Inhibition of ACE decreases the systemic vascular resistance and mean, diastolic, and systolic blood pressures 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).
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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 never is 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 blood pressure in approximately 50% of patients with mild to moderate hypertension. Ninety percent of patients with mild to moderate hypertension will be controlled by the combination of an ACE inhibitor and either a Ca2+ channel blocker, Î±-adrenergic receptor blocker, or a diuretic. Diuretics in particular augment the antihypertensive response to ACE inhibitors by rendering the patient's blood pressure 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 radical species like reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a twin role 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, a deleterious process that can be an important mediator of damage to cell structures, including lipids 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).
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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 atherosclerosis, ischemic heart disease, hypertension, cardiomyopathies, cardiac hypertrophy and congestive heart failure. However, there is general consensus that reactive oxygen species play a role, mediating oxidative damage to target organs, decreasing nitric oxide 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 coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease and renal 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 containing 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 electron 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 reactive oxygen species (ROS). Oxygen centered free radicals hold two unpaired electrons in the outer shell. When free radicals capture an electron from the neighboring compound or molecule a new free radical is formed in its place (Wijk et al., 2008).
Causes of free radicals Formation
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MECHANISM OF ACTION OF FREE RADICALS OR ROS FORMATION
Oxygen in the atmosphere has two unpaired electrons and these unpaired electrons have parallel spins. Oxygen is usually non reactive to organic molecules that have paired electrons with opposite spins. This oxygen is considered to be in a ground (inactive) state and is activated to a singlet (active) state by two different mechanisms.
Absorption of sufficient 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).
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