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Diet has for years been known to play a decisive role in the development ofchronic diseases. At the end of the 20th century there has been a prominent change in food habits almost all around the world. Food consumption has changed from a traditionally plant based diet containing complex carbohydrates and dietary fibers present in vegetables, fruits and berries to a diet rich in saturated fats and simple carbohydrates i.e. a diet consisting mainly of meat and products with high energy content. Approximately 60% of total deaths reported in the world and approximately 46% of the global burden of diseases are contributed to chronic diseases (WHO, 2008). Almost half of the deaths related to chronic diseases are attributed to cardiovascular events.
Hypertension is the most extensive cardiovascular disease and with advancing age there is a greater prevalence of hypertension; for example, about half of the people between the age of 60 and 69 years are found to have hypertension and the occurrence is seen to increase beyond the age of 70 (Hoffman, 2006). Approximately one in four individuals living in the developed countries suffers from high blood pressure (BP) and of these, only 27% are receiving adequate therapy while 32% are not aware of their condition, 26% on inadequate drug therapy and the rest 15% are not on any therapy.
Patients suffering from hypertension are generally asymptomatic and treatment is normally preventive rather than palliative and thus it is often considered as a difficult condition to manage. A major challenge currently faced by most clinicians involved in reducing cardiovascular mortality and morbidity due to high BP is to pursue patients of the need to take their medications in the face of well being and if no treatment is taken timely, it can lead to serious consequences like cerebrovascular accidents, renal diseases and myocardial infarction (MI).
Hypertension is defined normally as a sustained increase in BP 140/90 mm Hg, a criterion that characterizes a group of patients whose risk of hypertension related cardiovascular disease is high enough to merit medical attention. Actually, the risk of both critical and non-critical cardiovascular disease in adults is lowest with systolic BP < than or equal to 120 mm Hg and diastolic BP < than or equal to 80 mm Hg; these risks increase progressively with higher systolic and diastolic blood pressures. Acknowledgment of this continuously increasing risk provides a simple definition of hypertension.
Although many of the clinical trials classify the severity of hypertension by diastolic pressure, progressive elevations of systolic pressure are similarly predictive of adverse cardiovascular events; at every level of diastolic pressure, risks are greater with higher levels of systolic BP. Indeed, beyond age 50 years, systolic BP predicts better outcome than diastolic BP. Systolic BP tends to rise disproportionately greater in the elderly due to decreased compliance in blood vessels associated with aging and atherosclerosis. Isolated systolic hypertension (sometimes defined as systolic BP >140 to 160 mm Hg with diastolic BP <90 mm Hg) is largely confined to people greater than 60 years of age.
Benign or essential hypertension
'Essential hypertension' is generally used to refer idiopathic or primary hypertension. Majority of patients (90%) with hypertension have no known cause, and thus fall into the category of essential hypertension. It can affect any age group and when untreated can lead to many complications, including accelerated phase hypertension.
Malignant hypertension (accelerated phase hypertension)
In 1% of patients with hypertension the situation follows an accelerated course. BP is distinctly raised (diastolic greater than 130 mm Hg) and is mainly accompanied with grade III-IV retinopathy. There can also be the possibility of rapidly deteriorating kidney functions, encephalopathy (coma, confusion, seizures and visual disturbances) and cardiac failure. The vascular lesions related to accelerated phase hypertension is fibrinoid necrosis of the walls of arteries and arterioles. The diagnosis is very poor when left untreated and almost 90% of the patients die within a year and even after adequate treatment the 5 year survival rate is only 60%.
Failure in reduction of BP to less than 140/90 mm Hg with simultaneous use of three or more drugs classifies the individual as resistant. Resistant hypertensives usually suffer from plasma volume expansion and an aggressive diuretic therapy is used to accomplish the required therapeutic result. Secondary causes are basically common in resistant hypertensives and they should be referred to a specialist to guarantee a complete diagnostic check up.
The causes of secondary hypertension are:
Drug induced hypertension
The precise cause of high blood pressure in chronic renal failure is not clear. Adequate management of hypertension is important to prevent vascular complications and prevent further deterioration of renal functions. The importance of diagnosing renovascular hypertension has increased in recent years with the introduction of angiotensin converting enzyme inhibitors (ACEI). These are to be avoided in renovascular hypertensives, as they can precipitate renal failure owing to the importance of angiotensin II in maintaining intra-renal haemodynamics in the under perfused kidney.
