Introduction

Smooth muscle has a wide distribution in the body, and its functional specializations are extraordinarily varied. Smooth muscle is chiefly located in the wall of hollow organs, where it occurs in broad and thin sheets, in arrays of bundles, or, in the case of the taeniae, as conspicuous long cords. Other cordlike smooth muscles connect the ovaries, duodenum, and rectum to the posterior abdominal wall, and link hair follicles to the surrounding connective tissue. In mammals, a ring of smooth muscle lies close to the pupillary edge of the iris. Individual smooth muscle cells are scattered within connective tissues or close to epithelia in many organs. The total amount of musculature in the body is difficult to calculate. On the basis of the estimates shown in Table 1, smooth muscle may represent 2% of human body weight.

Similarities and dissimilarities with striated muscles are obvious. Smooth muscles are made of small, elongated, uninucleated cells, embedded in abundant extracellular material with a large fibrous component (Figure 1): intercellular cooperativity and role of extracellular material are greater than in striated muscles. A smooth muscle cell has no transverse striations in spite of its actin and myosin filaments, has no T tubules, has numerous caveolae, and has an extensive insertion of the contractile apparatus on its cell membrane over the entire cell length. Its contractile machinery, based on actin and myosin filaments and on a dominant role of calcium (as in striated muscle), has an architecture and consequent mechanical properties that are substantially different from those of striated muscles.

Introduction

The obligatory role of Ca2+ in muscle contraction was first described by Ringer (1882), and subsequently Ca2+ was shown to stimulate a host of regulatory enzymes. The change in intracellular free Ca2+ necessary for contraction is very small, on the order of 1 μM. This chapter deals with the variety of organelles, regulatory factors, and mechanisms that work together to maintain this tight control of the intracellular free Ca2+ concentration in smooth muscles.

Overview

The control of intracellular free Ca2+ concentration was first explored in skeletal and cardiac muscles. Now, knowledge of events in smooth muscles is also progressing rapidly. Major quantitative and qualitative differences between skeletal and smooth muscles are evident. Whereas in skeletal muscle Ca2+ flux and contraction are initiated by Na+ influx and membrane depolarization, in smooth muscles Ca2+ translocation and contraction can occur independently of changes in membrane potential (Edman and Schild 1963). This phenomenon, called pharmacomechanical coupling (Somlyo and Somlyo 1968), can be initiated by agonist receptor binding, release of second messengers, release of Ca2+ from internal stores, or opening of receptor-operated Ca2+ channels. Influx of Ca2+ through Ca2+ channels is very important for tension development in smooth muscles, but not in skeletal muscle.

Although smooth muscles resemble each other more than they do cardiac or skeletal muscles, major differences are evident in the structures and functions among different smooth muscles. These differences may be determined by the number and specificity of receptors, the second messengers generated, the Ca2+ pathway involved, and the activity of Ca2+−sensitive enzymes including the protein kinases.

A decline in the function of the kidneys is a warning that something is wrong. Fall in urine output, increasingly acidic urine and retention of potassium ions (K+) in the urine are symptoms which alert the doctor to the possibility of developing kidney failure. Warning signs include:

• impaired concentration, drowsiness and convulsions;

• heart failure;

• nausea and vomiting;

• swollen feet.

A doctor's first task is to distinguish between acute kidney failure and chronic kidney failure. The symptoms of acute disease are abrupt, short term and, once diagnosed, may be reversible. The symptoms of chronic disease are long term, often irreversible and may require more drastic treatment. In both cases some of the symptoms are the same, making assessment of the condition difficult. However, precise diagnosis is important so that the correct treatment of the patient can begin.

Acute kidney failure

The causes of acute renal failure fall into three broad categories:

• the blood supply to the kidneys can decrease because of heavy bleeding, infection or loss of fluids as a result of burns or severe diarrhoea;

• thrombosis (page 39), bacterial infection or various drugs can cause structural changes in the nephrons and accumulation of fluid in the kidneys;

• blockage of the collecting ducts or obstruction of the ureter or urethra can be a result of cancer, ‘stones’ (ureter only) or swelling of the prostate gland (urethra only).

Disease and good health are two sides of the same coin – how well we feel. A healthy person feels well because all parts of the body are working efficiently. Disease disrupts normal bodily functions and makes a person feel ill. A feeling of wellness is not just the absence of illness. Wellness includes mental health as well as bodily health – both are part of the equation defining good health.

