Metabolism to Prostaglandins
The first and rate-limiting step in the metabolism of essential fatty acids to biologically active cellular modulators is controlled by the enzyme D6D. This enzyme activity declines with age (Horrobin 1981), inhibits the synthesis of GLA and DHA, and leads to a prostaglandin imbalance characterized by a decline of the (good) series-1 and series-3 prostaglandins, which exhibit potent anti-inflammatory effects. The diminished capacity to convert EFAs to GLA and DHA is associated with cardiovascular disease and diabetes (Bolton-Smith et al. 1997; Horrobin 19 98 83 ).
Supplementation with GLA and DHA can circumvent impaired D6D function by increasing D6D activity, thus reversing the effect of aging on the enzyme (Biagi et al. 1991). GLA supplementation improves metabolism of omega-6 and omega-3 fatty acids. DHA and EPA limit the production of series-2 prostaglandins by preventing release of arachidonic acid from cell membranes. This inhibits further metabolism of arachidonic acid into inflammatory prostaglandins. High dietary linoleic acid (omega-6) limits the availability of alpha-linolenic acid (omega-3) as a precursor for the series-3 prostaglandins and stimulates the release from membranes of arachidonic acid, the precursor to (series-2) prostaglandins and other pro-inflammatory eicosanoids.
Prostaglandin E1 relaxes blood vessels, improving circulation, lowering blood pressure and reducing inflammation. GLA increases this beneficial prostaglandin. Prostaglandin E2 promotes sodium retention by the kidney, leading to water retention and inflammation. Diets high in saturated fats (and therefore arachidonic acid) increase levels of inflammatory E2 prostaglandins. Prostaglandin E3 functions similar to prostaglandin E1. Omega-3 fatty acids generate the E3 series.
Old animals show a clear decline in delta-6-desaturated metabolites of the omega-6 and the omega-3 series (Biagi et al. 1991). Animals fed GLA show no decline. Aging influences the fatty acid composition of adipose tissue independent of diet (Bolton-Smith et al. 1997). This confirms the age-related decline in delta-6-desaturation. GLA and DHA lower blood pressure and cardiovascular reactions to stress. Beneficial effects of both GLA and DHA on hypertension have been documented in human studies that show a moderate but consistent effect in lowering blood pressure and insulin resistance.
Systolic blood pressure increases with aging as a result of increased stiffness of the arteries. Venter et al. (1988) hypothesized that a deficiency of D6D with aging is important in the etiology of essential hypertension. One group of patients with mild-moderate essential hypertension was given 360 mg GLA and 180 mg EPA per day, while the other group received only linoleic acid and alpha-linolenic acid (the parent EFAs that require D6D for metabolism to GLA and EPA/DHA). Systolic blood pressure in the first group was reduced (~ 10%) after 8-12 weeks, while no significant change occurred in the second group, indicating that deficiency of the enzyme D6D can promote hypertension.
Aldosterone plays a key role in hypertension, and aldosterone-reducing drugs are used in the treatment of hypertension (Weber 1999; Oates and Brown 2001). Primary aldosteronism is usually regarded as a rare cause of hypertension (<1%), but some investigators have found that 10% to 15% of patients with essential hypertension had aldosteronism (Fardella et al. 1999 2000 ). Borage oil (23% GLA) and DHA lower blood pressure in hypertensive, normotensive, old and young rats (Engler et al. 1992, 1993). In rats genetically programmed for hypertension (Engler et al. 1998, 1999), EFAs modulate the renin-angiotensin-aldosterone system. GLA and DHA inhibit aldosterone release or production. DHA lowered aldosterone (33%), compared to animals fed corn/soybean oil.
A remarkable reduction of the systolic blood pressure was seen. Borage oil (GLA) feeding decreased blood pressure by 12 mmHg after three weeks, and DHA lowered blood pressure by 34 mmHg after six weeks. These studies suggest that borage oil inhibits the adrenal responsiveness to angiotensin II through diminished angiotensin receptor activity in aldosterone producing cells. DHA supplementation could prevent the increase in blood pressure in rats genetically programmed to develop hypertension (Kimura et al. 1995).
