A simple model of the arterial circulation is shown in Figure 10.1. Blood pressure can be regulated by changes in either cardiac output or the peripheral resistance.

Fig. 10.1 Simple model of the circulation. Blood pressure in the arterial vessels (the driving force to push blood around the body) depends on the input of blood from the heart (cardiac output) and the resistance to outflow (total peripheral resistance).

Arterial blood pressure provides the driving force to perfuse the tissues of the body with blood. This driving force is dissipated as blood moves round the circulation and there is a continuous fall in pressure between the arteries and the right atrium (see Fig. 9.1). Mean aortic pressure is typically about 95 mm Hg whereas right atrial pressure is about 0–5 mm Hg. Although the output of the heart is phasic, i.e. blood enters the circulatory system during cardiac systole and this ceases when the heart refills during diastole, circulation of blood around all the tissues of the body is continuous. This is driven by the head of pressure maintained in the arterial tree (see page 86). Blood pressure in the arteries is pulsatile but by the time blood reaches the capillaries, where the important functions of the circulatory system take place, the pressure fluctuations have been damped out (see Fig. 9.1).

It is important that arterial pressure is maintained quite constant, as a fall in pressure below a critical level leads to underperfusion of the brain and the subject faints (see Chapter 9). A sustained rise in arterial blood pressure—hypertension—leads to the pathological changes in blood vessels described later in this chapter. Moment to moment fluctuations in arterial blood pressure are minimized by the baroreceptor reflex. This reflex is summarized in Figure 10.2.

Fig. 10.2 The baroreceptor reflex. The response to a fall in arterial blood pressure is an increase in both cardiac output and peripheral resistance that will restore blood pressure.

An outline of a case history of a patient with hypertension is shown in Case 10.1:1.

Case 10.1 Arterial blood pressure: 1

An insurance medical

Mr John Ames is a 45-year-old smoker who is overweight (body mass index 28) but he has been feeling well and has no symptoms of cardiovascular disease. He applied for life insurance cover and was referred for a medical examination. His blood pressure was found to be 188/106 mm Hg. Examination of the cardiovascular system showed no evidence of cardiac disease with no murmurs and with normal pulses all round. His GP arranged a blood test for serum fasting lipids (LDL and HDL cholesterol and triglycerides) and also to check renal function (urea, creatinine and electrolyte concentrations). A urine sample was checked using a dipstick test for glucose and protein. A renal ultrasound test to assess kidney size was arranged at the local hospital.

While waiting for the results of these tests to return the GP insisted that John should come to the surgery to have his blood pressure measured twice more by the practice nurse in the coming 10 days. The blood, urine and ultrasound tests all provided normal results but John’s blood pressure was still high on the subsequent checks and the GP told him he had essential hypertension. A thiazide diuretic was prescribed. This history raises the following questions.

1. John was told he had essential hypertension. What does this mean? At what level of blood pressure elevation should therapy be considered?

2. Why was it important to check John’s blood lipid levels?

3. What was the reason behind the repeated blood pressure measurements?

4. Why was John’s renal function checked?

5. What does body mass index mean?

Aspects of the answers to these questions are to be found in the text of this chapter and in Box 10.1.

The factors determining cardiac output have been discussed in Chapter 4. The essential features are that the heart has an intrinsic contractile rate which can be modified by the parasympathetic (vagus) nerve to slow the heart or by the sympathetic nerves to increase heart rate. The force of contraction of the heart and, therefore, the stroke volume is determined by a combination of preload effects (blood volume, venous return, venous tone), contractility effects (changes in myocyte [Ca⁺⁺] produced physiologically by sympathetic nerve stimulation) and afterload effects (mainly opposition to opening the aortic valve produced by the arterial blood pressure).

The factors determining peripheral blood vessel resistance to flow have been discussed in Chapter 9. Some of the mechanisms (metabolite, endothelial and local hormone effects) ensure an appropriate distribution of flow within tissues to match the local metabolic activity. Adjustment of the overall resistance to maintain arterial blood pressure at a relatively constant level is achieved by the autonomic nerve supply to peripheral blood vessels. This has the fundamental characteristics that it is sympathetic in origin, using noradrenaline (norepinephrine) as the main neurotransmitter which, acting primarily through α₁-receptors, leads to vasoconstriction (see Chapter 9). Although there are parts of the circulation where one or other of these characteristics does not apply, these are very limited and specialized aspects of vascular control and are not major factors determining the total peripheral resistance.