Hyperaldosteronism is the overproduction of aldosterone which may be due to single or multiple autonomous adrenal adenomas (Conn's syndrome) or bilateral micro nodular hyperplasia of the zona glomerulosa. Clinical suspicion of primary hyperaldosteronism is raised when untreated hypertension is associated with hypokalaemia.
Pheochromocytomas are tumors, usually found in the adrenal glands that secrete a mixture of catecholamines. They are responsible for clinical syndromes where hypertension may be episodic and alternate with episodes of postural hypotension. Paroxysms of hypertension are often associated with a constellation of symptoms, including headache, sweating, palpitations, feelings of apprehension and tremor.
Mineralocorticoid-induced hypertension with hypokalaemia and alkalosis accompanies with the use of steroids, and may occur with carbenoxolone and excessive liquorice consumption. Hypertension induced by the contraceptive pill is generally mild and reversible on stoppage of therapy, although this may take several months.
The risk of cardiovascular disease, disability, and death in hypertensive patients is also increased markedly by cigarette smoking, diabetes, or elevated low density lipoprotein (LDL). The coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to a degree that is compounded by each additional risk factor. Since the purpose of treating hypertension is to decrease cardiovascular risk, other dietary and pharmacological interventions may also be required. Pharmacological treatment of patients with hypertension associated with elevated diastolic pressure reduces morbidity and mortality from cardiovascular disease. Effective antihypertensive therapy markedly reduces the risk of stroke, cardiac failure, and renal insufficiency. However, reduction in risk of myocardial infarction may be less impressive (Walker and Tan, 2002).
PRINCIPLES OF ANTI-HYPERTENSIVE THERAPY
Non-pharmacological therapy is an important part of treatment of patients with hypertension. In some conditions, BP can be effectively controlled by a combination of weight reduction (in obese individuals), reducing sodium consumption, increasing aerobic exercise, and moderating alcohol consumption. These lifestyle changes, although difficult for many to implement, may provide beneficial control of BP in such patients.
Many randomized controlled trials have shown that a reduction in BP prevents the complications of hypertension. Early trials have shown an important improvement in the risk of stroke, but not in the reduction of coronary heart disease (CHD) events but later trials, particularly in the elderly, have shown a reduction in CHD events, even though the benefit is not as great as certain studies predicted.
Arterial pressure is the result of cardiac output and peripheral vascular resistance. Drugs lower blood pressure by its action on the peripheral resistance, cardiac output, or both. Drugs may reduce the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by action on the venous tone or on blood volume via renal effects. Drugs can decrease peripheral resistance by acting on smooth muscle to cause relaxation of the resistant vessels or by interfering with the activity of systems that produce constriction of resistance vessels (e.g., the sympathetic nervous system). Antihypertensive drugs can thus be classified according to their sites or mechanism of action. The hemodynamic consequences of long-term treatment with antihypertensive agents provide a rationale for potential complementary effects of concurrent therapy with two or more drugs. The simultaneous use of drugs with similar mechanisms of action and hemodynamic effects often produces little additional benefit. However, concurrent use of drugs from different classes is a strategy for achieving effective control of BP while minimizing dose-related adverse effects (Hoffman, 2006).
RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS)
. The RAAS participates extensively in the pathophysiology of myocardial infarction, diabetic nephropathy and congestive heart failure. This realization has led to a thorough exploration of the RAAS and the development of new ways for inhibiting its actions.
Fig. 1 Renin-Angiotensin-Aldosterone system in cardiac failure
In 1898, Tiegerstedt and Bergman established that crude saline extracts of the kidney contained a pressor substance that they named renin. Although their discovery had an evident bearing on the problem of arterial hypertension and its relation to kidney disease, the finding generated little interest until 1934, when Goldblatt and his colleagues demonstrated that constriction of the renal arteries produced persistent hypertension in dogs. Latter it was reported that renin was an enzyme (Braun-Menendez et al, 1940) that acted on a plasma protein substrate to catalyze the formation of the actual pressor material, a peptide that was named hypertensin by the former group and angiotonin by the latter. These two terms were used for 20 years until it was agreed to rename the pressor substance angiotensin and to call the plasma substrate angiotensinogen. In 1950, two forms of angiotensin were recognized, a decapeptide (angiotensin I) and an octapeptide (angiotensin II) formed by proteolytic cleavage of angiotensin I by an enzyme termed angiotensin-converting enzyme (ACE) (Jackson, 2006).
