Classification*	Systolic (mm Hg)		Diastolic (mm Hg)
Normal	<120	and	<80
Prehypertension	120–139	or	80–89
Stage 1 Hypertension	140–159	or	90–99
Stage 2 Hypertension	≥160	or	≥100

^*Not taking any antihypertensive drugs and not acutely ill. When systolic and diastolic pressures fall into different categories, the higher category should be selected to classify BP status. For example, 160/92 mm Hg should be classified as stage 2 hypertension. Isolated systolic hypertension is defined as systolic BP of 140 mm Hg or higher and diastolic BP below 90 mm Hg and staged appropriately (eg, 170/82 is defined as stage 2 isolated systolic hypertension).

Data from The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 289:2560–2572, 2003.

• The cutoff values for normal BP have been reduced.

• A new category—prehypertension—has been added.

• Two classes of hypertension—stages 2 and 3 from JNC 6—have been combined into one—stage 2 in JNC 7—because management of both is much the same.

Types of hypertension

There are two broad categories of hypertension: primary hypertension and secondary hypertension. As indicated in Table 47–2, primary hypertension is by far the most common form of hypertensive disease. Less than 10% of people with hypertension have a secondary form.

TABLE 47–2

Types of Hypertension and Their Frequency

Type of Hypertension	Frequency (%)
Primary (Essential) Hypertension	92
Secondary Hypertension
Chronic renal disease	4
Renovascular disease	2
Oral contraceptive–induced	1
Coarctation of the aorta	0.3
Primary aldosteronism	0.2
Cushing’s syndrome	0.1
Pheochromocytoma	0.1
Sleep apnea	?
Thyroid or parathyroid disease	?

Primary (essential) hypertension

Primary hypertension is defined as hypertension that has no identifiable cause. A diagnosis of primary hypertension is made by ruling out probable specific causes of BP elevation. Primary hypertension is a chronic, progressive disorder. In the absence of treatment, patients will experience a continuous, gradual rise in BP over the rest of their lives.

In the United States, primary hypertension affects about 30% of adults. However, not all groups are at equal risk: Older people are at higher risk than younger people; African Americans and Hispanic Americans are at higher risk than white Americans; postmenopausal women are at higher risk than premenopausal women; and obese people are at higher risk than lean people.

Although the cause of primary hypertension is unknown, the condition can be successfully treated. Please understand, however, that treatment is not curative: Drugs can lower BP, but they can’t eliminate the underlying pathology. Consequently, treatment must continue lifelong.

Primary hypertension is also referred to as essential hypertension. This alternative name preceded the term primary hypertension and reflects our ignorance about the cause of the problem. Historically, it had been noted that, as people grew older, their BP rose. Why older people had elevated BP was (and remains) unknown. One hypothesis noted that, as people aged, their vascular systems offered greater resistance to blood flow. In order to move blood against this increased resistance, a compensatory increase in BP was required. Therefore, the hypertension that occurred with age was seen as being “essential” for providing adequate tissue perfusion—hence, the term essential hypertension. Over time, the term came to be applied to all cases of hypertension for which an underlying cause could not be found.

Secondary hypertension

Secondary hypertension is defined as an elevation of BP brought on by an identifiable primary cause. The most common are listed in Table 47–2.

Because secondary hypertension results from an identifiable cause, it may be possible to treat that cause directly, rather than relying on antihypertensive drugs for symptomatic relief. As a result, some individuals can actually be cured. For example, if hypertension occurs secondary to pheochromocytoma (a catecholamine-secreting tumor), surgical removal of the tumor may produce permanent cure. When cure is not possible, secondary hypertension can be managed with the same drugs used for primary hypertension.

Consequences of hypertension

Chronic hypertension is associated with increased morbidity and mortality. Left untreated, prolonged elevation of BP can lead to heart disease (myocardial infarction [MI], heart failure, angina pectoris), kidney disease, and stroke. The degree of injury is directly related to the degree of pressure elevation: The higher the pressure, the greater the risk. Among people 40 to 70 years old, the risk of cardiovascular disease is doubled for each 20 mm Hg increase in systolic BP or each 10 mm Hg increase in diastolic BP—beginning at 115/75 mm Hg and continuing through 185/155 mm Hg. For people over the age of 50, elevated systolic BP poses a greater risk than elevated diastolic BP (Box 47–1). For patients of all ages, hypertension-related deaths result largely from cerebral hemorrhage, renal failure, heart failure, and MI.