In clinical trials on humans (Mori et al. 1999), DHA had lowered blood pressure and heart rate. These results also show that DHA, rather than EPA, is the principal omega-3 fatty acid responsible for the beneficial effects on the cardiovascular system and hypertension. The beneficial effects of the omega-3 fatty acids EPA and DHA had previously been attributed mainly to EPA because of its predominance in fish oil. DHA is the more important of the two. DHA has consistently proven to be more effective than EPA in lowering blood pressure in mildly hypertensive men (Prisco et al. 1998).Genetic Mechanisms
A fundamental mechanism for the regulation of fat metabolism in the body involves the interaction of EFAs with nuclear receptors and transcription factors called peroxisome proliferator-activated receptors (PPARs). PPARs have been identified as nuclear hormone receptors, linking metabolism and gene expression. PPARs are transcription factors that regulate the expression of genes involved in fatty acid metabolism (Wahli et al. 1999). Polyunsaturated fatty acids, particularly EFAs and their metabolites, biologically interact with PPARs, binding to and activating these nuclear receptors. The anti-diabetic drugs, including the glitazones or thiazolidinediones, act similarly as PPAR ligands. Forman et al. (1997) discovered that GLA, DHA and other EFAs are efficient activators of PPARs. To activate gene transcription, PPARs must combine with the retinoic X receptor. DHA has been found to directly bind to PPARs and is an RXR-activating factor (de Urquiza M et al. 2000).Membrane Biochemistry
To understand the biological significance of the essential fatty acids (EFAs), polyunsaturated fatty acids (PUFAs), saturated and trans -fatty acids, one needs to visualize how these fats are stored and used in our cells at the molecular level. This following technical section will detail several points:
1. Each fatty acid (FA) is structurally different; can be metabolized into potent modulators of inflammation, immunity, and coagulation that reflect these subtle structural differences; and thus, can skew the resultant biological effects (for example, from pro-inflammatory to anti-inflammatory). The enzymes that act upon these different FAs are not entirely selective.
2. The source of these FAs is dependent upon the kinds of dietary FAs one has ingested over the last many months to years. In other words, if your diet is skewed to a high saturated and omega-6 FA (soybean) intake, as is the typical American diet, there is a huge buffer of these FAs bound to cell membranes and triglycerides (TGs). These FAs are released in response to various signals that 'activate' the vascular endothelial cells or vascular smooth muscle cells and modulate the responses to these signals (such as angiotensin II or adrenaline). When the cell is stimulated, a mixture of FAs is released for conversion into prostaglandins, thromboxanes, and leukotrienes. The physiological actions exerted by these compounds on inflammation, coagulation, and immune function, respectively, are thus related to the structure of original FA.
3. While these FAs are stored in the cell membrane they influence the fluidity of the membrane, alter the interactions of surface proteins within that membrane, and undergo various degrees of peroxidation, depending upon the degree of desaturation and the status of such antioxidant vitamins as vitamin E, coenzyme Q10, and other detoxifying systems.
4. Some of the EFAs are now known to exert direct actions on the genome, influencing the synthesis of new proteins and enzymes by their presence (Wahli et al. 1999; Forman et al. 1997; de Urquiza et al. 2000). For these reasons, dietary changes may take many months to years to reveal their beneficial effects. Consequently, it can take a long time for a diet supplemented with a greater percentage of omega-3 FAs to displace the excess of omega-6 FAs from binding sites in cell membranes. (Soybean oil is 54 % linoleic acid, an omega-6 FA, with some arachidonic acid.).
Biochemically, membranes are composed of TGs containing three FAs esterified to a glycerol backbone. Glycerol is a simple three-carbon chain with alcohol moieties attached to each of three carbon atoms. FAs and EFAs are long-chained hydrocarbons (n = 16-20) with carboxylic acid moieties (or chemical functional groups) at one end. Esterification of these weak (carboxylic) FAs with glycerol creates a TG that is fat soluble. It is stored within (fatty) cellular membranes (and adipose tissue). The PUFAs, including the omega-3 and omega-6 FAs are also linked to the TGs. When a hormone (adrenaline) stimulates the (endothelial) cell, it triggers a reaction inside the cell that allows enzymes (like phospholipase A 2 ) to cleave FAs from the TGs, leaving a diglyceride and, ideally an omega-3 EFA.
The free PUFA or EFA then is acted upon by other enzymes which convert it into prostaglandins, thromboxanes or leukotrienes of various classes. The class of cellular mediator created is determined by the starting FA. Omega-3 precursors like DHA and EPA lead to slightly (chemically) different prostaglandins, thromboxanes, and leukotrienes then the omega-6 precursors, arachidonic acid or other PUFAs (that are not essential). Whichever FA is released determines the biological effects of the final metabolite. Some prostaglandins are pro-inflammatory (series-2), others are anti-inflammatory (series 1 and 3); some of the thromboxane series promote platelet aggregation and vasoconstriction (A2), whereas others do not; some of the leukotrienes (B4) induce inflammation, chemotaxis, and adherence.