ANGIOTENSIN CONVERTING ENZYME
ACE is an ectoenzyme and glycoprotein with an apparent molecular weight of 1, 70,000. ACE present in humans contain 1277 amino acid residues and is found to have 2 homologous domains, each with a catalytic site and a Zn2+-binding region. ACE has a large amino terminal extracellular domain, a short carboxyl-terminal intracellular domain, and a 17 amino acid lipophillic region that binds the ectoenzyme to the cell membrane. ACE may lose its C-terminal end and become dissolved in plasma as circulating ACE and is found mainly in the lungs due to their vast surface of vascular endothelium. ACE is also present in other vascular tissues other than endothelium; such as smooth muscle cells the heart fibroblasts, the kidney, CNS, placenta and testis. ACE is a polyspecific enzyme metabolizing angiotensin, angiotensin 1-7, enkephalins, substance P and luteinizing hormone-releasing hormone (LH-RH).
Fig. 2 Formation of angiotensins I-IV from the N-terminal of the precursor protein angiotensinogen.
ACE is rather nonspecific and cleaves di-peptide unit from substrate with different amino acid sequence and these substrates should have only 1 free carboxyl group in the C-terminal of amino acid and proline must not be the penultimate amino acid, thus the enzyme does not degrade angiotensin II. ACE is very much similar to kininase II, an enzyme that degrades various potent vasodilator peptides and bradykinin. Even though, the conversion of angiotensin I into angiotensin II that occurs in plasma is slow, a very rapid conversion is seen in vivo due to the presence of membrane bound ACE on the luminal surface of the endothelial cells throughout the vascular system.
The circulating form of angiotensin II regulates systemic blood flow and pressure. The local or tissue formation of angiotensin II ensures the local control of blood flow independently of blood-borne angiotensin II e.g. inside the brain and in the eye. An intracellular form of angiotensin II has recently been discovered (Kumar et al., 2007) and this makes RAAS not only an endocrine, but also a paracrine and intracrine system. Angiotensin II functions as a potent vasoconstrictor and also causes cell growth (hypertrophy of smooth muscle cells) and impairs learning and memory functions.
ROLE OF ACE INHIBITORS IN HYPERTENSION
Inhibition of ACE decreases the vascular resistance as well as the mean systolic and diastolic BP in a number of diverse hypertensive states. The effects are observed readily in animal models of renal and genetic hypertension. In human subjects with hypertension, ACE inhibitors commonly lower blood pressure, except when high blood pressure is due to primary aldosteronism. The initial change in blood pressure tends to be positively correlated with plasma renin activity (PRA) and angiotensin II plasma levels prior to treatment. However, after several weeks of treatment patients show a sizable reduction in blood pressure and the antihypertensive effect then correlates poorly or not at all with pretreatment values of PRA. It is possible that increased local (tissue) production of angiotensin II and/or increased responsiveness of tissues to normal levels of angiotensin II in some hypertensive patients make them sensitive to ACE inhibitors despite normal PRA. Regardless of the mechanisms, ACE inhibitors have broad clinical utility as antihypertensive agents (Ingrid, 2009)
The long-term fall in systemic blood pressure observed in hypertensive individuals treated with ACE inhibitors is accompanied by a leftward shift in the renal pressure-natriuresis curve and a reduction in total peripheral resistance in which there is variable participation by different vascular beds. The kidney is a notable exception to this variability because increased renal blood flow owing to vasodilation is a relatively constant finding. This is not unexpected because the renal vessels are remarkably sensitive to the vasoconstrictor actions of angiotensin II. Increased renal blood flow occurs without an increase in glomerular filtration rate and thus the filtration fraction is reduced.
Besides causing systemic arteriolar dilatation, ACE inhibitors increase the compliance of large arteries, which contributes to a reduction of systolic pressure. Cardiac function in patients with uncomplicated hypertension generally is little changed, although stroke volume and cardiac output may increase slightly with sustained treatment.
Fig. 3 The active site of angiotensin-converting enzyme.
Baroreceptor function and cardiovascular reflexes are not compromised, and responses to postural changes and exercise are little impaired. Surprisingly, even when a substantial lowering of blood pressure is achieved, heart rate and concentration of catecholamine in plasma generally increases only slightly, this perhaps reflects an alteration of baroreceptor function with increased arterial compliance and the loss of the normal tonic influence of angiotensin II on the sympathetic nervous system.