BOX 47–1 SPECIAL INTEREST TOPIC

ISOLATED SYSTOLIC HYPERTENSION: THE REAL KILLER OF AGING AMERICANS

Over the past 20 years, several large randomized clinical trials involving older hypertensive patients have produced unequivocal evidence that, compared with elevated diastolic BP, elevated systolic BP is the stronger predictor of cardiovascular disease, kidney disease, stroke, and death. Additional studies have shown that, when elevated systolic BP is reduced, there is a corresponding reduction in the incidence of kidney failure, heart failure, MI, stroke, and death. Accordingly, in 2000, the Coordinating Committee of the National High Blood Pressure Education Program issued a clinical advisory recommending that systolic BP—rather than diastolic BP—be used as the major clinical endpoint for the detection, evaluation, and treatment of hypertension, especially in middle-aged and older Americans. The importance of elevated systolic pressure is reflected in the recommendations of JNC 7, released in 2003.

Some readers may be asking, “What’s new here? I mean, hasn’t elevated systolic BP always been a concern?” Well, no, it hasn’t. In fact, until recently, isolated systolic hypertension (ISH)—defined as systolic BP above 140 mm Hg and diastolic BP below 90 mm Hg—was considered a relatively benign condition that did not merit treatment. After all, most experts agreed that, in people with hypertension, elevated diastolic BP—not elevated systolic BP—was the principal cause of morbidity and mortality. Of course, this view has been proven dead wrong.

ISH is primarily a disease of the elderly. As we grow older, systolic BP gradually rises. The underlying cause is increased stiffness (reduced compliance) in large arteries—owing to progressive replacement of elastin with collagen in the arterial wall. Among older Americans, ISH is the most common form of hypertension: Of all hypertensive individuals over the age of 70, over 90% have ISH. Because of their ISH, older people are at increased risk, as demonstrated in the Multiple Risk Factor Intervention Trial (MRFIT), which evaluated over 316,000 men and found a nearly linear relationship between increased systolic BP and increased risk of adverse cardiovascular events.

Does lowering elevated systolic BP reduce cardiovascular risk? Yes indeed! The benefits of treating ISH have been documented in several large, randomized controlled trials. Important among these are the Systolic Hypertension in the Elderly Program (SHEP) and the Systolic Hypertension in Europe (Syst-Eur) trial. An analysis of the results of these trials indicated that lowering systolic BP decreased overall mortality by 13%, cardiovascular mortality by 18%, cardiovascular complications by 26%, coronary events by 23%, and stroke by 30%.

Unfortunately, among people with ISH, control of BP is generally poor. For most hypertensive people, the target BP is 140/90 mm Hg. However, among elderly African Americans, only 25% achieve this goal. And among white Americans, the success rate is even worse: Only 18% achieve the goal. This low success rate is both sad and troubling, in that it means many people will experience unnecessary morbidity and mortality.

The low rate of BP control in the elderly, coupled with our heightened appreciation of the dangers of ISH, led the Coordinating Committee to issue its advisory. As noted, the Committee recommended that systolic BP, rather than diastolic BP, be the major consideration in the detection, evaluation, and treatment of hypertension—especially in older Americans. The Committee recommended using either a low-dose thiazide diuretic (with or without a beta blocker) or a long-acting dihydropyridine CCB for initial treatment. These recommendations were based in part on the successful use of these drugs in the SHEP and Syst-Eur trials. Although ACE inhibitors were not recommended by the Committee, recent evidence indicates that these drugs too can reduce the risk of stroke, MI, heart failure, and death in older hypertensive people.

Unfortunately, despite its potential for serious harm, hypertension usually remains asymptomatic until long after injury has begun to develop. As a result, the disease can exist for years before overt pathology is evident. Because injury develops slowly and progressively, and because hypertension rarely causes discomfort, many people who have the disease don’t know it. Furthermore, many who do know it forgo treatment anyway, largely because hypertension doesn’t make them feel bad—that is, until it’s too late.

Management of chronic hypertension

In this section we consider treatments for chronic hypertension. We begin by addressing patient evaluation and other basic issues, after which we discuss the two modes of management: lifestyle modifications and drug therapy.

Basic considerations

Diagnosis

According to JNC 7, diagnosis should be based on several BP readings, not just one. If an initial screen shows that BP is elevated (but does not represent an immediate danger), measurement should be repeated on two subsequent office visits. At each visit, two measurements should be made, at least 5 minutes apart. The patient should be seated in a chair—not on an examination table—with his or her feet on the floor. High readings should be confirmed in the contralateral arm. If the mean of all readings shows that systolic BP is indeed greater than 140 mm Hg or that diastolic BP is greater than 90 mm Hg, a diagnosis of hypertension can be made.

