INTRODUCTION
Cardiovascular disease still accounts for the majority of morbidity and mortality in western countries. Most forms of cardiovascular disease involve atherosclerotic vascular changes in the coronary, cerebral, renal and peripheral circulation leading to angina pectoris and myocardial infarction (MI), stroke, renal failure and claudication.
The endothelium is a monolayer of cells lying on the vascular wall, which for years was considered to be only a protective barrier. In the past two decades, however, it has been shown that the endothelium plays indeed an active role in the regulation of vascular smooth muscle cell function and tone. The endothelium is in a strategic anatomical position within the blood vessel wall, located between the circulating blood and vascular smooth muscles cells of the media. It can respond to mechanical and hormonal signals from the blood. Of particular importance is that the endothelium is a source of mediators which can, in a predominantly paracrine fashion, modulate the contractile state and proliferative responses of vascular smooth muscle cells, platelet function, coagulation as well as monocyte adhesion. The important role taken by the endothelium in the control of vascular tone is due to its capacity to release both vasodilating and vasoconstricting substances (1-3).
The endothelium plays a protective role as it prevents adhesion of circulating blood cells, keeps the vasculature in a dilated state and inhibits vascular smooth muscle proliferation and migration. In certain disease states, as atherosclerosis (4) or in the presence of risk factors, such as diabetes (5), smoking (6), hypercholesterolemia (7-9), aging (10), menopause (11) and hypertension (12-14) endothelial function is impaired. Endothelial dysfunction contributes to enhanced vasoconstrictor responses, adhesion of platelets and monocytes as well as proliferation and migration of vascular smooth muscle cells, all known as events occuring in atherosclerosis.
Normally the vessel wall is in a constant state of vasodilation due to the basal formation of nitric oxide by endothelial cells (15). This dominant vasorelaxing propriety of the endothelium may act as a compensatory mechanism in an attempt to limit vascular resistance. On the other hand, the vascular endothelium might be involved directly to increase peripheral resistance, via an enhanced release of constricting factors and/or a decreased release of relaxing factors (16,17).
THE PHYSIOLOGICAL FUNCTION OF THE ENDOTHELIUM
The endothelium plays an important regulatory role in the cardiovascular system by the expression of numerous molecules and the release of a myriad of substances such as nitric oxide, endothelin (ET), prostacyclin and endothelium-derived hyperpolarising factor (EDHF) making the endothelium a highly active endocrine organ. These factors are mainly vasoactive and can elicit contraction or relaxation respectively (1). Many stimuli, such as increased shear forces exerted by increased blood flow the endothelium releases nitric oxide, which is a potent vasodilator and also possesses inhibitory properties on cellular growth and migration (1-3). Furthermore nitric oxide has an anti-atherogenic and thromboresistant effect by preventing platelet aggregation and adhesion. Nitric oxide is formed from L-arginine by oxidation of its guanidine-nitrogen terminal. The catalizing enzyme nitric oxide-synthase (NOS) is constitutively expressed. Different isoforms of NOS are found in endothelial cells, platelets, macrophages, vascular smooth muscle cells and the brain (18).
Endothelins are the most potent vasoconstrictors known. They have emerged to play an important role in the pathogenesis of several cardiovascular disorders. The family of ETs consists of three closely related peptides - ET-1, ET-2, and ET-3 - which are converted by endothelin- converting enzymes (ECE) from “big endothelins” originating from large preproendothelin peptides cleaved by endopeptidases (19-22). The ET peptides are not only synthesized in vascular endothelial and smooth muscle cells, but also in neural, renal, pulmonal, and some circulatory cells holding the genes for ETs (23,24). In these tissues they act as modulators of vasomotor tone, cell proliferation and hormone production.