The human body is an ideal environment for a range of organisms that cause different diseases. Bacteria are blamed for most human ailments, but viruses are also important disease-causing agents. Protists, fungi and different animal parasites also cause disease as a result of their activities inside our bodies.

Disease-causing organisms are called pathogens. Diseases are said to be infectious (communicable) if the organisms can be passed from one person to another. Not all diseases are infectious. Many non-infectious diseases develop because the body is not working properly. Increasing age and the way we treat our bodies affect the onset of non-infectious diseases. Many disorders can be avoided or at least delayed by changing our life-style.

Infectious diseases

During the nineteenth century the population of Britain more than trebled. People in search of work flocked to the cities, which were growing fast in the wake of the Industrial Revolution. London was typical of the times. With no proper means of waste disposal or sanitation, London's teeming population piled household rubbish and excrement outside the home.

What is heart disease?

The walls of the heart are very thick. Food and oxygen dissolved in the blood cannot pass quickly enough from inside the heart to all of the heart muscles by diffusion alone. The coronary arteries running over the surface of the heart transport blood, carrying dissolved food and oxygen, to the heart muscles.

The smooth inner wall of healthy blood vessels allows blood to flow easily through them. Anticoagulants such as heparin (from the liver) and prostacyclin (from the lining of blood vessels) prevent blood from clotting inside vessels. However, deposits of a fatty material called plaque can roughen the inner wall. As plaque builds up it causes a type of ‘hardening’ of the arteries called arteriosclerosis. The roughened blood vessels become narrower, blood flows through the vessels more slowly and the release of prostacyclin is inhibited. As a result:

• platelets (page 35) clump together (agglutinate);

• thromboplastin is released – the enzyme that begins the process of blood clotting.

These events increase the risk of blood clotting and blocking blood vessels. If an artery is blocked completely, then food and oxygen cannot reach the tissue that the artery supplies. The tissue is damaged and may die (infarction). The clot is called a thrombus and the blockage a thrombosis.

Sometimes a thrombus may be dislodged and carried in the bloodstream. The mobile thrombus is called an embolus.

Date: 15 October 1980. Place: New York Stock Exchange. The launch of a small company called Genentech sparked frenetic business, driving up its share price from $35 to $89 within the first 20 minutes of trading. At the end of the day, each Genentech share was worth $71.25. Why was there so much interest in a small four-year-old Californian company specialising in genetic engineering?

Two years previously, scientists at Genentech had isolated the genes that code for the A and B polypeptide chains of human insulin, spliced them into a loop of bacterial DNA called a plasmid and inserted the modified plasmid into the bacterium Escherichia coli. They had achieved what previously had seemed impossible, but by today's standards is commonplace. An organism (E. coli) had been genetically engineered to produce a medicine (the hormone insulin used to treat diabetes) with a worldwide market worth many hundreds of millions of dollars a year. Before then, insulin could only be obtained from slaughtered cattle and pigs. It was expensive to produce and in limited supply. Also, the chemical structure of animal insulin is different from human insulin; some diabetics react allergically to it. Genentech's achievement seemed to open the way to the large-scale production of medicines which were reliable, cheap and, in the case of insulin, more suitable for the human patient. No wonder the New York Stock Exchange was frantic on that October day – the future promised not only medical progress but also unrivalled profits!

The title of this chapter raises questions that are at the leading edge of research. To make sense of this subject, we can investigate brain structure, its neurones (nerve cells) and synapses or its biochemistry, or seek a route for our understanding through functional deficiences such as Alzheimer's disease, Creutzfeldt-Jacob disease that constitute brain dementia. In fact, the whole picture only emerges through the combination of level upon level of organisation – molecules to memory. We shall adopt just such a multilevel approach to glimpse the functioning brain at work in health and disease.

The human brain weighs about 1.3 kg. Divided into different regions – forebrain, midbrain and hindbrain – it is the body's thinking and control centre. Reactions to stimuli that are under the brain's control are called voluntary responses. Memory and learning are also controlled by the brain.

The neurones in the brain are called multipolar neurones because each one has numerous dendrites which can form synapses with incoming axons, connecting each multipolar neurone to as many as 80 000 other neurones. It has been estimated that the human brain consists of up to 20 000 million neurones, but this does not take into account the non-neural glia cells in which neurones are embedded. Supporting, nurturing and protecting the neurones, glia cells outnumber neurones ten-fold.

Memory

Today, understanding the mechanisms of memory is one of the great scientific challenges. Memory allows us to recall past experiences, connecting learning to remembering.

