Reprinted with permission of Life Extension®.
- Anatomy and Physiology
- Pharmacology and Toxicology
- Nutritional Therapy
- Functional Medicine
- Scientific Summary
- General Precautions
Hypertension (high blood pressure) is the primary and most important manifesting symptom of hypertensive vascular disease. A diseased vasculature predisposes one to further hypertension, and thus, further vascular disease. Hypertension often progresses with the development of various diseases involving the circulatory system, such as arteriosclerosis, atherosclerosis, coronary heart disease, congestive heart failure, and disorders of coagulation (stroke, hemorrhage, heart attack), immunity (inflammation, infection), and diabetes. All of these disorders are both causative and secondary to the development of hypertension.
The purpose of this discussion is to ultimately substantiate and provide a protocol that can be followed that will prevent the development of hypertension, and thus, the development of hypertensive vascular disease and its subsequent and allied disease states. Protocols have been described in other sections of this book that concern the prevention and treatment of most of these other diseases of the cardiovascular system (see Cardiovascular Disease: Overview and Comprehensive Analysis ). Some degree of overlap is inevitable here, however, this section will more specifically focus on understanding the mechanisms behind the development of hypertension; a symptom that frequently precedes and further aggravates the progression of a number of common cardiovascular-related diseases.
Hypertension will be defined in terms of the physiological and endocrinological systems that control blood pressure. The genetic and epidemiological basis of hypertension will be characterized, particularly with respect to the role of salt intake (as sodium chloride). Physiological and endocrinological systems that control sodium retention are extremely crucial to the maintenance of blood pressure. Accordingly, all of our most effective drug therapies for hypertension impact one or more of the components in these highly complex and highly interrelated organ systems.
At the organ level, sodium intake triggers a well-characterized, coordinated sequence of physiological events that typically causes some degree of hypertension, particularly in those genetically predisposed to the effects of salt, or who, as a result of aging or other nutritional/environmental factors are otherwise sensitized to sodium intake. At the tissue level, there is strong evidence that regulatory processes within vascular smooth muscle or vascular endothelial cells are dysfunctional and/or compromised by the affects of hypertension, declining testosterone levels, and also accumulated age-related damage or other nutritional and hormone imbalances.
In summary and in general, disorders of electrolyte balance result in chronic hypertension (and then hypertensive vascular disease), which leads to further cardiovascular disease. This section details the physiology of hypertension, the pharmacological approaches used to treat pathophysiologic states that result from hypertension, and the biochemical basis of nutritional approaches useful in the prevention of hypertension, or as adjuvant therapy to ongoing, traditional medical treatment.Epidemiology
It is estimated that over 50 million Americans have hypertension. Eventually, especially if left untreated, they develop the common cardiovascular disease known as hypertensive vascular disease. The disease is primarily a manifestation of elevated arterial pressure (high blood pressure). However, high blood pressure is really a symptom of one or more of the many underlying disease processes that often express the symptom of hypertension.
Hypertension is two times more prevalent in Blacks versus Whites, higher in men versus women (until after menopause), and is typically related to many dietary factors, particularly salt intake (Appel et al. 1997). Hypertension is commonly seen in the elderly. Over 70% of women and 50% of men over the age of 70 have hypertension. These latter factors are associated with hypertension because they all are independent risk factors for accelerated atherosclerosis. It is a disorder traditionally characterized by blood pressure persistently exceeding 140/90 mmHg. Current research indicates that an optimal blood pressure is below 120/80 mmHg.
It is important to note that damage to the vasculature can occur when the blood pressure is moderately but chronically elevated. Some individuals may not realize they are hypertensive because symptoms such as epistaxis (nosebleed), tinnitus, dizziness, headache, blurred vision, and arrhythmias are not always present. Other risk factors include high cholesterol levels, smoking, obesity, and diabetes (Calvert 2001). There are newer risk factors including homocysteine and C-reactive protein.