Aldosterone secretion in the general population of hypertensive individuals is reduced, but not seriously impaired, by ACE inhibitors. Aldosterone secretion is maintained at adequate levels by other steroidogenic stimuli, such as adrenocorticotropic hormone and K+. The activity of these secretogogues on the zona glomerulosa of the adrenal cortex requires, at most, only very small trophic or permissive amounts of angiotensin II, which always are present because ACE inhibition is never complete. Excessive retention of K+ is encountered only in patients taking supplemental K+, in patients with renal impairment, or in patients taking other medications that reduce K+ excretion.
ACE inhibitors alone can normalize BP in about 50% of the patients with moderate to mild hypertension, but when used in combination with a Ca2+ channel blocker, Î±-adrenergic receptor blocker, or a diuretic was found to control 90% of the hypertension in the patients. Diuretic in particular can increase the antihypertensive effect of ACE inhibitors by rendering the patients BP renin dependent (Jackson, 2006).
There is increasing evidence that ACE inhibitors are superior to other antihypertensive drugs in hypertensive patients with diabetes, in whom they improve endothelial function and reduce cardiovascular events more so than Ca2+ channel blockers or diuretics and Î±- adrenergic receptor antagonists (Jackson, 2006).
FREE RADICALS AND CARDIOVASCULAR DISEASES
Free radicals like reactive nitrogen species (RNS) and reactive oxygen species (ROS) plays twin roles, as both deleterious and beneficial agents. ROS and RNS are generally generated by tightly regulated enzymes like NO synthase (NOS) and Nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) oxidase isoforms, respectively. Overproduction of ROS, arising from mitochondrial electron transport chain or by excessive stimulation of NADPH results in oxidative stress, is a deleterious process that can act as an important mediator of damage to cell constituents like lipid membranes, proteins and DNA. In disparity, positive effects of ROS/RNS (e.g. O2
and nitric oxide (NO)) occur at very low concentration and promote vital physiological roles in various cellular responses. Thus ROS-mediated actions virtually protect cells from ROS-induced oxidative stress and reinstate or sustain "redox balance" also termed as "redox homeostasis" (Valkoa et al., 2006).
The ROS induced oxidative stress in cardiac and vascular myocytes has been linked with cardiovascular tissue injury. Regardless of the direct evidence for a link between oxidative stress and cardiovascular disease, ROS-induced oxidative stress plays a role in various cardiovascular diseases such as cardiac hypertrophy, cardiomyopathies, ischemic heart diseases, congestive heart failure and hypertension. However, there is general consensus that ROS play a role, mediating oxidative damage to target organs, decreasing NO bioavailability, and giving rise to endothelial dysfunction. It has also been found that in some disease conditions angiotensin-II play an important role in the formation of free radicals; e.g. angiotensin-II induced superoxide release via statin-sensitive Rac2 isoprenylation plays a key role in the impairment of Ca2+ transport in neutrophils of hemodialyzed patients (Seres et al.,2008).
To maintain homeostasis of the vascular wall, a balance between the endogenous transmitter's angiotensin II, NO, and ROS is of great value. Angiotensin II, NO and ROS are important participators in the pathogenetic mechanisms of cardiovascular diseases. It has been clearly noted that hypertension caused by chronically increased levels of angiotensin II is mediated in part by superoxide ions (O2-) and hypertension is a major risk factor for renal failure, cerebrovascular disease, coronary artery disease, peripheral vascular disease and congestive heart failure. This suggests that cardiovascular diseases caused by increased levels of angiotensin II are found to be mediated by vasoconstriction and thus decreased concentration of vascular NO seems to promote the angiotensin II dependent cardiovascular diseases (deGasparo, 2002). Angiotensin II acting through angiotensin-1 receptors (AT1) mediates vasoconstriction and stimulates membrane bound NADPH oxidase causing accumulation of ROS. Angiotensin II acting on angiotensin-2 receptors (AT2), increases the level of NO which scavenges ROS in turn consuming NO and blocking the beneficial properties of NO (Doughan et al., 2008). Accumulation of ROS stimulates mitogen activated protein (MAP) kinases which promote cell growth and cell proliferation. The angiotensin receptors AT1 and AT2 with their physiologically antagonistic effects maintain the balance between NO and ROS. It is proposed that stimulation of AT1 receptors by increased circulating or tissue levels of angiotensin II will stimulate cell growth, cell proliferation, affect homeostasis of the vascular wall and give rise to inflammation and cardiovascular diseases (deGasparo, 2002). ACE is a key enzyme involved in the formation of the physiological antagonists angiotensin II and NO (Ingrid, 2002).