The chemical structure of the ETs is closely related to neurotoxins (sarafotoxins) produced by scorpions and snakes (25-27). Factors modulating the expression and release of ETs are shear-stress, epinephrine, angiotensin- II (A-II), cortisol, thrombin, inflammatory cytokines (tumor necrosis factor α, interleukin-1 and -2), transforming growth factor β and hypoxia (28-39). Prostacyclin and nitric oxide inhibit ET production via a cyclic-GMP-dependent mechanism (28). Atrial natriuretic peptide (ANP) also inhibits production of of ET-1. Under most conditions, the production of ET appears to require de novo protein synthesis. ET-1 synthesis is catalyzed by at least two ECEs, ECE-1 and ECE-2 (40,41). ETs exert their biological effects via activation of specific receptors (Fig. 1). These membrane bound receptors consist of seven transmembrane domains and are coupled to G-proteins. At present two types of ET receptors have been cloned, i.e. ETA and ETB in mammalian tissues (42,43). ET can stimulate the release and action of nitric oxide via a distinct endothelial receptor (ETB-receptor). This explains the finding that ET causes a transient vasodilation at lower concentrations, which precedes its pressor effect (2,44,45).
;)
FIG. 1.:
Endothelium derived vasoactive substances: various blood- and platelet-derived substances can activate specific receptors (open circles) on the endothelial membrane to release relaxing factors such as nitric oxide (NO), prostacyclin (PGH2) and an endotheliumderived hyperpolarizing factor (EDHF). Furthermore, contracting factors are released such as endothelin-1 (ET-1), angiotensin (A), and thromboxane A2 (TXA2) as well as prostaglandin H2 (H2). Thr=thrombin, Ach=Acetylcholine, M=muscarinic receptor, 5-HT=serotonin, O2 = superoxide, NOS = NO-synthase, cGMP = cyclic GMP, L-Arg = L-arginine (from Lüscher and Noll in Braunwald's Heart Disease 1997).
ROLE OF ACE IN ENDOTHELIAL DYSFUNCTION
Angiotensin converting enzyme (ACE) or kininase is a zinc metalloprotein that catalyzes the conversion of angiotensin-I (A-I) to the potent vasoconstrictor A-II in the Renin-Angiotensin-System (RAS). Furthermore it rapidly degrades kinins like bradykinin and therefore inactivates their vasodilative effects (46). Also the enzyme is present in the plasma, its activity is essentially tissue based and less than 10% of ACE is found in the circulating form in the plasma (47).
The effects of nitric oxide on regulation of vascular tone have been extensively studied in a variety of experimental settings. Nitric oxide inhibition can be achieved by substances such as L-NG-monomethylarginine (L-NMMA) and L-nitroargininemethylester (L-NAME) which are related to the NOS substrate L-arginine but act as competitive inhibitors of the catalizing unit of the enzyme. This inhibition causes endothelium-dependent vasoconstriction in isolated arteries (48), decrease perfusion (49,50) and induce pronounced and sustained hypertension when infused intravenously or given orally in vivo. Nitric oxide also prevents structural changes by inhibiting growth and migration of vascular smooth muscle cells. These processes can be disrupted by A-II, which impairs nitric oxide bioactivity through A-II induced production of superoxide radicals. These radicals can scavenge nitric oxide and reduce endothelium-derived vasodilation. In line with these findings, improvement of endothelial dysfunction after treatment with ACE inhibitors has been shown by several investigators (51,52).
Depending on the model of hypertension, as well as on the vascular bed studied, the extent of endotheliumdependent relaxation is not uniform. In some vascular beds of hypertensive rats such as the aorta, mesenteric, carotid and cerebral vessels, endothelium-dependent relaxation is impaired (53-60). In contrast, in coronary and renal arteries of spontaneously hypertensive rats, endothelial function does not seem to be affected by high blood pressure (61,62). In some animal models, endothelium- dependent contractions have been documented. Since cyclooxygenase inhibitors and thromboxane receptor antagonists can inhibit this response, the most likely contractile factors are thromboxane A2 and/or prostaglandin H2 (60,63).
Role of nitric oxide
Endothelium-dependent vasodilation in response to acetylcholine is impaired in patients with arterial hypertension, both in the forearm circulation, (10,13,64-72) as well as in the coronary vascular bed (73,74). Endothelium-dependent vasodilation in the human forearm and coronary vascular beds are strongly correlated (75,76).