In order to link all these components together we need a baroreceptor mechanism to continuously provide central control mechanisms in the brain with information about the current arterial blood pressure.

Interesting facts

In 1733 the Englishman, the Reverend Stephen Hales, made the first successful measurement of blood pressure by inserting a long glass tube into the carotid artery and jugular vein of a horse. Blood in the arterial cannula rose 2.92 metres up the tube, but in the venous cannula it was only 0.5 metres.

Arterial baroreceptors

Baroreceptors are actually modified nerve endings buried in the blood vessel wall. An increase in pressure within the vessel stretches the blood vessel wall and therefore distorts the nerve endings. This leads to the opening of ion channels and the generation of action potentials in the baroreceptor nerves. If the blood vessel is experimentally prevented from expanding in response to a change in internal pressure, then there is no change in action potential number. This demonstrates that the baroreceptor does not directly monitor pressure as such but rather pressure is sensed indirectly as stretch produced in blood vessel walls.

Anatomical location of baroreceptors

The location of the main arterial baroreceptors is shown in Figure 10.3.

Fig. 10.3 Location of major arterial baroreceptors.

The carotid sinus is a thin-walled dilatation of the internal carotid artery which occurs just after the bifurcation of the common carotid artery into the internal and external carotid arteries. The carotid sinus baroreceptor is a bundle of nerve fibres which is a part of the glossopharygeal (IX) cranial nerve.

The aortic arch baroreceptor is a part of the vagus (X) cranial nerve and the nerve endings are distributed in the wall of the aortic arch.

Information from these two groups of baroreceptors enters the brain at the level of the medulla.

Central control of the cardiovascular system

The view that the cardiovascular system is regulated from a ‘vasomotor centre’ located in the medulla is now obsolete. This concept implies an anatomically distinct part of the brain which could be demonstrated in a dissection room. In practice cardiovascular control involves interaction between diffuse parts of the medulla, hypothalamus, cerebral cortex and cerebellum.

The initial processing of information from the baroreceptors occurs in the nucleus tractus solitarius (NTS) in the medulla. The NTS has connections to the regions of the medulla which organize the outflow to the two divisions of the autonomic nervous system. The cell bodies of the preganglionic parasympathetic nerves, which slow heart rate, are located in the nucleus ambiguus and the dorsal motor nucleus. There are also neural connections from the NTS to the rostral ventrolateral medulla, a region of the brainstem controlling the sympathetic outflow to the heart (increases rate) and to the peripheral blood vessels (mainly leading to vasoconstriction). Figure 10.4 summarizes the main pathways in the medulla involved in the control of arterial blood pressure.

Fig. 10.4 Blood pressure regulation by medulla. Major pathways in medulla which are concerned with blood pressure regulation. CVLM = caudal ventrolateral medulla; NA = nucleus ambiguus; NTS = nucleus tractus solitarius; RVLM = rostral ventrolateral medulla.

The hypothalamus functions effectively as the site within the brain which contains information about the ‘set point’ for arterial blood pressure i.e. what the pressure should normally be held at. The hypothalamus has a number of regions involved in cardiovascular control. The hypothalamic depressor area receives an input from the NTS. It is therefore informed about the arterial blood pressure and plays a very significant role in the baroreceptor reflex. The defence area of the hypothalamus plays a part in the cardiovascular responses to acute stress. The response to stress is an increase in heart rate and sympathetically mediated vasoconstriction particularly in the skin, the splanchnic (gut and liver) and the kidney circulations. An acute rise in blood pressure occurs in response to stress which means that the normal baroreceptor reflex, which keeps blood pressure constant, has been overridden. The brain regions involved in this include the amygdala, part of the limbic system. The series of responses to acute stress, which include changes in blood pressure, has been given various names including the term ‘alerting response’. The cardiovascular responses are reversed quite quickly when the perceived threat is removed.

A further function of the hypothalamus in vascular control relates to the fact that the temperature regulating area in the anterior hypothalamus controls the changes in skin blood flow which are part of the response to changes in body temperature.

The cerebellum is involved in the coordination of muscle movement in exercise and is also involved in the circulatory responses to exercise. Aspects of this are discussed in Chapter 13.

The baroreceptor reflex

A flow chart summarizing the baroreceptor reflex for the regulation of arterial blood pressure is shown in Figure 10.2. The responses to a fall in blood pressure are illustrated. The reflex response is an increase in heart rate, an increase in the force of cardiac contraction and an increase in peripheral vasoconstriction, all of which will help to restore blood pressure to normal levels. It has been said that regulation of heart rate is the primary role of the baroreceptor reflex and that responses leading to vasoconstriction and venoconstriction are of secondary importance.