A free radical may be defined as any atom, group of atoms or molecule having one or more unpaired electrons in its outermost orbital and are capable of independent existence. They are typically unstable and highly reactive. A free radical is formed when a covalent bond between molecules is broken and the corresponding electron remains with the newly formed atom.
Free radicals are extremely reactive due to the presence of unpaired electrons as it gives the molecule a considerable degree of reactivity and once formed they act as highly reactive radicals capable of chain reactions.
Fig. 4 Free radical formation
Any free radical having oxygen can be referred to as a ROS. Oxygen centered free radical species hold 2 unpaired electrons in the outer shell. When free radicals capture an electron from the neighboring compound or molecule a new free radical is formed and this reaction proceeds as a chain reaction until the free radicals are all neutralised (Wijk et al., 2008).
Causes of free radicals Formation
Food preservatives and pesticides
MECHANISM OF ACTION OF FREE RADICALS OR ROS FORMATION
Oxygen in the atmosphere has two unpaired electrons and these unpaired electrons have parallel spins and it is considered to be in a ground (inactive) state. Oxygen is normally non reactive to organic molecules that have paired electrons with opposite spin, but can be activated to singlet excited (active) state by two mechanisms.
Absorption of adequate energy to reverse the spin on one of the unpaired electrons.
Monovalent reduction (accept a single electron)
Superoxide is formed during the monovalent reduction reaction which further gets reduced to form H2O2. H2O2 then in the presence of ferrous salts (Fe2+) gets reduced to hydroxyl radicals. This reaction was initially described by Fenton and later developed by Haber and Weiss (Daniel et al., 1998).
The term oxidative stress is defined as a shift in the balance between the pro oxidants and antioxidants towards pro oxidants that occurs as a result of increase in oxidative metabolism. The improper balance between ROS production and antioxidant defenses results in oxidative stress. Its increase at cellular level can come as a consequence of several factors, including exposure to alcohol, cold, medication, trauma, infections, toxins, radiation, strenuous physical activity, and poor diet (Ray and Hussain, 2002).
Fig. 5 Free radical and Oxidative stress.
Oxidative stress is assumed to play a vital role in the development of hypertension. The accurate mechanisms related to the role of oxidative stress and hypertension remains to be elucidated. However, there is a common consensus that ROS play an important role in mediating oxidative damage to various organs by decreasing NO bioavailability and causing endothelial dysfunction.
Proof that hypertension is a condition of oxidative stress is derived from a wide range of sources and it is found that hypertensive subjects are observed to have elevated levels of superoxide, H2O2, lipid peroxides and decreased superoxide dismutase (SOD) and vitamin E when compared with normotensive controls. These patients have a significant relationship between plasma H2O2 production and BP.
Treatment with an ACE inhibitor, AT2 blocker, or calcium antagonist has been shown to reduce nonspecific markers of oxidative stress. Angiotensin II is known to induce superoxide radical production, and blocking its formation via either an ACE inhibitor or an AT2 antagonist would represent a possible mechanism for their antioxidant activity.
Antioxidants are any substance, present at lower concentration compared to that of oxidizable substance that delay or inhibits oxidative damage to a target molecule. Antioxidants defuse the free radicals by donating their electrons and thus putting an end to the carbon stealing property of the free radical. They work as scavengers and thus prevent cell and tissue damage that can lead to cellular injury and disease. They are agents that protect other vital chemicals and macro molecules of the body from oxidation reactions by reacting with free radicals and other ROS within the body. One antioxidant molecule can only react with single free radical and hence there is a constant necessity to replenish antioxidant reserves either endogenously or through dietary supplements.
Fig. 6 Balance of Antioxidant and ROS In vivo
The body has developed numerous endogenous antioxidant systems to combat the production of reactive oxygen intermediates (ROI). These systems can be broadly divided into:
Non - Enzymatic. Fig 7 shows the antioxidant system.
