscle and endothelial cell: critical events in restenosis. Circulation 1992;86:723-9.
56. Jackson CL, Schwartz SM. Pharmacology of SMC replication. Hypertension 1992;20:713-36.
57. Dubey RK, Jackson EK, Lüscher TF. Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell. J Clin Invest 1995;96:141-9.
58. Powell JS, Clozel JP, Muller RK. Inhibitors of angiotensin-converting enzyme prevent neointimal proliferation after vascular injury. Science 1989;245:186-8.
59. Lüscher TF, Tanner FC. Endothelial regulation of vascular tone and growth. Am J Hypertens 1993;6:283S-93S.
60. Timmermanns PBMWM, Benfield P, Chiu AT, Herblin WF, Wong PC, Smith RD. Angiotensin II receptors and functional correlates. Am J Hypertens 1992;5:221S-35S.
61. Stoll M, Steckelings M, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 1995;95:651-7.
62. Caldwell PR, Seegal BC, Hsu KC, Das M, Soffer RL. Angiotensin-converting enzyme: vascular endothelial localization. Science 1976;191:1050-1.
63. Mombouli JV, Nephtali M, Vanhoutte PM. Effects of the converting enzyme inhibitor cilazaprilat on endothelium-dependent responses. Hypertension 1991;18(suppl 4):22-9.
64. Feletou M, Germain M, Teisseire B. Converting-enzyme inhibitors potentiate bradykinin-induced relaxation in vitro. Am J Physiol 1990;262:H839-45.
65. Feletou M, Teisseire B. Converting enzyme inhibition in isolated porcine resistance artery potentiates bradykinin relaxation. Eur J Pharmacol 1990;190:159-66.
66. Yang Z, Arnet U, von Segesser L, Siebenmann R, Turina M, Lüscher TF. Different effects of angiotensin-converting enzyme inhibition in human arteries and veins. J Cardiovasc Pharmacol 1993;22:17-22.
67. Wiemer G, Scholkens BA, Becker RH, Busse R. Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 1991;18:558-63.
68. Bogle RG, Coade SB, Moncada S, Pearson JD, Mann GE. Bradykinin and ATP stimulate L-arginine uptake and nitric oxide release in vascular endothelial cells. Biochem Biophys Res Commun 1991;180:926-32.
69. Richard V, Tanner FC, Tschudi M, Lüscher TF. Different activation of L-arginine pathway by bradykinin, serotonin, and clonidine in coronary arteries. Am J Physiol 1990;259:1433-9.
70. Auch-Schwelk W, Bossaller C, Claus M, Graf K, Gräfe M, Fleck E. ACE inhibitors are endothelium-dependent vasodilators of coronary arteries during submaximal stimulation with bradykinin. Cardiovasc Res 1993;27:312-7.
71. Haefeli WE, Linder L, Lüscher TF. Effects of inhibition of tissue angiotensin-converting enzyme with quinaprilat on bradykinin-induced relaxation in the human forearm circulation in vivo [Abstract]. Eur Heart J 1994.
72. Rajagopalan S, Kurz S, Münzel T, et al. J Clin Invest 1996;97:1916-23.
73. Griendling K, Ollerenshaw JD, Minieri CA, Alexander RW. Angiotensin II stimulates NADH and NADPH activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141-8.
74. Dohi Z, Hahn AWA, Boulanger CM, Lüscher TF. Vascular renin angiotensin system and endothelial function: effect of ACE-inhibitors. In: MacGregor EA, Safar PS, Caldwell D, Hollenberg NK, eds. Current advance in ACE-inhibition II. Edinburgh: Churchill Livingstone, 1991:226-9.
75. Ito H, Hirata Y, Adachi S. Endothelin-1 is an autocrine/paracrine factor in the regulation of angiotensin-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993;92:398-403.
76. Dohi Y, Hahn AW, Boulanger CM, Bühler FR, Lüscher TF. Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries. Hypertension 1992;19:131-7.
77. Moreau P, d'Uscio LV, Shaw S, Takase H, Barton M, Lüscher TF. Angiotensin II increases tissue endothelin and induces vascular hypertrophy. Circulation [in press].
78. d'Uscio LV, Moreau P, Shaw S, Takase H, Barton M, Lüscher TF. Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. Hypertension 1997;29:435-41.
79. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 1988;93:515-24.
80. Vanhoutte PM, Boulanger CM, Illiano SC, Nagao T, Vidal M, Mombouli JV. Endothelium-dependent effects of converting-enzyme inhibitors. J Cardiovasc Pharmacol 1993;22(suppl 5):S10-6.
81. van Leeuwen RTJ, Kol A, Andreotti F, Kluft C, Maseri A, Sperti G. Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells. Circulation 1994;90:362-8.
82. Naftilan AJ, Pratt RE, Dzau VJ. Induction of platelet-derived growth-factor A chain and c-myc gene expression by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1419-23.
83. Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest 1993;91:2268-72.
84. Bossaller C, Auch-Schwelk W, Weber F, et al. Endothelium-dependent relaxations are augmented in rats chronically treated with the angiotensin-converting enzyme inhibitor enalapril. J Cardiovasc Pharmacol 1992;20(suppl 9):S91-5.