The lifetime risk for hypertension among middle-aged and elderly individuals is 90%; corrective intervention (at an earlier age) could relieve a huge public health burden (Miura et al. 2001; Vasan et al. 2002). Hypertension refers to the high tension levels (or pressure levels) that must be developed in the heart to eject blood into the arterial system. Blood pressure is always the result of cardiac output multiplied by the peripheral vascular resistance. The role of salt (sodium chloride) is particularly important in the development of hypertension and in the understanding of the etiology of the disease. It is noteworthy that the amount of salt in the typical American diet greatly exceeds what is derived from a natural diet. In this respect, this level of sodium chloride intake is pharmacological, with pronounced but insidious adverse side effects. Because the isotonicity (salt content) of the blood is very critically regulated by many interconnected systems, elevated retention of sodium chloride and fluid by the body is pathological. This retained salt water expands the volume of the plasma compartment, increases demands on the heart to pump more volume (increased cardiac output), and thus, raises blood pressure.
Healthy blood pressure readings are below 120/80 mmHg. Hypertension that requires medical intervention is generally defined as systolic and/or diastolic blood pressures of 140/90 or higher. Naturally, higher blood pressures are associated with more serious degrees of hypertension. It is noteworthy that individuals with pressures in between these values still show an increased risk of cardiovascular disease. Generally, a higher diastolic pressure presents a more serious risk than a higher systolic pressure. Although the symptom of hypertension is the best indicator of developing hypertensive vascular disease, it is a symptom that is usually only detected by more than one measurement of blood pressure.
The exact cause of hypertension is not clearly understood in approximately 90-95% of those affected, so it is accordingly referred to as essential hypertension, primary hypertension, or idiopathic hypertension. Secondary hypertension results from defined causes and includes roughly 5-10% of people with hypertension. Many of these cases can be treated because we know n n the cause. A clear understanding of the cause of primary hypertension is critical to properly controlling hypertension, and ultimately treating hypertensive vascular disease and its associated cardiovascular diseases. By instituting treatment regimens to reduce high blood pressure we significantly arrest the development of related cardiovascular diseases, but we may not correct some of the disease processes that are still present, still progressing, or minimally affected by the level of blood pressure. This is the danger of this silent disease, often only detectable through repeated measurement of blood pressure. It is possible that the underlying disease is still progressing, now even more silently, after blood pressure is controlled (Calvert 2001).
There are numerous processes that have been identified as contributing causes to hypertension or to the diseases that are related to hypertensive vascular disease. Because of the complex relationships associating the symptom of hypertension with the cardiovascular diseases, diseases such as hypertensive vascular disease, congestive heart failure, renal disease, stroke, arteriosclerosis, atherosclerosis, and diabetes are often interrelated. They all can ultimately express the symptom of high blood pressure or develop as a result of high blood pressure. Each disease can both cause hypertension, and in turn, is aggravated by hypertension. Control of hypertension can sometimes prevent the development of some diseases like congestive heart failure, but only modestly slow the progression of diseases like diabetes and atherosclerosis. In the end, uncontrolled hypertension generally leads to death secondary to atherosclerosis (Williams 2001). Most deaths due to hypertension result from myocardial infarction or congestive heart failure.Etiology
- Essential Hypertension
- Genetic Predisposition
- Environmental Factors
- Secondary Hypertension
Hypertension is generally referred to as either essential or secondary. It's not completely known what causes essential hypertension that accounts for 90% to 95% of cases. Research indicates that significant factors include a complex interaction between genetic, environmental and other variables. Secondary hypertension is caused by known medical conditions, such as kidney disease, pregnancy, hyperthyroidism, or aldosteronism.