Fig. 7 Antioxidant system
Superoxide Dismutase (SOD)
SODs are a family of metalloenzymes that converts superoxide to hydrogen peroxide (H2O2) and are mainly the primary line of protection against oxygen toxicity. Basically three isoforms of the enzyme have been discovered. The first is mainly found in the cytoplasm of cells and it containing Cu and Zn at its active site (Cu/Zn SOD-1), the second containing Mn at its active site is located in mitochondria (Mn SOD-2) and the third (Cu/Zn SOD-3) is present in the extracellular fluid like plasma. SOD is a stress protein which is synthesized mostly in response to oxidative stress. It is found that little amount of Cu, Zn and Mn metals are crucial for maintaining the antioxidant activity of SOD (Ray and Husain, 2002).
Glutathione Peroxidase (GPx)
GPx is one of the important enzymes responsible for the degradation of H2O2 and organic peroxides in the brain. GPx catalyse the oxidation of glutathione into its oxidized form (GSSG) at the expense of H2O2. Two isoforms have been identified; selenium-dependent GPx which is highly active towards H2O2 and organic hydroperoxides and selenium independent GPx. GPx activity is found to be less in selenium deficiency.
It is a heme-containing protein present in some cells. Catalase is 104 times faster than GPx and it consists of four protein subunits, each containing a heme fe(III)-protoporphyrin group bound to its active site (Ray and Husain, 2002).
MECHANISM OF ACTION OF ANTIOXIDANTS
They mainly act as
Ø Physical barriers preventing ROS generation or ROS access to important biological sites.
E.g. UV filters, cell membranes
Ø Chemical traps / sinks absorb energy and electrons quenching ROS.
E.g. Carotenoids, anthocyanidins
Ø Catalytic systems neutralize or divert ROS.
E.g. SOD, catalase and glutathione peroxidase
Ø Binding / inactivation of metal ion prevents generation of ROS by Haber-Weiss reaction.
E.g. Ferritin, catechins
Ø Sacrificial and chain propagation inhibitor antioxidants scavenge and destroy ROS.
E.g. Ascorbic acid (Vit.C), tocopherols (Vit E), uric acid, glutathione, flavonoids (Benzie, 2003).
ALTERNATE MEDICINES FOR TREATMENT OF HYPERTENSION
Various food habits are known to contribute to the development of chronic diseases and it is a clear that the consumption of vegetables, fruits and berries reduce the risk of development of CV diseases which is one of the leading causes of death in the world. To maintain homeostasis of the vascular wall, the balance between angiotensin II, NO and ROS is of great importance.
Angiotensin II a strong vasoconstrictor causing cell growth and NO a signalling molecule influencing the vascular system as a vasodilatator inhibiting cell proliferation and ROS are linked together in the RAAS. ACE in the RAAS convert angiotensin I to form angiotensin II and NO is known to inhibit ACE and act as a scavenger of ROS.
Although many synthetic ACE inhibitors in the market significantly reduce the elevated BP, their extended use is usually accompanied by adverse side effects. In addition, most ACE inhibitory drugs are to be avoided during the pregnancy period as it can cause potential harm to the fetus. Therefore, it is highly essential that new therapeutic agents to combat hypertension are derived.
ACE inhibitory peptides derived by proteolytic digestion of proteins from various sources like milk, fish and plants are being sought after for commercial use as they are safer and cheaper. Plant derived substances such as flavonoids, tocopherols and carotenoids, phenolics, anthocyanins have shown beneficial effects on the cardiovascular system due to their antioxidative effects.
Flavonoids and Î²-carotene inter relate with the cardiovascular system in several ways, by reducing reactive oxygen species, increasing nitric oxide concentrations and also by inhibiting angiotensin-converting enzyme activity. Infusions and extracts as tea containing high amounts of flavonoids function as ACE inhibitors.
ACE contains two zink-dependent catalytic domains and ACE inhibitors are designed to bind to the Zn2+ at the active site. If the inhibitory mechanism of flavonoids on ACE activity is due to their ability to bind to Zn2+ ions then it would be possible for the flavonoids to also inhibit other zinc metallopeptidases, i.e. endothelin-converting enzyme, matrix metallopeptidases, neutral endopeptidase and maybe insulin-degrading enzyme, thereby exerting several additional positive effects on the cardiovascular system (Ingrid, 2002).
An intake of 400-500 gram of vegetables (apart from potatoes), fruits, berries and green leaves per day is said to reduce the risk of development of stroke, coronary heart diseases and high BP. Only a very small and negligible minority of the world population consumes this recommended intake of vegetables, fruits and berries (WHO, 2008).