The functional characteristics of the carotid sinus and aortic arch baroreceptors are essentially similar. Both consist of a mixture of large myelinated nerve fibres (A fibres) and a greater number of small, unmyelinated C fibres. The A fibres have a lower threshold response (30–90 mm Hg) than the C fibres (70–140 mm Hg). Thus, at normal pressures, A fibres are all stimulated to generate action potentials but only about a quarter of the C fibres are active. The A fibres reach a maximum firing rate before the C fibres. A generalization would therefore be that the myelinated A fibres are most important at normal pressure ranges but the C fibres become increasingly activated as pressure rises above the normal level. The arterial baroreceptors provide an input to the brain relaying pulse pressure, i.e. rate of change of pressure, as well as mean arterial pressure.

Baroreceptor reflex resetting occurs during the long-term rises in blood pressure known as hypertension and also during the changes in blood pressure which occur with increasing age. The site of these adaptive changes is in the central control mechanisms. The changes in baroreceptor function are a consequence of raised blood pressure rather than a primary cause of hypertension. Sensitivity of the baroreceptor mechanism may decrease when there are changes in the arterial wall compliance which sometimes occur as a consequence of atherosclerotic changes (see Chapter 8).

In humans, circulatory control mechanisms are dominated by the baroreceptor reflex but there are also other reflex responses which contribute to overall control.

Cardiopulmonary reflexes

Sensory inputs from receptors in the heart and lungs contribute to overall circulatory regulation. The receptors are located mainly, but not exclusively, on the low pressure side of the circulation. The effect of these reflexes under normal circumstances is thought to be to elicit a tonic (continuous) reduction in heart rate and to reduce peripheral vasoconstriction. Several different reflex mechanisms have been identified, some of which have opposing effects. They have been studied mainly in animals and their role in humans is poorly understood.

Groups of receptors located at the junction of the atria and the great veins effectively monitor blood volume. Approximately two thirds of blood volume is contained in the veins and changes in this volume will alter the stretch in the wall of the veins. This stretch is detected by myelinated vagal afferent nerves. In the control of blood volume this information is supplemented by an input from the arterial baroreceptors and by hormonally mediated changes in kidney function. An increase in blood volume leads to decreased secretion of antidiuretic hormone (ADH) and therefore a diuresis. Concurrently a decrease in renin secretion from the kidney leads to a decrease in aldosterone mediated sodium retention (see Chapter 9). An increase in the secretion of atrial natriuretic peptide (ANP), released in response to increased atrial stretch, also contributes to a diuretic and natriuretic response. All of these endocrine responses to increased blood volume help to return blood volume to normal. There is also a neurally mediated component to the response. Increase in blood volume leads to reflex inhibition of sympathetic vasoconstriction within the kidney. The resulting vasodilatation leads to an increase in glomerular filtration rate (GFR) and contributes to the diuretic response. These hormonal mechanisms which regulate kidney function effectively control blood volume and therefore play a major role in the long-term control of arterial blood pressure (BP). The mechanisms for acute control of BP (primarily the baroreceptor reflex) are superimposed on this background.

Stretch receptors at the vena cava–right atrium junction provide the sensory component of the Bainbridge reflex. A rapid infusion of saline, and consequent stretch of the great veins, leads to a reflex increase in heart rate. This reflex would help to shift blood from a congested venous system through to the arterial side of the circulation. The reflex may be important in the early stages of exercise when the skeletal muscle pump first produces an increase in venous return (see Chapter 13).

Chemoreceptor reflexes

The aortic bodies and carotid bodies are chemoreceptors which are primarily involved in the control of lung ventilation but they also have a role in cardiovascular regulation. These peripheral chemoreceptors respond to changes in Po₂, Pco₂ and pH and their afferent nerves run with the nearby baroreceptor afferents to enter the brain at the medulla. Although the contribution of chemoreceptor reflexes to circulatory control under normal circumstances is small, under conditions of low arterial Po₂ (hypoxaemia) or high arterial Pco₂ (hypercapnia) they elicit a sympathetically driven vasoconstriction and an increase in heart rate. The physiological role of the chemoreceptor reflex is thought to be to protect brain blood flow when arterial blood pressure falls.