Otherwise known as primary or idiopathic hypertension, essential hypertension affects a number of physiological systems that regulate (arterial) blood pressure, including the autonomic nervous system, adrenal glands, kidneys, vasculature, and complex hormonal systems that interconnect these systems. It is likely that the causes of essential hypertension are in some ways related to the known causes of secondary hypertension. An understanding of those known causes is useful in hypothesizing and understanding the etiology of essential hypertension.Genetic Predisposition
The heritability of hypertension supports a genetic basis to hypertensive vascular disease. Given the many different and interrelated physiological systems affected by hypertension and which contribute to hypertension, it is likely that many different genes and genetic mutations contribute to hypertension and other cardiovascular diseases. Many specific gene defects have been linked to susceptibility for hypertension, most of which control the expression of proteins involved in the renin-angiotensin-aldosterone-axis or endothelial cell function. However, the evidence is particularly strong for linkage of the angiotensinogen gene (Williams 2001). This gene, presumably, codes for a collection of different proteins that participate in the regulation of the renin-angiotensin-aldosterone-axis, not simply the protein structure for angiotensinogen present in the plasma.Environmental Factors
- Environmental Salt
- The Renin-Angiotensin-Aldosterone-Axis
Many environmental factors determine the expression of the degree of hypertension that results in particular individuals. The manipulation of these environmental factors through changes in salt restriction, diet, alcohol intake, and stress, can reduce or eliminate less serious forms of hypertension.Environmental Salt
"The environmental factor that has received the greatest attention is salt intake. [T]his factor illustrates the heterogeneous nature of the essential hypertensive population, in that the blood pressure in only approximately 60% of hypertensives is particularly responsive to the level of sodium intake. The cause of this special sensitivity to salt varies, with primary aldosteronism, bilateral renal artery stenosis, renal parenchymal disease, and low-renin essential hypertension accounting for about half the patients. In the remainder, the pathophysiology is still uncertain, but postulated contributing factors include chloride intake, calcium intake, a generalized cellular membrane defect, insulin resistance, and "nonmodulation" [status] (see below)" (Williams 2001).
Because the response to salt is so important to understanding the etiology of hypertension, it is important to know which physiological systems respond to salt intake and how each system influences the function of complementary systems. This understanding is paramount in understanding not only hypertensive vascular disease, but also the other cardiovascular diseases. It is beyond the scope of this writing to provide a detailed understanding of all of these allied diseases; however, some basic understanding of each of the cardiovascular diseases provides insight into the probable etiology of hypertension.
Salt sensitivity tells us more about the disease than other environmental factors like smoking, alcohol, exercise, and obesity. The acute and chronic responses to high sodium chloride intake are well-characterized. Without diminishing the importance of these other environmental factors, it is a fairly straight-forward judgment that smoking most likely affects the vasculature through oxidative stress (as does stress, in general). Similarly, chronic obesity clearly increases the work load on the cardiovascular system, and in the long term, alters lipid metabolism, insulin response, and blood pressure adversely. The high correlation of obesity with diabetes is important in understanding pathological changes in the vascular system relevant to hypertension. Diabetes mellitus is associated with physiological changes that potentiate endothelial dysfunction, including hypertension (Brown and Hu 2001). Alcohol causes many metabolic disturbances, drug effects, and alterations to lipid metabolism. Accordingly, a detailed look into its mechanisms of action would be highly confounded, contributing little to our understanding of hypertension.The Renin-Angiotensin-Aldosterone-Axis
Drugs that target the renin-angiotensin-aldosterone-axis represent the most effective medications available for hypertensive vascular disease. They are the most selective agents in use that offer the least side effects. This level of drug specificity generally indicates that the critical systems in a given disease are probably being affected. Recall that alterations in the angiotensinogen gene are positively correlated with hypertension and may represent part of the genetic basis for this heritable disease (Williams 2001). The enzyme called renin is secreted by juxta-glomerular cells in the kidney. These cells release the enzyme renin whenever there is increased filtration of sodium (chloride) by the kidney, perhaps secondary to high dietary salt intake.
Renin release is the most important endocrine response of the kidney. It exerts pronounced influences o f n the cardiovascular system and blood pressure and is primary controlled by three factors:
1. Beta-1 adrenergic agents directly stimulate renin release by acting on the juxta-glomerular cells. This stimulation of the sympathetic nervous system (through noradrenaline release) prepares the body for potential acute emergencies requiring the maintenance of blood volume and pressure (such as dehydration and hemorrhage) or to redirect blood flow to the muscles for "fight or flight" situations.