The point is, that our cell membranes are currently overloaded with either saturated fatty acids or omega-6 fatty acids rather than omega-3 fatty acids. When these endothelial or vascular cells are chronically stimulated, mediators are released that often favor vascular and endothelial cell responses that are more inflammatory and vasoconstrictive. This causes a predisposition to hypertension and other cardiovascular diseases (Simopoulos 1999; Brown and Hu 2001).
The literature is confounded with favorable in vitro findings for many of the EFAs that are not being reproduced in vivo. This probably results from the fact that it takes many months and/or years to shift the ratio of EFAs back to that resulting from a natural diet, that is, a much lower saturated or omega-6/omega-3 ratio. The composition of the FAs in the cell membrane determines the fluidity of the membrane, the positioning of proteins embedded in the membrane, and the interaction between these proteins in response to hormones.
It can be hypothesized that sodium intake might modulate responses of aldosterone to angiotensin II, or adversely effect the microvasculature (see discussion on Environmental Factors, sodium ). Cellular membranes containing a higher percentage of EFAs or PUFAs are more prone to free radical attack and peroxidation. Increased levels of antioxidants are needed to counteract this effect because a badly peroxidized membrane will compromise the function of cellular proteins and hormone-receptor interactions occurring in those membranes. Peroxidized EFAs and PUFAs irreversibly (covalently) bond with these proteins, destroying their function and promoting cell death. Vitamin E and coenzyme Q10 are particularly useful because of known functions as free-radical trapping agents, membrane stabilizers, and antioxidants.Stress
Repeated exposure to stress is a risk factor for hypertension. Elevated levels of stress hormones (catecholamines and glucocorticoids) inhibit the activity of D6D. DHA intake prevents mental stress (Hamazaki et al. 1996; Sawazaki et al. 1999). DHA (1.5 g/day) reduced levels of norepinephrine (-31%), which benefits hypertension (Singer et al. 1990; Christensen et al. 1994). However, dietary omega-6 and omega-3 fatty acids reduced the cardiovascular reaction to stress (Mills et al. 1985, 1986). Both GLA and DHA reduce blood pressure and heart rate responses to stress in humans. Borage oil (GLA) significantly reduced stress-induced rises in systolic blood pressure and heart rate, whereas, fish oil (EPA, DHA) was without effect. Borage oil reduces cardiovascular reactions to many stressors. We need a sufficient amount of EFAs in a balanced proportion.Endocrine Correlates
Insulin resistance is strongly linked to type-2 diabetes, obesity, hypertension, and heart disease. Insulin resistance is found in approximately 25% of healthy humans. Insulin resistance is characterized by cells that are desensitized to insulin that otherwise normally take up glucose. To compensate for higher levels of circulating glucose, insulin production increases. Elevated glucose leads to diabetes and degenerative complications in the vasculature.
GLA and DHA improve insulin sensitivity. Dietary intake of EFAs increases the proportion of unsaturated fatty acids in phospholipid (cellular) membranes, making the cell more insulin sensitive (Storlien et al. 1986, 1987; Borkman et al. 1993; Vessby et al. 1994; Pan et al. 1995; Storlien et al. 1996). Scientists now understand the mechanisms of EFAs on insulin resistance.
Recently developed drugs, called glitazones or thiazolidinediones that bind to and activate PPAR, increase insulin sensitivity. We now know that GLA and DHA, and certain other essential fatty acids, work in the same way by binding to and activating PPARs. It is possible to hypothesize that the different responses noted to sodium intake in hypertensive patients may be related to subtle differences in gene transcription that relate to altered proportions of EFAs in tissue membranes.Dietary Fats
Hydrogenation is a common way of changing natural oils to more solid fats with longer shelf life but profoundly altered biochemical properties. Double bonds are either saturated or switched from cis - to trans -configuration. Trans -fatty acids act as antagonists to essential fatty acids and interfere with the production of good prostaglandins. Partially hydrogenated products rich in trans -fatty acids are margarines, shortenings and hydrogenated oils. We need to reduce the intake of omega-6 oils, except GLA, and increase omega-3 fatty acids, particularly DHA. Cold-water fish, nuts and seeds provide a balanced mix of omega-3 and omega-6 fatty acids.Homocysteine
Homocysteine is a substance that is worse than cholesterol (Braverman 1987; McCully 1996). Homocysteine damages the artery and is now widely recognized by scientists as the single greatest biochemical risk factor for heart disease. Homocysteine may be a participant in 90% of cardiovascular problems. Two pathways detoxify homocysteine: the remethylation pathway and the trans -sulfuration pathway. If homocysteine is not detoxified, plaque builds up in the endothelial cells lining the arteries. Homocysteine speeds the oxidation of cholesterol, and then macrophages take up the particles to become foam cells in plaque (Naruszewicz et al. 1994; Cranton et al. 2001). Homocysteine plays a key role in every pathophysiologic process that leads to arteriosclerotic plaque (McCully 1996).