Ideally, diagnosis would be based on ambulatory blood pressure monitoring (ABPM). Why? Because office-based measurements are often abnormally high, causing individuals to be diagnosed with hypertension when they don’t really have it. By contrast, when BP is measured with ABPM, false-positive diagnoses can be avoided. Accordingly, some experts recommend that office-based measurements be used only for screening, and that treatment be postponed until the diagnosis is confirmed using ABPM. In this way, the risks and expense of unnecessary treatment will be avoided.

Benefits of lowering blood pressure

Multiple clinical trials have demonstrated unequivocally that, when the BP of hypertensive individuals is lowered, morbidity is decreased and life is prolonged. Treatment reduces the incidence of stroke by 35% to 40%, MI by 20% to 25%, and heart failure by more than 50%. Although reductions in morbidity are not as dramatic, they are nonetheless significant: Among patients with stage 1 hypertension plus additional cardiovascular risk factors, one death would be prevented for every 11 patients who reduced systolic pressure by 12 mm Hg for a period of 10 years—and among those with hypertension plus cardiovascular disease or target-organ damage, one death would be prevented for every 9 patients who achieved a sustained 12 mm Hg reduction in pressure.

Patient evaluation

Evaluation of patients with hypertension has two major objectives. Specifically, we must assess for (1) identifiable causes of hypertension, and (2) factors that increase cardiovascular risk. To aid evaluation, diagnostic tests are required.

Hypertension with a treatable cause.

As discussed above, some forms of hypertension result from a treatable cause, such as Cushing’s syndrome, pheochromocytoma, and use of oral contraceptives (see Table 47–2). Patients should be evaluated for these causes and managed appropriately. In many cases, direct treatment of the underlying cause can control BP, thereby eliminating the need for further antihypertensive therapy.

Factors that increase cardiovascular risk.

Two types of factors—existing target-organ damage and major cardiovascular risk factors—increase the risk of cardiovascular events in people with hypertension. When these factors are present, aggressive therapy is indicated. Accordingly, in order to select appropriate interventions, we must identify patients with the following types of target-organ damage:

• Heart disease

• Left ventricular hypertrophy

• Angina pectoris

• Prior MI

• Prior coronary revascularization

• Heart failure

• Stroke or transient ischemic attack

• Chronic kidney disease

• Peripheral arterial disease

• Retinopathy

as well as patients with the following major cardiovascular risk factors (other than hypertension):

• Cigarette smoking

• Obesity

• Inadequate exercise

• Dyslipidemia

• Diabetes

• Microalbuminuria

• Advancing age (above 55 years for men, above 65 years for women)

• Family history of premature cardiovascular disease

Diagnostic tests.

The following tests should be done in all patients: electrocardiogram; complete urinalysis; hemoglobin and hematocrit; and blood levels of sodium, potassium, calcium, creatinine, glucose, uric acid, triglycerides, and cholesterol (total, LDL, and HDL cholesterol).

Treatment goals

The ultimate goal in treating hypertension is to reduce cardiovascular and renal morbidity and mortality. Hopefully, this can be accomplished without decreasing quality of life with the drugs employed. For most patients with stage 1 or stage 2 hypertension, the goal is to maintain systolic BP below 140 mm Hg and diastolic BP below 90 mm Hg. For patients with diabetes or chronic kidney disease, the target BP is lower: 130/80 mm Hg. As discussed later in the chapter, treatment of elderly patients focuses on systolic pressure. The treatment goal is a pressure below 140 mm Hg (for patients ages 65 to 79) or below 145 mm Hg (for patients age 80 and older).

We can reduce BP in two ways: We can implement healthy lifestyle changes and we can treat with antihypertensive drugs. As shown in Table 47–3, for people with prehypertension, lifestyle changes are all that is needed. In contrast, for those with hypertension—either stage 1 or stage 2—a combination of lifestyle changes and drugs is indicated. Lifestyle changes and drug therapy are discussed in detail below.

