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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
ïƒ˜ Physical barriers preventing ROS generation or ROS access to important biological sites.
E.g. UV filters, cell membranes
ïƒ˜ Chemical traps / sinks 'absorb' energy and electrons quenching ROS.
E.g. Carotenoids, anthocyanidins
ïƒ˜ Catalytic systems neutralize or divert ROS.
E.g. SOD, catalase and glutathione peroxidase
ïƒ˜ Binding / inactivation of metal ion prevents generation of ROS by Haber-Weiss reaction.
E.g. Ferritin, catechins
ïƒ˜ 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 β-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).