Homocysteine promotes coagulation factors, favoring clot formation (Magott 1998). About 40% of all stroke victims have elevated homocysteine levels compared to only 6% of controls (Brattstrom et al. 1992). Elevations in homocysteine with peripheral vascular disease (28%) have been reported (Clarke et al. 1991). Hyperhomocysteinemia encourages smooth muscle cell proliferation (Magott 1998; Sandrick 2000). Homocysteine blocks production of nitric oxide, causing vessels to become less pliable and more susceptible to plaque buildup (Boger et al. 2000). Vessels lose their expansion capacities as homocysteine reduces nitric oxide's availability (Tawakol et al. 2002). Homocysteine significantly hampers microvascular circulation by impairing dilation functions. Nitric oxide (also known as endothelium-derived relaxing factor) normally protects endothelial cells from damage by reacting with homocysteine, forming S-nitrosohomocysteine, which inhibits hydrogen peroxide formation.
However, as homocysteine levels increase, this protective mechanism becomes overloaded, allowing damage to the endothelial cells to occur (Stamler et al. 1992, 1993, 1996). Homocysteine activates genes in blood vessels, encouraging the coagulation process and the proliferation of smooth muscle cells (Outinen et al. 1999). Based on a random testing of 600 hospitalized elderly patients, researchers found evidence of hyperhomocysteinemia in over 60% of those with serious chronic conditions: 70% presented with vascular disease (Ventura et al. 2001). The use of drugs (particularly diuretics), and malnutrition were suspected as causes of age-related hyperhomocysteinemia. Homocysteine levels should be kept below 7 micromoles/L, however, laboratories regard levels up to 15 micromoles/L as normal, while epidemiological data reveal that homocysteine levels above 6.3 reflect a steep, progressive increase in the risk of a heart attack (Robinson et al. 1995). The incidence of hypertension and peripheral vascular disease escalates as homocysteine levels increase.
Homocysteine is a significant biochemical risk factor for heart disease (McCully 1996). A combination of folic acid, vitamin B12, and pyridoxine reduced homocysteine levels (Schnyder et al. 2001). Pretreatment with 800 IU of vitamin E and 1000 mg of C (before an oral methionine load to experimentally produce homocysteine) blocked the damaging effects of hyperhomocysteinemia (Kumar and Das 1993). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone but not after methionine ingestion with vitamins (Nappo et al. 1999). Medications to treat congestive heart failure commonly result in multiple B vitamin deficiencies, disrupting metabolism of homocysteine (Sinatra 2001).C-Reactive Protein (CRP)
CRP is a marker for systemic inflammation. CRP levels indicate chronic low-grade inflammation, with linkage to blood vessel damage and vascular disease (Pasceri et al. 2000). When CRP levels are factored in along with hypertension, there is significant improvement in predicting cardiac health. CRP is more than a measurable antecedent preceding a cardiac problem. CRP acts directly upon the blood vessels to activate adhesion molecules in endothelial cells: the intercellular adhesion molecule (ICAM-1) and the vascular cell adhesion molecule (VCAM-1). VCAM-1 may be an early molecular marker of lesion-prone areas to experimental hypercholesterolemia. CRP appears intricately involved in the inflammatory process, a target for the treatment of atherosclerosis (Pasceri et al. 2000).Neurophysiology
The primary neurophysiological component of hypertension includes the autonomic nervous system. Although both the parasympathetic and sympathetic nervous systems participate in the acute regulation of blood pressure, the sympathetic nervous system component is dominant and particularly involved in situations requiring rapid elevations of blood pressure through the release of norepinephrine. Sympathetic nervous system activity also stimulates adrenal release of adrenaline (epinephrine), which via beta-receptors in the heart and kidney, increases cardiac output and release of angiotensin II, respectively. Drugs that are effective in controlling hypertensive vascular disease are described in the Pharmacology section in detail, but generally include agents that block beta-receptors (heart, kidney) and alpha-receptors (peripheral vasculature).Continued
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