TABLE 47–3

Overview of Blood Pressure Management in Adults 18 Years and Older

		Blood Pressure Goal
BP Classification	Therapeutic Interventions	Patients Without Diabetes or Chronic Kidney Disease	Patients With Diabetes or Chronic Kidney Disease
Normal	Encourage lifestyle changes	Prevent increase	Prevent increase
Prehypertension	Initiate lifestyle changes	Prevent increase/promote decrease	Prevent increase/promote decrease
Stage 1 Hypertension	Initiate or continue lifestyle changes and begin antihypertensive drug therapy	<140/<90 mm Hg	<130/<80 mm Hg
Stage 2 Hypertension	Initiate or continue lifestyle changes and begin or intensify antihypertensive drug therapy	<140/<90 mm Hg	<130/<80 mm Hg

Recommendations from The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 289:2560–2572, 2003.

Lifestyle modifications

Lifestyle changes offer multiple cardiovascular benefits—and they do so with little cost and minimal risk. When implemented before hypertension develops, they may actually prevent hypertension. When implemented after hypertension has developed, they can lower BP, thereby decreasing or eliminating the need for drugs. Lastly, lifestyle modifications can decrease other cardiovascular risk factors. Accordingly, all patients should be strongly encouraged to adopt a healthy lifestyle. Key components are discussed below.

Weight loss.

There is a direct relationship between obesity and elevation of BP. Fortunately, weight loss can reduce BP in 60% to 80% of overweight hypertensive individuals. In addition, weight loss can enhance responses to antihypertensive drugs. Consequently, a program of calorie restriction and exercise is recommended for all patients who are overweight. The goal is to achieve a body mass index in the normal range (18.5 to 24.9).*

Sodium restriction.

Reducing sodium chloride (salt) intake can lower BP in people with hypertension, and can help prevent overt hypertension in those with prehypertension. In addition, salt restriction can enhance the hypotensive effects of drugs. However, the benefits of sodium restriction are both small and short lasting: Over time, BP returns to its original level, despite continued salt restriction. Nonetheless, JNC 7 recommends that all people with hypertension consume no more than 6 gm of sodium chloride (2.4 gm of sodium) a day. The Institute of Medicine recommends even lower salt consumption: 3.8 gm/day for adults age 50 and younger, 3.2 gm/day for adults ages 51 to 70, and 2.9 gm/day for adults age 71 and older. To facilitate salt restriction, patients should be given information on the salt content of foods.

Experts disagree about the relationship between salt intake and BP in normotensive patients. In particular, they disagree as to whether a high-salt diet causes hypertension. Hence, for people with normal BP, a low-salt diet may be considered healthy or unnecessary, depending on the expert you consult.

The DASH eating plan.

Two studies have shown that we can reduce BP by adopting a healthy diet, known as the Dietary Approaches to Stop Hypertension (DASH) eating plan. This diet is rich in fruits, vegetables, and low-fat dairy products, and low in total fat, saturated fats, and cholesterol. In addition, the plan encourages intake of whole-grain products, fish, poultry, and nuts, and recommends minimal intake of red meat and sweets. Details are available online at www.nhlbi.nih.gov/health/public/heart/hbp/dash.

Alcohol restriction.

Excessive alcohol consumption can raise BP and create resistance to antihypertensive drugs. Accordingly, patients should limit alcohol intake: Most men should consume no more than 1 ounce/day; women and lighter weight men should consume no more than 0.5 ounce/day. (One ounce of ethanol is equivalent to about two mixed drinks, two glasses of wine, or two cans of beer.)

Aerobic exercise.

Regular aerobic exercise (eg, jogging, walking, swimming, bicycling) can reduce BP by about 10 mm Hg. In addition, exercise facilitates weight loss, reduces the risk of cardiovascular disease, and reduces all-cause mortality. In normotensive people, exercise decreases the risk of developing hypertension. Accordingly, all people with a sedentary lifestyle should be encouraged to develop an exercise program. An activity as simple as brisk walking 30 to 45 minutes most days of the week is beneficial.

Smoking cessation.

Smoking is a major risk factor for cardiovascular disease. Each time a cigarette is smoked, BP rises. In patients with hypertension, smoking can reduce the effects of antihypertensive drugs. Clearly, all patients who smoke should be strongly encouraged to quit. (Pharmacologic aids to smoking cessation are discussed in Chapter 39.) As a rule, use of nicotine replacement products (eg, nicotine gum, nicotine patch) does not elevate BP. The cardiovascular benefits of quitting become evident within 1 year.

Maintenance of potassium and calcium intake.