Measurement of arterial blood pressure

The first recorded measurement of arterial blood pressure was made in 1773 by the Reverend Stephen Hales. The measurement was made by direct cannulation of an artery in a horse. Although derivatives of this approach are still used in, for example, intensive care units or for experimental studies, direct artery cannulation is certainly not the basis for routine blood pressure measurements. Historically much effort was devoted to finding non-invasive methods. In 1896 the Italian physician Riva-Rocci produced a sphygmomanometer with an inflatable cuff. This heralded the modern method for blood pressure measurement, the ausculatory method developed by the Russian surgeon Korotkoff in 1905.

The fundamental physical principle used is the transition from laminar flow to turbulent blood flow in an artery. Laminar flow (see Chapter 8) is essentially silent but turbulent flow sets up vibrations in the blood vessel wall which can be heard using a stethoscope placed over the artery. These flow murmurs are known as Korotkoff sounds. The conditions for the development of turbulence are that it is more likely to develop when the flow velocity is high and when the tube has a large diameter.

During blood pressure measurement, the sphygmomanometer cuff is placed over an artery, usually the brachial artery in an upper arm, and inflated. When the pressure within the cuff exceeds the pressure in the artery, the blood vessel is compressed and no blood flow occurs (Fig. 10.5). The peak of the arterial pressure wave is called the systolic pressure. If the pressure in the cuff is allowed to fall slowly, eventually the point is reached at which the cuff pressure is slightly below the systolic pressure. At this peak of the pressure wave, the blood will flow, at increased velocity, through the still greatly narrowed section of blood vessel and emerge into the uncompressed section of downstream blood vessel. This is a situation in which turbulence will develop and Korotkoff sounds will be generated. Systolic pressure is recorded as the cuff pressure at which Korotkoff sounds are first heard (phase 1).

Fig. 10.5 Korotkoff sounds. Generation of Korotkoff sounds during measurement of arterial blood pressure using a sphygmomanometer cuff.

Interesting facts

The French physician Laennec invented the stethoscope in the early 19th century. His prototype was a tube of rolled up paper.

As the pressure in the cuff is allowed to fall further the vessel will only be completely occluded for progressively shorter periods of time (Fig. 10.5). Although Korotkoff sounds are still produced, the character of the sounds changes (phases 2 and 3). The problem now becomes to record the diastolic pressure, the trough pressure reached in the arterial tree. This pressure is reached just before the aortic valve reopens and a further volume of blood enters the arteries. The best correlation with direct (arterial cannulation) methods for blood pressure measurement is when the Korotkoff sounds become muffled (phase 4). This is often very difficult to discern, especially in an environment such as a hospital ward where there may be considerable background noise. Disappearance of the Korotkoff sounds (phase 5) is routinely used even though it occurs slightly below the true diastolic pressure. In some situations, for example sometimes in pregnancy when blood viscosity is reduced, the Korotkoff sounds do not disappear and so phase 4 (muffling) must be used to record diastolic pressure.

The upper part of the arm is normally used for blood pressure measurements. This is not just a convenient appendage to wrap the cuff around with a convenient artery, the brachial artery, in which to listen for Kortkoff sounds. Using the upper arm means that the pressure is recorded at the level of the heart, a useful reference point.

Mercury in glass manometers have traditionally been used to record blood pressures. This is of course the reason for the convention of recording blood pressure in units of millimetres of mercury (mm Hg). Pressure is determined as the height of the column of mercury in the manometer tube. Concerns regarding possible safety hazards associated with mercury have led to the progressive adoption of alternative pressure recording devices. However, the fundamental principle of generating Korotkoff sounds in order to record systolic and diastolic pressures remains unchanged.

Mean arterial blood pressure is often calculated. Because of the shape of the arterial pressure wave (Fig. 10.6) mean pressure is not the same as the average of the systolic and diastolic pressures. The mean pressure through the duration of the arterial pressure wave is weighted more towards the diastolic pressure. A convenient way to calculate mean arterial blood pressure (MABP) is therefore:

Fig. 10.6 Mean arterial blood pressure. Because of the shape of the arterial pressure wave, mean pressure is closer to the diastolic pressure than to systolic pressure.

This is the same as the alternative formula:

Normal arterial pressure

A typical ‘normal’ blood pressure measurement is often quoted as 120/80 mm Hg (systolic/diastolic). While this value is appropriate for the textbook subject (male, 20–25 years old weighing 70 kg), it is not appropriate for the entire population. There is firstly a gender-related difference. Considering large population groups, blood pressures in premenopausal females are a little (5–10 mm Hg) lower than in males. There are also changes in blood pressure with age with lower than ‘textbook’ values in children (see Chapter 12) and higher pressures in older people (Fig. 10.7).