2. Blood pressure inhibits renin release via the intrarenal baroreceptor pathway, which may use prostaglandins as mediators (see the section on Membrane Biochemistry and Essential Fatty Acids ). Renin secretion and blood pressure has been shown to be selectively reduced by inhibitors of cyclooxygenase-2 (COX-2).
3. The macula densa cells, that reabsorb almost all of the filtered sodium, inhibit renin release. These specialized kidney cells "sense" the amount of sodium chloride that is not reabsorbed by the kidney. When significant amounts of sodium chloride are not reabsorbed, prostaglandins (of the series-2, PGI2 and PGE2) are released that stimulate renin release (Williams 2001). Macula densa-induced stimulation of renin release may be mediated by both COX-2 and nitric oxide synthase, which generates nitric oxide (NO) from arginine to promote vasodilation (Williams, 2001).
Once released, renin enzymatically converts circulating angiotensinogen into angiotensin I. Further and usually immediate conversion into angiotensin II by angiotensinogen-converting enzyme produces the most powerful vasoconstricting substance in the body, causing vasoconstriction of smooth muscle cells in the arterial tree, especially in the vascular capillary beds lined with endothelial cells. This action raises blood pressure by increasing total peripheral vascular resistance.
The second primary action of angiotensin II is to stimulate aldosterone release from the adrenal glands, which in turn, acts on the kidney to promote sodium retention in exchange for potassium loss. Water is retained along with sodium in the plasma, volume expands, and the juxta-glomerular cells stop secreting renin. This is an example of a classical negative feedback-loop, typical of all functional endocrine systems in the body. Furthermore, this endocrine system interconnects the physiological functions of the circulatory, renal, and adrenal systems in the highly important physiological function of regulating blood pressure and electrolyte balance.
There is a subgroup of people (20%) that have essential hypertension with low plasma renin activity. They have expanded fluid volumes (which probably increases their blood pressure), but normal serum potassium levels (suggesting no stimulation of aldosterone release). This condition prevails more commonly in Blacks. They appear to be more sensitive to angiotensin II (which is why renin can remain low), and which probably accounts for their hypertension and (aldosterone-mediated) sodium retention. Normal and high salt diets in this subgroup do not suppress aldosterone. The subgroup overlaps with people with normal levels of renin and essential hypertension (Williams 2001). These groups are sensitive to salt intake and should eliminate or restrict it.
Another 25-30% of people with essential hypertension demonstrate a reduced adrenal (aldosterone) response to sodium. "[S]odium intake does not modulate either adrenal or renal vascular responses to angiotensin II. Hypertensives in this subset have been termed nonmodulators because of the absence of the sodium-mediated modulation of target tissue responses to angiotensin II. These individuals make up 25 to 30% of the hypertensive population, have plasma renin activity levels that are normal to high if measured when the patient is on a low-salt diet, and have hypertension that is salt-sensitive because of a defect in the kidney's ability to excrete sodium appropriately. They also are more insulin-resistant than other hypertensive patients, and the pathophysiologic characteristics can be corrected by the administration of a converting-enzyme inhibitor. Furthermore, the nonmodulation characteristic appears to be genetically determined (associated with a certain allele of the angiotensinogen gene). Thus, nonmodulators are probably the most completely characterized intermediate phenotype in the hypertensive population" (Williams 2001). They are not sensitive to dietary intake of salt.