Potassium has a beneficial effect on BP. In patients with hypertension, potassium can lower BP. In normotensive people, high potassium intake helps protect against hypertension, whereas low intake elevates BP. For optimal cardiovascular effects, all people should take in 50 to 90 mmol of potassium a day. Preferred sources are fresh fruits and vegetables. If hypokalemia develops secondary to diuretic therapy, dietary intake may be insufficient to correct the problem. In this case, the patient may need to use a potassium supplement, a potassium-sparing diuretic, or a potassium-containing salt substitute.

Although adequate calcium is needed for overall good health, the impact of calcium on BP is only modest. In epidemiologic studies, high calcium intake is associated with a reduced incidence of hypertension. Among patients with hypertension, a few may be helped by increasing calcium intake. To maintain good health, calcium intake should be 1000 mg/day (for males ages 19 to 70, and females ages 19 to 50), and 1200 mg/day (for males over age 70, and females over age 50).

Drug therapy

Drug therapy, together with lifestyle modifications, can control BP in all patients with chronic hypertension. The decision to use drugs should be the result of collaboration between prescriber and patient. We have a wide assortment of antihypertensive drugs. Consequently, for the majority of patients, it should be possible to establish a program that is effective and yet devoid of objectionable side effects.

Review of blood pressure control

Before discussing the antihypertensive drugs, we need to review the major mechanisms by which BP is controlled. This information will help you understand the mechanisms by which drugs lower BP.

Principal determinants of blood pressure

The principal determinants of BP are summarized in Figure 47–1. As indicated, arterial pressure is the product of cardiac output and peripheral resistance. An increase in either will increase BP.

Figure 47–1 Primary determinants of arterial blood pressure.

Cardiac output.

Cardiac output is influenced by four factors: (1) heart rate, (2) myocardial contractility (force of contraction), (3) blood volume, and (4) venous return of blood to the heart. An increase in any of these will increase cardiac output, thereby causing BP to rise. Conversely, a decrease in these factors will make BP fall. Hence, to reduce BP, we might give a beta blocker to reduce cardiac output, or a diuretic to reduce blood volume, or a venodilator to reduce venous return.

Peripheral vascular resistance.

Vascular resistance is increased by arteriolar constriction. Accordingly, we can reduce BP with drugs that promote arteriolar dilation.

Systems that help regulate blood pressure

Having established that BP is determined by heart rate, myocardial contractility, blood volume, venous return, and arteriolar constriction, we can now examine how these factors are regulated. Three regulatory systems are of particular significance: (1) the sympathetic nervous system, (2) the renin-angiotensin-aldosterone system (RAAS), and (3) the kidney.

Sympathetic baroreceptor reflex.

The sympathetic nervous system employs a reflex circuit—the baroreceptor reflex—to keep BP at a preset level. This circuit operates as follows: (1) Baroreceptors in the aortic arch and carotid sinus sense BP and relay this information to the brainstem. (2) When BP is perceived as too low, the brainstem sends impulses along sympathetic nerves to stimulate the heart and blood vessels. (3) BP is then elevated by (a) activation of beta₁ receptors in the heart, resulting in increased cardiac output; and (b) activation of vascular alpha₁ receptors, resulting in vasoconstriction. (4) When BP has been restored to an acceptable level, sympathetic stimulation of the heart and vascular smooth muscle subsides.

The baroreceptor reflex frequently opposes our attempts to reduce BP with drugs. Opposition occurs because the “set point” of the baroreceptors is high in people with hypertension. That is, the baroreceptors are set to perceive excessively high BP as “normal” (ie, appropriate). As a result, the system operates to maintain BP at pathologic levels. Consequently, when we attempt to lower BP using drugs, the reduced (healthier) pressure is interpreted by the baroreceptors as below what it should be, and, in response, signals are sent along sympathetic nerves to “correct” the reduction. These signals produce reflex tachycardia and vasoconstriction—responses that can counteract the hypotensive effects of drugs. Clearly, if treatment is to succeed, the regimen must compensate for the resistance offered by this reflex. Taking a beta blocker, which will block reflex tachycardia, can be an effective method of compensation. Fortunately, when BP has been suppressed with drugs for an extended time, the baroreceptors become reset at a lower level. Consequently, as therapy proceeds, sympathetic reflexes offer progressively less resistance to the hypotensive effects of medication.

Renin-Angiotensin-Aldosterone system.

The RAAS can elevate BP, thereby negating the hypotensive effects of drugs. The RAAS is discussed at length in Chapter 44 and reviewed briefly here.