Fig. 10.7 Relationship between age and arterial blood pressure in males and females.

Acute rises in arterial pressure occur frequently in normal people. These may happen in response to stress or even events such as having a full bladder. During sexual intercourse systolic blood pressure may sometimes rise towards 300 mm Hg. After short term acute fluctuations blood pressure will return to basal levels, normally without any pathological damage occurring.

The fact that blood pressure is labile and that there are age and gender related differences in blood pressure clouds the issue over defining what normal blood pressure is and therefore what constitutes an abnormally high pressure, i.e. hypertension.

Hypertension

There is a continuous spectrum of arterial blood pressures within the population. It is not a bimodal distribution with one group in whom blood pressure is ‘normal’ and a clear dividing line to the ‘abnormal’ pressure group. There is disagreement as to whether systolic pressure or diastolic pressure is the most important indicator for a decision to initiate treatment for hypertension. There is also no clear internationally agreed definition as to what constitutes hypertension. Effectively it is a question of making a judgement about whether blood pressure is sufficiently high to be likely to result in significant end-organ damage. Initiating treatment with drugs carries with it its own set of risks and side effects. The pragmatic definition of hypertension advanced in 1971 by Professor Geoffrey Rose is still appropriate, i.e. ‘that level of blood pressure above which investigation and treatment do more good than harm’.

There are various sets of guidelines which suggest when treatment for raised blood pressure should be initiated. One such set of guidelines was published by the British Hypertension Society in 2004. It suggests that antihypertensive drug therapy should certainly be initiated in anyone with a systolic blood pressure >160 mm Hg or a diastolic pressure >100 mm Hg. In people with systolic pressures between 140 and 159 mm Hg or diastolic pressures between 90 and 99 mm Hg other factors must be part of the decision to treat. These other factors include evidence of damage to tissues such as the cerebral circulation, the heart or kidneys and also whether the patient is diabetic. The pathological consequences which result from hypertension are discussed later in this chapter. Where evidence of end organ damage exists, treatment should be started at the lower ranges of blood pressure outlined above. Note that this is only a brief illustrative summary of some much more complex recommendations. Other sets of guidelines have been published by the World Health Organization (WHO) together with the International Society of Hypertension (ISH) and also by the European Society of Hypertension (ESH).

The prevalence of ‘mild hypertension’ within the population changes with age. In Europe and the USA it is approximately 2% in the under 25 year old group and rises to 25% in the 50–59 year old group and to 50% in the 70+ year old group. ‘Malignant or accelerated hypertension’ is fortunately rare. In this case patients may present with uncontrolled hypertension and blood pressures perhaps in excess of 220/120 mm Hg. It is vitally important to initiate treatment immediately in this group.

Interesting facts

Despite the widespread recognition that high blood pressure is ‘bad for you’, it is still impossible to provide a universally acceptable quantitative definition of hypertension.

One of the problems of managing hypertension is in deciding whether the patient truly has raised blood pressure, especially as hypertension is often asymptomatic until end-organ damage becomes apparent. A proportion of patients have a higher blood pressure when it is measured in a clinic or surgery than when going about their daily life. It is clearly the blood pressure which the subject has for most of their daily life, rather than the short time spent in a doctor’s surgery, which is the relevant figure to consider. To gain more information, blood pressure may be monitored throughout the day by using ambulatory blood pressure monitoring (ABPM) devices. A significant difference between clinic and ABPM recorded pressures is called ‘white-coat hypertension’ or ‘isolated office hypertension’. Interestingly, patients with white coat hypertension, although their blood pressure is normal during most of their daily lives, are at higher risk of adverse cardiovascular events than patients whose blood pressure is normal in the surgery.

Box 10.1 Plasma lipids and body mass index

Lipoproteins are the form in which lipids circulate in the blood. Triglycerides and cholesterol are absorbed from the gut into the lymphatic system of the intestinal villi in the form of chylomicrons and reach the circulation via the thoracic duct (see Chapter 11). In muscle and adipose tissue the triglycerides are hydrolysed by lipoprotein lipase and absorbed into the tissues. The residue of the chylomicrons which includes cholesterol is taken up by the liver. Further cholesterol is synthesized by the liver itself, a process for which the activity of the enzyme hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) is the rate limiting step. The use of ‘statin’ drugs which block this enzyme and therefore reduce circulating cholesterol lipid levels is widely advocated to reduce the risk of atherosclerosis related cardiovascular disease.