Basal nitric oxide activity is decreased in hypertensive patients (77). Furthermore, urinary excretion of the metabolic oxidation product of nitric oxide, 15N-nitrate, after administration of 15N-labelled arginine (i.e. the substrate for the generation of nitric oxide) is reduced in hypertensive patients compared to normotensive controls (78). Thus, whole-body nitric oxide production in patients with essential hypertension is diminished under basal conditions. In line with these findings, the vasoconstrictor response to L-NMMA, an inhibitor of nitric oxide synthesis, was significantly less in hypertensive patients compared with normotensives, whereas there was no difference in the response to norepinephrine, an endothelium-independent vasoconstrictor, between hypertensives and normotensives (77,79).
Normotensive offsprings of hypertensive parents exhibit impaired endothelium-dependent vasodilation to acetylcholine (80). In parallel to manifest hypertension, in normotensive offsprings, vasoconstriction due to inhibition of nitric oxide synthesis is decreased (81). Thus, derangement of endothelial function in hypertension is likely to be caused in part by genetic factors, and not just a consequence of elevated blood pressure (although the hemodynamic factor importantly contributes) (82).
Nitric oxide plays an important role in renal function. Indeed, the kidney is extremely sensitive to nitric oxide inhibition as very low doses of L-arginine analogous, which do not affect blood pressure, diminish diuresis, natriuresis and renal plasma flow (83,84). It is possible that in some forms of hypertension, minimal alterations in the renal production of nitric oxide, which do not alter endothelium-dependent relaxations, lead to systemic hypertension due to a change in the management of body fluids by the kidney. Moreover, it has been recently shown that renal failure is also associated with an accumulation of an endogenous inhibitor of nitric oxide synthesis, asymmetrical dimethylarginine (85), which could also explain the increase in peripheral resistance and hypertension observed in these patients.
Role of endothelin
Imbalance of endothelium-derived relaxing and contracting substances disturbs the normal function of the vascular endothelium (1,86). ET acts as the natural counterpart to endothelium-derived nitric oxide (28). Besides from its arterial blood pressure rising effect in man (87,88), ET-1 induces vascular and myocardial hypertrophy (89-91), which are independent risk factors for cardiovascular morbidity and mortality (92-94). Indeed, in patients with essential hypertension, carotid wall thickening and left ventricular mass correlate with reduced endothelium-dependent vasodilation (95,96).
Whether or not ET is involved in hypertension is still controversial (97). Because of its vasoconstrictor action and its effects on vascular hypertrophy, ET-1 has also been implicated in the pathogenesis and/or the maintenance of hypertension. However, whether ET production is altered in human hypertension remains still elusive (97,98). Although few studies found increased plasma levels of ET in hypertensives, many others found no differences as compared to controls. Interestingly, patients with ET-secreting hemangioendotheliomas have huge increases in plasma ET and are hypertensive (99). Plasma ET concentrations are also elevated in women with preeclampsia (100-102). Increased ET levels in African- Americans who often present with severe and salt-sensitive (low-renin) hypertension, point to the fact that severity of the blood pressure increase as well as saltsensitivity (as suggested by the experimental models) are important denominators for the activation of the ET system in hypertension (103). Because most ET-1 synthesized in endothelial cells is secreted abluminally, it might attain a higher concentration in the vessel wall than in plasma. Indeed, significant correlations between the amount of immunoreactive ET-1 in the tunica media and blood pressure, total serum cholesterol, and number of atherosclerotic sites were found (104). In blood vessels of healthy controls, ET-1 was detectable almost exclusively in endothelial cells, whereas in patients with coronary artery disease and/or arterial hypertension, sizeable amounts of ET-1 were detectable in the tunica media of different types of arteries (104). Furthermore, there is evidence that certain gene polymorphisms of ET-1 and ET receptors could be associated with blood pressure levels (105-108). Moreover, in hypertensive patients, TAK- 044, a mixed ETA/B receptor antagonist, caused a significantly greater vasodilation than in normotensive subjects (79). Since in this study plasma levels of ET-1 were similar in normo- and hypertensive patients, increased sensitivity to endogenous ET-1 has to be postulated. Decreased bioavailability of nitric oxide may be involved in this phenomenon, since nitric oxide antagonizes some of the effects of ET-1.
