HEALTHCARE

Overview.The majority of patients with hypertension have primary (or essential) hypertension. The pathogenesis of primary hypertension is not completely understood; at best, it is known that there are risk factors and conditions that may contribute
to development of primary hypertension. This lack of understanding precludes a true cure of primary hypertension. Rather, the clinician is limited to reducing the patient’s BP to goal values through lifestyle modification and prescribing antihypertensive medications. With this approach, BP can often be reduced to normotensive levels. In the majority of cases, the only treatment is long-term BP control. In some patients, hypertension may be secondary to other, coexisting conditions, and in these cases the cause of the hypertension is better understood. Usually, the elevated BP can be resolved or improved with correction to the underlying condition, and this becomes the focus of treatment. Approximately 5% of patients with hypertension have a secondary form of hypertension.

Determinants of blood pressure .The BP is determined by a combination of factors, including CO, total body fluid volume, and resistance of blood moving through the arterial system. In addition, many environmental factors alter the function of organ systems, thereby generating a complex interaction of multiple factors, all adding to the difficulty in determining the cause(s) of primary hypertension.

 Cardiac output and blood volume.CO is the amount of blood pumped by the heart over a period of time and is determined by the speed at which the heart beats (heart rate) and the amount of blood pumped by each heart beat (stroke volume). Left ventricular stroke volume is the difference between the volume of blood that has filled the left ventricle at  the end of diastole (end diastolic volume, EDV) and the amount of blood left in the left ventricle immediately following systolic contraction (end systolic volume, ESV). Stroke volume is dependent on the preload, the afterload, and the contractility of the heart:

A) Preload is the amount of stretch of the cardiac muscle due to blood filling the heart, which is controlloed by the EDV filled by venous return from circulation. Any factor that alters the returning volume will alter the EDV and the preload. Changes in the EDV affect the stroke volume and, ultimately, CO. A more rapid heart rate, for example, diminishes the amount of blood filling the ventricles and thus decreases preload.                                    B)Afterload is back pressure from the arteries near the heart because of blood movement. Afterload is relatively constant and does not normally make a large contribution to changes in stroke volume. In patients with hypertension, however, afterload is more important, as elevated BP reduces the amount of blood ejected from the heart with each heart contraction. This leaves more blood in the heart after each contraction, raising the ESV and thus reducing
the stroke volume.                                                                            C)    An extrinsic factor affecting stroke volume is cardiac contractility. Cardiac contractility is termed extrinsic because it does not depend on myocardial stretch. Increased contractility increases the force and amount of blood ejected with each heart beat. This reduces the ESV, increasing the stroke volume. Contractility is increased due to cytosolic increase in calcium ions prior tocontraction.
The components that regulate CO rely on a number of sensors sensitive to hemodynamic changes including baroreceptors and chemoreceptors located within arteries and receptors in skeletal muscle that sense contractions.Baroreceptors are mechanoreceptors that sense changes in vessel wall stretch and produce a rapid response to alterations in BP. They act as a buffering system to moderate normal short-term changes in BP. In hypertension, the increased stretching of arterial walls activates these receptors, causing inhibition of the vasomotor center and resultant reduction in heart rate (to lower CO) and vasodilation (to decrease SVR). These changes reduce the BP. If the BP is too low,
these receptors sense the reduction in arterial pressure and increase the CO and stimulate vasoconstriction. The long-term function of baroreceptors is not known. Baroreceptors can be reset and may no longer respond to changes in stretching associated with increased BP, which may occur in hypertension.Blood volume is another important factor in BP level. Regulation of blood volume is a long-term modulator of CO. Blood volume influences venous pressure and ventricular filling, which causes changes in EDV and stroke volume. BP is directly tied to blood volume; when blood volume increases, BP rises.The kidneys have an important role in controlling blood and fluid volume. They can directly alter blood volume by increasing the filtration of fluid and reducing sodium retention and the fluid that accompanies it. Indirectly, the kidneys can regulate the renin–angiotensin–aldosterone system (RAAS) to change BP and ultimately increase the blood volume. 

 A partial list of mechanisms that can influence cardiac output or systemic vascular resistance. This list only includes a few neurotransmitters and hormonal signaling molecules.