The ‘endogenous pathway’ shuttles lipids between the liver and peripheral tissues, thus creating a family of lipid–protein complexes. Low density lipoprotein (LDL) contains mainly cholesterol esters and uptake into tissues is mediated by LDL receptors. High levels of LDL increase the risk of cardiovascular disease. Conversely high density lipoprotein (HDL) functions to remove cholesterol from tissues and so cardiovascular risk is inversely related to the HDL levels. The beneficial effects of statin drugs include reduction of circulating LDL cholesterol and a modest rise in HDL.

Body mass index (BMI) is calculated as the weight (in kilograms) divided by the height (in metres) squared. It is frequently used as an index to define obesity. The normal range for BMI is 19–24.9 and 25–29.9 is considered to be overweight.

A figure greater than 30 is considered to be obese. John would therefore be considered overweight but not quite obese. Obesity is a risk factor for cardiovascular disease.

Mechanisms of hypertension

All forms of established hypertension are primarily associated with an increase in the resistance to blood flow. There may be changes in cardiac output in the early stages of the development of some forms of hypertension but, fundamentally, raised resistance in the arterioles is the basic mechanism for established hypertension. Nevertheless, drugs which act by reducing cardiac output may be used therapeutically to reduce blood pressure.

There are some forms of raised arterial pressure, mainly involving renal or endocrine disorders, for which it is possible to attribute a mechanism based on disturbances of known physiological mechanisms. These include several forms of renal disease (linked to increased activity of the renin-angiotensin system), phaeochromocytoma (linked to raised adrenal medulla catecholamine secretion) and Conn’s syndrome (linked to raised adrenal cortex aldosterone secretion). When all of these mechanisms of hypertension with a physiologically definable cause are put together they only account for about 5% of the total hypertensive population. The remaining 95% of hypertensive people are said to have essential (or idiopathic) hypertension. In this group there is no single definable mechanism but there have been a large number of theories put forward.

Interesting facts

Although hypertension affects about a quarter of adults in the western world, we can still only provide a suggestion of the altered physiological mechanism involved in about 5% of cases. This group of patients have ‘secondary hypertension’. The remaining 95% are described as essential hypertensives.

There is evidence that essential hypertension may be associated with a reduction in the number of nephrons within the kidneys. How precisely this links to peripheral vasoconstriction is not entirely clear. A possibility is that reduced renal function leads to a failure to adequately excrete a sodium load. This could trigger the release of a hypothalamic natriuretic peptide which has a cardiac glycoside structure. This is variously described as a digoxin-like or ouabain-like glycoside. As with the action of digoxin on the heart (see Chapter 4), the hormone inhibits Na⁺/K⁺-ATPase. In the smooth muscle cell membrane there is also a Na⁺/Ca⁺⁺ passive exchange co-transporter (see Chapter 9). This is driven by the [Na⁺] gradient across the membrane, with Na⁺ moving into the cell and Ca⁺⁺ moving out. Inhibition of the Na⁺/K⁺-ATPase would lead to increased intracellular [Na⁺] and hence reduced Ca⁺⁺ extrusion from the cell. Such an action on vascular smooth muscle would raise intracellular [Ca⁺⁺], promote contraction and hence raise the peripheral resistance. Other popular mechanisms for the pathogenesis of hypertension include some aspect of overactivity of the renin-angiotensin system or the sympathetic nervous system. No one mechanism can currently explain all of the experimental data. Essential hypertension in any one individual may eventually prove to be the cumulative effect of a number of genetic, lifestyle and environmental factors.

Case 10.1 Arterial blood pressure: 2

Initially John was advised to lose weight, give up smoking and take more regular exercise. Over the next 6 months he joined a gym, managed to lose a significant amount of weight and gave up smoking. However over this period of time his BP fluctuated between 155 and 180 systolic and 85 and 95 diastolic.

Although John was feeling more healthy, the GP was concerned that his blood pressure was still not adequately controlled. A beta-blocker was therefore added to the prescribed diuretic. However this made John feel lethargic and tired. He was changed to slow release nifedipine (a calcium channel antagonist). Whilst this move effectively controlled John’s BP he found that he did get more frequent headaches whilst taking the drug. A further change in medication was made and he was switched to the ACEI drug enalapril supplemented with the thiazide diuretic bendroflumethazide. A check was made of his renal function profile after 5 days’ medication.