There is final subgroup of individuals possessing high renin levels (15%). However, half of these people are not benefited by the highly effective angiotensin II receptor antagonists and it is hypothesized that hypertension in this subgroup is related to over-activity of the adrenergic system (Brown and Hu 2001; Williams 2001).Secondary Hypertension
- Renal Hypertension
- Endocrine Hypertension
- Adrenal Hypertension
Research into the known causes of secondary hypertension tells us that all forms of hypertension may be related to altered kidney function or hormone secretion, and particularly, to altered renal endocrine function. Again, sodium homeostasis and adrenergic factors are the primary and most important considerations to our understanding of chronic and acute hypertension, respectively.Renal Hypertension
Activation of the renin-angiotensin-aldosterone-axis is the cause of secondary hypertension caused by "renal hypertension". Renal hypertension generally results when blood flow to one of the kidneys is reduced to less than 30% of normal. Activation of the renin-angiotensin-aldosterone-axis is simply the normal physiologic response of the kidney to perform its primary function of filtering the blood. Its sensors principally monitor blood pressure and perfusion to the kidneys, but also the salt and water content of the plasma. Activation of this renal endocrine system can also account for "renal parenchymal disease", a relatively minor contributor to overall hypertension (Williams 2001).Endocrine Hypertension
Endocrine hypertension can be directly related to increased levels of aldosterone, a primary component of the renin-angiotensin-aldosterone-axis. Recall that the endocrine cascade begins with renal release of renin, conversion of angiotensinogen to angiotensin II, then aldosterone release. Sodium retention is the probable cause of this form of secondary hypertension. Even hypertension that is due to hyperaldosteronism is dependent upon sodium intake. Normal people given high levels of aldosterone do not develop hypertension unless they ingest sodium.
Hypertension that is caused by over-production of adrenal steroid hormones, as in Cushing's Disease, can also be related to excessive retention of sodium chloride. High amounts of glucocorticoids released in Cushing's Syndrome can stimulate aldosterone receptors and cause hypertension secondary to that hormone's effects in increasing sodium retention (Williams 2001). It is probable that the recently described "normal" decline of testosterone levels with advancing years contributes to hypertension (Fogari et al. 2003; Kannel et al. 2003).
The association of hypertension with insulin resistance and/or hyperinsulinemia is more than a coincidence. Insulin resistance is common in noninsulin-dependent diabetes mellitus (NIDDM). As described elsewhere, diabetics do not show sodium chloride-mediated modulation of responses to angiotensin II that increase aldosterone and vasoconstriction. Essentially, salt intake does not exert its normal function in lessening the hypertensive responses to angiotensin II. Consequently, residual levels of angiotensin II still are able to increase sodium retention and maintain higher levels of arterial vasoconstriction (Williams 2001).
Insulin may increase blood pressure by a number of possible mechanisms. Hyperinsulinemia produces sodium retention by the kidney and increased activity of the sympathetic nervous system. The mitogenic action of insulin produces vascular smooth muscle hypertrophy and enhances calcium ion transport into the vascular smooth muscle. All of these mechanisms promote increased vascular tone (hypertension) and are consistent with the hypothesis of a defective sodium transporter in vasculature smooth muscle, which may account for 35-50% of people with essential hypertension (Verges 1999; Williams 2001).Adrenal Hypertension
Certain tumors of the adrenal gland cause excessive release of adrenaline (epinephrine) and norepinephrine into the circulation. These hormones stimulate the adrenergic receptors of the sympathetic nervous system. The result is high blood pressure secondary to cardiac stimulation and peripheral vasoconstriction. The sympathetic nervous system responds principally to the immediate needs of the body to increase blood pressure, such as following orthostatic hypotension. Adrenaline and norepinephrine of adrenal origin supplement the actions of norepinephrine released from the sympathetic nervous system. Chronic release of these hormones in disease (or prolonged stress) goes beyond the acute physiological need for vasoconstriction (causing moderate hypertension) and is pathological.
Some evidence suggests that there might be a form of insulin-induced hypertension. Excess insulin combined with insulin-resistance, a hallmark of Syndrome X, makes the sympathetic nervous system dominant, resulting in the release of catecholamines, (dopamine, epinephrine, and norepinephrine) which cause hypertension via vasoconstriction. Hyperinsulinemia is a condition characterized by retention of salt and water, which increases blood volume and pressure. Half of all hypertensive patients that are insulin-resistant have hyperinsulinemia (Simopoulos 1999; Reaven et al. 2000).Continued
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