A) Norepinephrine/epinephrine                                                         B ) Angiotensin II                                                                               C ) Endothelin                                                                                    D)  Nitric oxide                                                                                 E) Atrial natriuretic peptide/brain natriuretic peptide                 F) Acetylcholine                                                                                G) Prostaglandins                                                                             H) Aldosterone                                                                                    I)  Bradykinin                                                                                   J)  Vasopressin 

 Systemic vascular resistance.SVR is the resistance to blood flow in the arterial tree. Arteries are composed of endothelial cells, vascular smooth muscle cells, and connective tissue. The intrinsic myogenic tone of the vascular smooth muscle and the sympathetic nervous system (SNS) control the diameter of the vessel, which influences the SVR. The nervous system and the endothelial cells play a major role in modifying smooth muscle cell tone. (See Table 3.1 for a partial list of factors that can alter SVR and CO.) There are several vasodilators that reduce SVR, notably nitric oxide. Nitric oxide activates guanylate cyclase in smooth muscle cells, resulting in an increase in cyclic guanosine monophosphate (GMP) and vessel relaxation. Constriction of smooth muscle cells, however, increases SVR. This system prevents BP from falling too low and increases BP in response to stress or activity. Principal vasoconstrictors are angiotensin (AT) II (produced in response to release of renin by the kidney) and endothelin-1 (ET-1) produced by endothelial cells. ET-1 binds to receptors of vascular smooth muscle cells to activate voltage-dependent calcium channels. AT II binds  the G-protein coupled receptor AT1 to increase cytoplasmic calcium concentrations.

Blood pressure regulation. Many physiological systems alter CO and SVR and thus regulate BP. Systemic and local hormones, metabolites, and neurotransmitters all contribute to signaling pathways that affect CO and SVR. The SNS and the RAAS play a particularly important role in BP management.

Sympathetic nervous system The SNS can alter SVR and CO and thus regulate BP in response to stimuli (Figures). The parasympathetic nervous system mostly functions to downregulate the system and the main parasympathetic neurotransmitter,
acetylcholine, is responsible for reducing heart rate. The SNS counteracts the relaxed state that dominates under parasympathetic activity to prepare the body for activity or stress. It is the SNS, through its main neurotransmitter, epinephrine, that results in many of the changes leading to increases in BP and, as such, it is an
important target in treating hypertension. The SNS signals via adrenergic receptors, which respond to the neurotransmitter
norepinephrine (NE) (and epinephrine). Both alpha- and beta-adrenergic receptors, and several subclasses of each receptor, are involved. Alpha1, alpha2, and beta1 adrenergic receptors are the most important receptors in increasing and regulating
BP. Stimulation of postsynaptic alpha1 and alpha2 adrenergic receptors located 

      Sympathetic nervous system and blood pressure regulation pathways.

 on smooth muscle cells causes vasoconstriction of the vessels. Activation of beta1 adrenergic receptors in heart muscle causes increased heart rate and increases the amount of calcium in the muscle cells, thereby increasing cardiac contractility. CO is raised due to increased stroke volume and heart rate. Beta1 adrenergic receptors within the kidney, when stimulated, signal for release of renin, resulting in the production of the vasoconstrictor AT II. This stimulation of the SNS increases CO and SVR, leading to increased BP.(Fig. )Pathological consequences of activation of the renin–angiotensin–aldosterone system.

Fig) Interaction between the renin–angiotensin–aldosterone
system and the sympathetic nervous system at the kidney.

Renin–angiotensin–aldosterone system Blood and fluid volume influence CO and are dependent on sodium regulation by the kidneys (Figure 3.3). The kidneys play a key role in controlling BP by causing changes in fluid volume, sodium homeostasis, and SVR. There are many different systems that regulate these factors, including the RAAS. This is a hormonal system that works to regulate BP and fluid volume through several mechanisms.
In response to decreased blood fluid volume, the kidneys release the proteolytic enzyme renin into circulation. Renin cleaves angiotensinogen in the blood stream into AT I. AT I is further processed into AT II by angiotensin-converting enzyme (ACE). AT II is an active molecule and can stimulate two subtypes of receptors. Stimulation of the AT1 receptor subclass can cause several changes that counteract low fluid levels and, in turn, increase BP. The first mechanism to increase blood fluid volume is through sodium retention. The AT II–AT1 receptor pathway acts
directly on the proximal renal tube and causes sodium reabsorption. AT1 receptor activation also stimulates aldosterone release, causing further salt retention by the kidney. Both of these mechanisms lead to fluid retention and increased BP. AT1 receptor stimulation causes changes in blood vessels via vasoconstriction. AT II, signaling through AT1 receptors, is known to stimulate the SNS. This leads to changes in CO and SVR. All of these functions of AT II stimulation of the AT1 subclass of receptors lead to an increase in systemic BP.