John found that he tolerated the enalapril well and had no problems with it. His BP was well controlled with systolic pressure generally in the range 140–155 mm Hg and diastolic pressure below 95 mm Hg. The drugs prescribed for John raise the following questions:

1. Why was John unable to tolerate the side effects of beta-blocker therapy?

2. Why should nifedipine give John a problem with headache?

3. How do angiotensin converting enzyme inhibitors lower blood pressure and why was it important to check renal function after a period of 5 days on the drug?

Answers to these questions are to be found in the text of this chapter and in Chapter 9 (p. 106).

Pathological consequences of raised arterial pressure

Worldwide, hypertension is estimated to cause 7.1 million premature deaths per year. Longstanding essential hypertension results in left ventricular hypertrophy. In this ‘pressure-overload’ effect on the heart additional sarcomeres are added in parallel to the original sarcomeres (see Chapter 2). However hypertrophy may progress to congestive failure with dilatation of the heart. This ‘volume overload’ means additional sarcomeres are added in series. Changes in the architecture of the heart which involve both the myocytes and the extracellular matrix are referred to as remodelling (see Chapter 6).

Hypertension is a risk factor for the development of atherosclerosis (see Chapter 9) and will accelerate its development in large arterial blood vessels. However, the structure of the lesions produced is the same as in normotensive subjects. In addition there are changes in the vascular wall which are selective responses to hypertension. These include thickening of the media layer of muscular arteries as a result of smooth muscle hyperplasia and collagen deposition. The latter changes occur in small arteries and arterioles rather than the large vessels affected by atherosclerosis (Fig. 10.8).

Fig. 10.8 Structure of a small artery from a patient with benign hypertension. The smooth muscle in the media (M) has undergone hypertrophy. The intima (I) and the elastic lamina (E) have become thickened. The lumen (L) is reduced in size. Source: Stevens & Lowe 2000.

Small arterial and arteriolar blood vessels within the kidney show intimal proliferation and deposition of large proteins such as fibrinogen, a process known as hyalinization, in the media layer. These pathological changes lead to nephron loss and the ultimate development of chronic renal failure. The nephron loss leads to exacerbation of the hypertension, a vicious circle.

Other vascular disorders associated with hypertension include intracerebral haemorrhage, dissecting aneurysm of the aorta and subarachnoid haemorrhage due to the rupture of berry aneurysms (see Chapter 8). Globally, data suggest that about 62% of cerebrovascular disease and 49% of ischaemic heart disease can be attributed to inadequate management of hypertension. However, in patients with hypertension 80% of strokes are caused by intra-arterial thrombosis or embolism from the heart or large arteries. Intuitively one might expect hypertension to be linked to haemorrhagic events as a cause of stroke, but in fact this represents only 20% of the total.

Endothelial dysfunction is characteristic of hypertension and also many other disease mechanisms associated with altered vascular function. The changes in the endothelium appear to be a response to hypertension rather than a cause of hypertension linked to reduced production of vasodilator mediators (nitric oxide or prostacyclin) or increased production of a vasoconstrictor (endothelins).

Treatment of hypertension

Treatment strategies for essential hypertension cannot be directly targeted at the disordered physiological mechanism because it is unknown. Good management includes the use of non-drug based methods. Weight reduction, reduced salt intake, limiting alcohol intake, increasing physical exercise, increasing fruit and vegetable consumption and reducing total fat and saturated fat intake are all thought to help to lower arterial blood pressure. Furthermore, failure to adopt these lifestyle changes may limit the response to antihypertensive drugs. Attention must also be given to other cardiovascular risk factors, smoking, control of diabetes and blood lipid levels. The use of statin drugs to reduce hepatic cholesterol synthesis should be considered. However, the extent to which blood pressure can be reduced purely by lifestyle changes is limited.

A considerable range of drugs is available to reduce blood pressure and a detailed discussion of these is outside the scope of this book. Individually each drug will only produce fairly modest (5–15 mm Hg) reductions in blood pressure and so combinations of different classes of drugs may be necessary to achieve adequate blood pressure control. Common strategies include the use of beta-blockers and/or thiazide diuretics as first line treatments. More recently, calcium channel blocking drugs (also called calcium antagonists) have been added to this list and angiotensin converting enzyme inhibitors (ACEI) (see Chapter 9) also have their advocates as first line drugs. Brief further details of all these groups of drugs is shown below.

Thiazide diuretics, e.g. bendroflumethiazide (bendrofluazide)

The initial diuretic response is produced by inhibition of a Na/Cl co-transporter on the lumenal membrane of the distal tubule of the nephron. Compensatory activation of the renin-angiotensin-aldosterone axis however limits salt and water depletion as a basis for blood pressure lowering. Longer term hypotensive actions of these ‘diuretic’ drugs come from direct effects on Ca⁺⁺ entry into vascular smooth muscle.