THERAPY OF ENDOTHELIAL DYSFUNCTION
Endothelial dysfunction is a common feature of several pathological processes including hypertension, hyperlipidemia and atherosclerosis. Drugs that could improve endothelial function or enhance alternative pathways to substitute for alterations of the release of endothelial mediators may have a potential advantage in the treatment of these pathological conditions and therefore reduce clinical events. Several antihypertensive agents can prevent and reverse impaired endotheliumdependent relaxations in large conduit arteries (109,110) as well as in resistance arteries of hypertensive rats (111). Since diuretics, calcium antagonists, ACE inhibitors and A-II receptor antagonists improve or normalize endothelial dysfunction in hypertensive rats, the blood pressure lowering properties of these agents appear to be involved in this effect. However, additional pressure-independent effects of the various drugs cannot be ruled out.
Angiotensin-converting enzyme inhibitors
It is well established that ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death (112). In hypertensive patients, these effects also have been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial (113).
ACE is mainly located on the endothelial cell membrane where it transforms A-I into A-II and breaks down bradykinin, a potent stimulator of the L-arginine and cyclooxygenase pathways (114). Therefore, ACE inhibitors not only prevent the formation of a potent vasoconstrictor with proliferative properties, but also increases the local concentration of bradykinin and, in turn the production of nitric oxide and prostacyclin (115). This latter effect may participate in the protective effects of the ACE inhibitors by improving local blood flow and preventing platelet activation. Accordingly, pretreatment of human saphenous vein and coronary artery with an ACE inhibitor enhances endothelium-dependent relaxation to bradykinin (116,117). The decreased degradation of bradykinin could therefore explain the improved endothelial function observed with ACE inhibitors in normotensive and particularly in hypertensive rats (111,118,119).
In contrast to the striking improvements obtained in experimental models of hypertension, data of studies in hypertensive patients are still controversial. ACE inhibitors seem to improve endothelial function in subcutaneous arteries (120) epicardial arteries (51) and renal circulation (121). In the forearm circulation, on the other hand, treatment with captopril and enalapril (71) or cilazapril (122) failed to improve vasodilation to a muscarinic agonist, while lisinopril selectively improves the vasodilating response to bradykinin without restoring nitric oxide bioavailability (123). The reasons for this discrepancy between results obtained in experimental models of hypertension and studies in hypertensive patients are not clear at the present time. This discrepancy may originate from the fact that endothelial dysfunction may be treated at a much later stage in patients than in the rat. Alternatively, prolonged therapy may be required to restore the endothelial function in hypertensive patients. Interestingly, in patients with coronary artery disease 6 months treatment with the ACE-inhibitor quinapril improved endothelial function of epicardial coronary arteries (51).
Consistent with these findings the ACE inhibition with trandolapril was associated with a reduction in mortality among patients with a history of hypertension (124). The HOPE-Study demonstrated a benefit in morbidity and mortality for patients with a high cardiovascular risk profile treated with ramipril (Fig. 2) (125).
FIG. 2.:
Kaplan-Meier estimates of the composite outcome of myocardial infarction, stroke, or death from cardiovascular causes in the ramipril group. The relative risk of the composite outcome in the ramipril group as compared with the placebo group was 0.78 (95% confidence interval, 0.70-0.86).
A-II receptor antagonists
The recently developed AII-receptor antagonists (AT1- receptor blockers) may have advantages, as they are more potent inhibitors of the A-II vasoconstrictor axis than ACE inhibitors (126). These new drugs are also not associated with cough, a side effect of ACE inhibitors generally attributed to the diminished breakdown of bradykinin. However, if indeed the concomitant stimulation of the L-arginine nitric oxide pathway by bradykinin also proves to be an important property of ACE inhibitors, AII-receptor antagonists would lack this beneficial effect.
In the experimental model of A-II-induced hypertension losartan enhanced endothelial-dependent relaxation to acetylcholine and prevented the increase in tissue ET- 1 content, suggesting that AT1-receptor blockers can modulate tissue ET-1 in vivo (127). In addition, losartan also blocks the angiotensin-induced production of oxygen- derived free radicals in this model (128).