 Primary hypertension:risk factors and blood pressure regulation
Although the cause of primary hypertension is unknown, there are many risk factors associated with hypertension. Children with hypertensive parents are more than twice as likely to develop hypertension, suggesting that there is a genetic component. This is supported by epidemiological evidence suggesting that up to 30% of BP variation in the overall population is due to genetic abnormalities. Hypertension is also more prevalent in the USA in the non-Hispanic black population compared with the non-Hispanic white or Mexican American population.Hypertension as a whole is more severe in the black population compared with other races. There are also many factors associated with lifestyle and environment that may contribute to an increased risk of developing hypertension (below2.1). Diet can enhance the susceptibility to develop, and once developed, sustain hypertension.
For example, excess sodium intake and alcohol have both been linked to an increased likelihood of hypertension. Obesity is also a major risk factor, and in the elderly it is the main risk factor associated with the onset of hypertension.Psychological stress and lack of physical activity are also linked with elevated BP. While it is likely that all of these risk factors contribute to hypertension, the
contribution of each risk factor depends on individual patient susceptibility.

Sodium intake and primary hypertension.Sodium balance correlates with raised BP. Primary hypertension is more common
in populations that consume higher amounts of sodium, especially if the average sodium intake is 100 mEq/day or more, but it is rare in populations that consume less than an average of 50 mEq/day. Reducing sodium intake can have a beneficial effect on BP. Sodium reduction from 170–100 mEq/day can reduce systolic BP 

 2.1 Some of the factors that may influence the development of primary hypertension.

 OO Increased sodium intake
OO Increased body mass
OO Increased alcohol intake
OO Increased psychological stress
OO Decreased physical activity
OO Genetic predisposition
OO Reduced potassium intake
OO Reduced calcium intake

 by 5 mmHg and diastolic BP by 3 mmHg on average. JNC 7 recommends that all persons with a sodium intake of 100–150 mEq/day should reduce their sodium intake to less than 100 mEq/day. Changes in BP due to excess sodium intake reflect sodium sensitivity. Sodium sensitivity varies among individuals, and it increases with age or obesity. Non- Hispanic blacks are also more susceptible to sodium sensitivity and individuals with
renal dysfunction have greater sodium sensitivity than people with normal kidney function. The relationship between sodium and BP is not ully understood, but may be related to fluid volume. Excess sodium intake requires the kidneys to filter more sodium out of the blood stream. If the level of sodium overwhelms the ability
of the kidneys to filter sodium, sodium retention occurs,contributing directly to excess fluid volume and, ultimately, hypertension. It is also possible that excess sodium causes other changes in the body, such as activating signaling pathways,which can lead to inappropriate vasodilation or vasoconstriction. Sodium also
exacerbates other risk factors such as microalbuminuria and dyslipidemia.

 Genetics and primary hypertension. Many genes have been linked to hypertension (Table 3.3). One example of a single gene mutation leading to hypertension is Liddle’s syndrome, caused by the dominant gain of function mutation in the sodium channel. This mutation prevents the degradation of the channel and leads to overactivity. The early and severe hypertension common in Liddle’s syndrome is due to excessive sodium reabsorption, which causes systemic volume overload.Primary hypertension, however, is unlikely to be due to a single gene mutation.There have been many genes associated with an increased risk of hypertension,but the individual contributions of each gene are currently unknown. Based on animal models, there is evidence that genes active in the kidney are the largest contributors to genetic-based hypertension. There is evidence that the AT, adducin,and connexin 40 genes have a pathogenetic role in high BP.Stress and primary hypertension.
Stress is believed to contribute to the development of hypertension. Physiological stress leads to activation of the SNS and can lead to vasoconstriction and changes to SVR. Stress associated with being seen in medical clinics (white-coat hypertension)is one of the leading causes of pseudoresistant hypertension. Over time, stress can lead to long-term hypertension; patients with repeated physiological stress have a higher incidence of elevated BP.
One way to combat stress is to increase physical activity. Lack of physical activity can contribute to essential hypertension by leading to higher stress levels, greater risk of obesity, and reduced cardiovascular function. Several epidemiological studies have demonstrated a link between low physical activity and higher BP,
mainly through the contribution of increased body mass in less active persons.