How does the RAAS elevate BP? The process begins with the release of renin from juxtaglomerular cells of the kidney. These cells release renin in response to reduced renal blood flow, reduced blood volume, reduced BP, and activation of beta₁-adrenergic receptors on the cell surface. Following its release, renin catalyzes the conversion of angiotensinogen into angiotensin I, a weak vasoconstrictor. After this, angiotensin-converting enzyme (ACE) acts on angiotensin I to form angiotensin II, a compound that constricts systemic and renal blood vessels. Constriction of systemic blood vessels elevates BP by increasing peripheral resistance. Constriction of renal blood vessels elevates BP by reducing glomerular filtration, which causes retention of salt and water, which in turn increases blood volume and BP. In addition to causing vasoconstriction, angiotensin II causes release of aldosterone from the adrenal cortex. Aldosterone acts on the kidney to further increase retention of sodium and water.

Since drug-induced reductions in BP can activate the RAAS, this system can counteract the effect we are trying to achieve. We have five ways to cope with this problem. First, we can suppress renin release with beta blockers. Second, we can prevent conversion of angiotensinogen to angiotensin I with a direct renin inhibitor. Third, we can prevent the conversion of angiotensin I into angiotensin II with an ACE inhibitor. Fourth, we can block receptors for angiotensin II with an angiotensin II receptor blocker. And fifth, we can block receptors for aldosterone with an aldosterone antagonist.

Renal regulation of blood pressure.

As discussed in Chapter 43, the kidney plays a central role in long-term regulation of BP. When BP falls, glomerular filtration rate (GFR) falls too, thereby promoting retention of sodium, chloride, and water. The resultant increase in blood volume increases venous return to the heart, causing an increase in cardiac output, which in turn increases arterial pressure. We can neutralize renal effects on BP with diuretics.

Antihypertensive mechanisms: sites of drug action and effects produced

As discussed above, drugs can lower BP by reducing heart rate, myocardial contractility, blood volume, venous return, and the tone of arteriolar smooth muscle. In this section we survey the principal mechanisms by which drugs produce these effects.

The major mechanisms for lowering BP are summarized in Figure 47–2 and Table 47–4. The figure depicts the principal sites at which antihypertensive drugs act. The table summarizes the effects elicited when drugs act at these sites. The numbering system used below corresponds with the system used in Figure 47–2 and Table 47–4.

TABLE 47–4

Summary of Antihypertensive Effects Elicited by Drug Actions at Specific Sites

Site of Drug Action*	Representative Drug	Drug Effects
1.Brainstem	Clonidine	Suppression of sympathetic outflow decreases sympathetic stimulation of the heart and blood vessels.
2.Sympathetic ganglia	Mecamylamine^†	Ganglionic blockade reduces sympathetic stimulation of the heart and blood vessels.
3.Adrenergic nerve terminals	Reserpine	Reduced norepinephrine release decreases sympathetic stimulation of the heart and blood vessels.
4.Cardiac beta₁ receptors	Propranolol	Beta₁ blockade decreases heart rate and myocardial contractility.
5.Vascular alpha₁ receptors	Prazosin	Alpha₁ blockade causes vasodilation.
6.Vascular smooth muscle	Hydralazine	Relaxation of vascular smooth muscle causes vasodilation.
7.Renal tubules	Hydrochlorothiazide	Promotion of diuresis decreases blood volume.
Components of the renin-angiotensin-aldosterone system (8a to 8e)
8a. Beta₁ receptors on juxtaglomerular cells	Propranolol	Beta₁ blockade suppresses renin release, resulting in (1) vasodilation secondary to reduced production of angiotensin II, and (2) prevention of aldosterone-mediated volume expansion.
8b. Renin	Aliskiren	Inhibition of renin suppresses formation of angiotensin I, which in turn decreases formation of angiotensin II, and thereby reduces (1) vasoconstriction and (2) aldosterone-mediated volume expansion
8c. Angiotensin-converting enzyme (ACE)	Captopril	Inhibition of ACE decreases formation of angiotensin II and thereby prevents (1) vasoconstriction, and (2) aldosterone-mediated volume expansion.
8d. Angiotensin II receptors	Losartan	Blockade of angiotensin II receptors prevents angiotensin-mediated vasoconstriction and aldosterone-mediated volume expansion.
8e. Aldosterone receptors	Eplerenone	Blockade of aldosterone receptors in the kidney promotes excretion of sodium and water, and thereby reduces blood volume.