Neutral endopeptidase inhibitors
Neutral endopeptidase (NEP) is a plasma membranebound zinc metalloprotease which is widely distributed in endothelial, vascular smooth muscle cells, cardiac monocytes, renal epithelial cells, and fibroblasts (129-131). It catalyzes the degradation of a number of endogenous vasodilator peptides, including ANP, brain natriuretic peptide, C-type natriuretic peptide, substance P, and bradykinin, as well as vasoconstrictor peptides, including ET-1 (132) and A-II (129,133-136). In addition to degrading vasoactive peptides to inactive breakdown products, NEP is also involved in the enzymatic conversion of big ET-1 to its active form, the vasoconstrictor peptide ET-1. Hence, the balance of effects of NEP inhibition on vascular tone, therefore, will depend on whether the predominant substrate(s) degraded by NEP are vasodilators or vasoconstrictors and on the extent of NEP involvement in the processing of big ET-1 (132) (Fig. 3). In the human forearm circulation, however, NEP inhibitors cause vasoconstriction rather than vasodilatation indicating that under physiological conditions, vasoconstrictor peptides, such as A-II and ET-1, are more important substrates for vascular NEP than dilator substances, such as the natriuretic peptides and bradykinin (137). Indeed, although NEP inhibitors, including candoxatrilat, thiorphan and phosphoramidon, increase circulating ANP concentrations in humans and induce natriuresis, they do not generally lower blood pressure in normotensive subjects (132,138-144) In contrast, candoxatril increases blood pressure in normotensive subjects (145). In patients with essential hypertension, NEP inhibitors have been reported to lower blood pressure, (146-148) though this finding has not been universal (143,149). Accordingly, in patients with congestive heart failure, NEP inhibitors do not reduce afterload although they do reduce pulmonary capillary wedge pressure, presumably because of natriuresis (141,150).
FIG. 3.:
Neutral endopeptidase (NEP) catalyzes the metabolism of the vasoconstrictor peptides endothelin 1 (ET-1) and angiotensin II (AII), as well as the metabolism of several vasodilator peptides, including bradykinin (BK), ANP, brain and C-type natriuretic peptides (BNP and CNP, respectively), and substance P (SP). NEP is also involved in the enzymatic conversion of big ET-1 to its active form, the vasoconstrictor peptide ET-1.
As NEP inhibitors lower blood pressure more effectively in salt- and volume-dependent than in renindependent forms of hypertension (151), it has been proposed that the combination of ACE and NEP inhibition may be particularly useful in the treatment of hypertension. Co-inhibition of ACE and NEP is suggested to lower blood pressure in a broader range of conditions than inhibition of ACE or NEP alone, independent of the activity of renin-angiotensin system or the degree of salt retention (152,153). Treatment with the dual NEP/ACE inhibitor S 21402 resulted in superior antihypertensive efficacy, attenuation of cardiac hypertrophy together with a reduction in albuminuria in an animal model of diabetes in hypertension featuring both angiotensin-dependent vasoconstriction and salt retention (154). Most interestingly, omapatrilat, a potent dual inhibitor of NEP and ACE, induced long lasting, oral antihypertensive effects in low, normal, and high renin models of hypertension greater than those elicited by selective inhibition of either enzyme alone indicating that combined NEP/ACE inhibition may advance as an effective, broad spectrum antihypertensive principle (155).
CONCLUSION
Cardiovascular protection aims at preventing vascular disease and the complications associated with it. In hypertensive patients, vascular disease occurs primarily in the coronary circulation, the cerebral circulation and renal circulation. The clinical conditions associated with it are stroke, MI and renal failure. Endothelial dysfunction occurs in experimental and human hypertension and may be particularly clinically relevant if it is further aggravated by other risk factors such as hypercholesterolemia, smoking and diabetes. However, further large scale clinical trials are required to prove if reversing endothelial dysfunction offers a new therapeutical approach for the benefit of our patients with cardiovascular disease.
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