Other diuretics such as the loop diuretic furosemide (frusemide) and the potassium sparing diuretics spironolactone, amiloride and triamterene, which block the sodium retaining actions of aldosterone, can also be used to help lower blood pressure but are not normally used as first line drugs.

Beta-blockers, e.g. atenolol (β₁ selective) propranolol (β₁/β₂ non-selective)

Beta-blockers have a number of pharmacological actions. Reductions in heart rate and myocardial contractility through actions on β₁ receptors lead to a decrease in cardiac output (see Chapter 4). Blockade of juxtaglomerular cell β receptors in the afferent arteriole of the kidney suppresses the secretion of renin. In addition to their role as antihypertensive agents, beta-blockers have other beneficial effects in relation to heart disease (see Chapter 6). β-adrenoceptor blocking drugs have a wide range of side effects. These include tiredness, exercise limitation, dizziness, nausea, anorexia and bradycardia. In patients with asthma the use of a β₁ selective drug is preferable as a non-selective β₁/β₂ blocker may contribute to bronchoconstriction.

Calcium channel blocking drugs, e.g. nifedipine, verapamil and diltiazem

These drugs block the entry of Ca⁺⁺ ions into voltage gated (L-type) calcium channels in vascular smooth muscle (see Chapter 9) and hence reduce the peripheral resistance. Nifedipine and structurally related drugs are mainly used in hypertension management. As these calcium channels exist in a number of tissues there are predictable side effects. They may include headache (cerebral vasodilatation), and constipation due to effects on gut wall smooth muscle. Some calcium channel blocking drugs also have a negative inotropic action on the heart (see Chapter 4).

Angiotensin converting enzyme inhibitors (ACEI)

These compounds, together with the more recently developed angiotensin receptor blockers (ARB), have been discussed in Chapter 9. In addition to their blood pressure lowering vasodilator effects and their mild diuretic actions, they have beneficial effects in relation to the prevention of fibrotic changes in the heart and slowing the progression of renal disease (renoprotective actions).

Other antihypertensive drugs

Alpha-blockers (e.g. prazosin, doxazosin) reduce sympathetic tone and therefore dilate both arteriolar and venous blood vessels. This reduces the peripheral resistance directly but also reduces cardiac output by an effect on the preload of the heart. A potential side effect of α₁ receptor blockade is postural hypotension as a result of venodilation.

Imidazoline I₁ receptors are concentrated in the medulla of the brain in areas concerned with the central regulation of arterial blood pressure (see page 116). Moxonidine is a drug which blocks imidazoline I₁ receptors and hence decreases sympathetic outflow and increases vagal tone.

The centrally acting α₂-adrenoceptor agonists such as methyldopa and clonidine now have only limited use as blood pressure lowering drugs. They reduce sympathetic outflow by actions in the medulla, particularly on the nucleus tractus solitarius (NTS) (see p. 116).

Hydrostatic pressure in the circulation

So far we have been considering pressure in the arterial system as being ‘dynamically’ generated through an interaction between the pumping action of the heart and the resistance to blood flowing out of the arterial tree.

Or:

We also need to consider a second type of pressure, often referred to as a ‘hydrostatic’ pressure, generated simply by the height of a column of blood. This is illustrated in Figure 10.9. Pressure at the bottom of a tube containing a fluid depends on the height of the column of fluid (h), the density of the fluid (ρ) and gravity (g). Pressure = hρg.

Fig. 10.9 Hydrostatic pressure in a glass tube. Pressure at the bottom of the tube depends on the height of the fluid column, the density of the fluid and gravity.

The circulatory system also has tubes containing a fluid and the hydrostatic fluid pressure generated is illustrated in Figure 10.10. Thus, in an upright person, the actual pressure in an artery in the ankle will be the sum of the ‘dynamic’ pressure (mean approximately 95 mm Hg) generated by the pumping action of the heart and the ‘hydrostatic’ pressure (about 90 mm Hg) produced by the height of the column of blood from the level of the tricuspid valve in the heart (the notional zero point) to the feet. This gives a total ankle artery pressure of about 185 mm Hg in an upright person. Note: the density of mercury is 13.6 times the density of water. Thus, as the convention is to express blood pressures in units of mm Hg, a column of 13.6 mm of blood will exert a pressure of 1 mm Hg. (This assumes that the density of blood is the same as the density of water.)