85. Dohi Y, Criscione L, Pfeiffer M, Lüscher TF. Angiotensin blockade or calcium antagonists improve endothelial dysfunction in hypertension: studies in perfused mesenteric resistance arteries. J Cardiovasc Pharmacol 1994;24:372-9.
86. Novosel D, Lang MG, Noll G, Lüscher TF. Endothelial dysfunction in aorta of the spontaneously hypertensive, stroke-prone rat: effects of therapy with verapamil and trandolapril alone or in combination. J Cardiovasc Pharmacol 1994;24:979-85.
87. Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 1996;94:254-65.
88. Creager MA, Roddy MA, Coleman SM, Dzau VJ. The effect of ACE-inhibition on endothelium-dependent vasodilation in hypertension. J Vasc Res 1992;29:97-101.
89. Fennessy PA, Campbell JH, Campbell GR. Perindopril inhibits both the development of atherosclerosis in the cholesterol-fed rabbit and lipoprotein binding to smooth muscle cells in culture. Atherosclerosis 1994;106:29-41.
90. Chobanian AV, Haudenschild CC, Nickerson C, Hope S. Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1992;20:473-7.
91. Clozel M. Mechanism of action of angiotensin converting enzyme inhibitors on endothelial function in hypertension. Hypertension 1991;18:1137-42.
92. Desmet W, Vrolix M, De Scheerder I, Van Lierde J, Willems JL, Piessens J. Angiotensin-converting enzyme inhibition with fosinopril sodium in the prevention of restenosis after coronary angioplasty. Circulation 1994;89:385-92.
93. MERCATOR. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group [Comment]. Circulation 1992;86:100-10.
94. Huber KC, Schwartz RS, Edwards WD, et al. Effects of angiotensin converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model. Am Heart J 1993;125:695-701.
95. Churchill DA, Siegel CO, Minor ST, West MS, Raizner AE. Enalapril in the prevention of restenosis following intracoronary intervention in a swine model. Coron Artery Dis 1993;4:461-7.
96. Buhler FR, Muller FB. Angiotensin converting enzyme inhibition and calcium channel blockade as primary antihypertensive therapy. J Hypertens (Suppl) 1986;4:S435-40.
97. Wenzel RR, Allegranza G, Binggeli C, et al. Differential activation of cardiac and peripheral sympathetic nervous system by nifedipine: role of pharmacokinetics and sympathetic stimulation. J Am Coll Cardiol 1997;29:1607-14.
98. Noll G, Wenzel RR, De Marchi S, Lüscher TF. Differential effects of nitrate and captopril on muscle sympathetic nerve activity. Circulation 1997;95:2286-92.
99. DAVIT-I. Verapamil in acute myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction. Eur Heart J 1984;5:516-28.
100. CONSENSUS SG. Effect of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35.
101. AIRE. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993;342:821-8.
102. Moye LA, Pfeffer MA, Braunwald E. Rationale, design and base-line characteristics of the Survival and Ventricular Enlargement trial. SAVE Investigators. Am J Cardiol 1991;68:70D-9D.
103. SOLVD: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293-302.
104. Fischer Hansen J, Hagerup L, Sigurd B, et al. Cardiac event rates after acute myocardial infarction in patients treated with verapamil and trandolapril versus trandolapril alone. Am J Cardiol 1997;79:738-41.
105. Hollenberg NK, Raij L. Angiotensin-converting enzyme inhibition and renal protection. An assessment of implications for therapy. Arch Intern Med 1993;153:2426-35.
106. Bigazzi R, Bianchi S, Baldari D, Sgherri G, Baldari G, Campese VM. Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors. Hypertension 1994;23:195-9.
107. Mimran A, Ribstein J, Du Cailar G. Is microalbuminuria a marker of early intrarenal vascular dysfunction in essential hypertension? Hypertension 1994;23:1018-21.
108. Lewis EJ, Hunsicker LJ, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition in patients with insulin-dependent diabetes mellitus and microalbuminuria. N Engl J Med 1993;329:1456-62.
109. Maschio G, Alberti D, Janin G, et al. Angiotensin converting enzyme inhibition in progressive renal insufficiency SG: effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996;334:939-45.
110. Fioretto P, Frigato F, Velussi M, et al. Effects of angiotensin converting enzyme inhibitors and calcium antagonists on atrial natriuretic peptide release and action and on albumin excretion rate in hypertensive insulin-dependent diabetic patients. Am J Hypertens 1992;5:837-46.

Section Description

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

Keywords:

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

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