Our genetic make-up (genotype) contributes to many common diseases, for example our vulnerability to diabetes and heart disease. Environmental factors, however, also have their effect. Knowing about the genetic contribution to our vulnerability to disease helps us to avoid problems by taking account of the environmental factors within our control. In the cases of diabetes and heart disease for example, a sensible diet helps increase our chances of reaching a ripe old age (page 68).

Medical genetics establishes the genetic basis of disease and guides the treatment of people with genetic disorders. It also provides the data which inform potential parents about the genetic risks of starting a family.

Any prospective or expectant parents who have reason to be worried about genetic disorders that their future children might inherit can receive genetic counselling (page 99). During genetic counselling, statistical evidence and results from amniocentesis, chorionic villus sampling (page 90) or other techniques are discussed by a trained genetic counsellor with the couple concerned. The counselling helps couples make informed choices about whether to start a family if there is a chance of them having children with genetic disorders. It also helps expectant mothers and their partners to decide whether to continue with a pregnancy when they know their baby has a genetic disorder.

Techniques

Before continuing you need to remember that:

• Genes are carried on chromosomes which form pairs during meiosis. The two chromosomes of a pair are called homologous chromosomes. […]

A cut is the signal that begins a series of events which eventually stops the bleeding:

• constriction of the ends of the damaged blood vessels reduces the loss of blood;

• clotting – blood leaking from damaged blood vessels solidifies and forms a clot which plugs the wound, sealing it against infection from pathogens.

Blood clotting

The release of certain substances into the blood plasma begins the process of clotting. Serotonin (5-hydroxytryptamine) causes constriction of the damaged blood vessels. Other substances react with blood factors in the plasma, beginning a cascade of at least 15 chemical reactions that ends with the soluble plasma protein fibrinogen changing into insoluble fibrin. Figure 3.1 shows the process of clot formation. Production of the lipoprotein thromboplastin is a key stage in the process. It requires various substances including factor VIII in the plasma. Thromboplastin originates from:

• damaged tissues outside the blood vessels (the extrinsic mechanism);

• platelets in the blood (the intrinsic mechanism).

Whether thromboplastin is extrinsic or intrinsic in origin, different blood clotting factors including calcium ions (Ca2+– factor IV) are required for it to convert the inactive blood protein prothrombin from the liver into its active form thrombin. Thrombin acts on fibrinogen (also produced in the liver), converting it to insoluble fibrin. The fibrin forms a mesh of fibres across the wound and traps red cells and platelets, forming a plug-like clot.

Our diet is the food we eat and drink. It is one of the most important environmental factors affecting health. However, links between diet and health problems are not always clear cut. It is often difficult to pin down cause and effect. Rather, different dietary factors are associated with particular diseases. For example, a high fat diet is associated with the development of heart disease (chapter 4). However, we are not sure that it causes heart disease, even though it seems highly likely that this is the case.

Basic principles

We need food because the body needs the nutrients and energy that food contains. Nutrients are substances necessary for health and growth. Table 6.1 lists the categories of nutrients and their functions in the body. Water is also essential and accounts for about two-thirds of body weight. It is a solvent in which the chemical reactions of metabolism take place and in which substances are transported around the body.

Notice that each category of nutrient performs one or more of three basic functions:

• provides energy – carbohydrates and fats (proteins only when carbohydrates and fats are in short supply);

• serves as components of body structures, and for growth and repair – proteins, minerals and water;

• regulates metabolism – minerals and vitamins.

The perinatal period

Few areas of medical care have seen so many technological advances in recent years as that of the perinatal period (around the time of birth). This is particularly true of the techniques available to the late fetus and newborn baby. Childbirth is a natural function, but if it is left to run its natural course, it may not have a successful outcome for the mother or the baby. The obstetric team regard their job of helping a couple at the time of the birth of their baby as a privilege, and their aim is to make it as natural and happy an experience as possible. However, the safety of the mother and baby is of overriding importance, and if anything goes wrong during the birth they may have to intervene and manage the birth in a way which detracts from the parents' wishes.

Many couples favour natural childbirth, including home deliveries, with little or no medical intervention. However, there is no doubt that the delivery suite in a hospital is in a position to act very quickly if an emergency arises.

Stages of normal labour

Labour is an appropriately named body function – it is very hard work. The staff of the antenatal clinic prepare the prospective parents for the birth of their child by organising classes at which the process of labour is explained and their own plans for the delivery are discussed.