The Internal Environment

Homeostasis is the maintenance of a constant internal environment within narrow limits, despite changes in internal and external conditions. The factors held steady include core temperature, blood pH, blood glucose concentration and the water potential of the blood.

Why it matters: enzyme-controlled reactions (a Unit 1 link) are extremely sensitive to temperature and pH; a swing in water potential would make cells shrink or swell by osmosis. Keeping these constant lets cells work reliably whatever the body is doing.

Negative feedback is the control mechanism. A change is detected and the response opposes (reverses) that change, returning the factor towards a fixed set point. The pathway is always:

$\text{stimulus (deviation from set point)} \rightarrow \text{receptor} \rightarrow \text{coordinator} \rightarrow \text{effector} \rightarrow \text{corrective response} \rightarrow \text{return to set point}$

• Receptor — detects the change (e.g. osmoreceptors, thermoreceptors, the islet cells that sense glucose).
• Coordinator (control centre) — usually the hypothalamus or an endocrine gland; it processes the information and sends instructions.
• Effector — a muscle or gland that carries out the corrective response (e.g. collecting-duct cells, liver cells, skin arterioles).

The key feature is that the corrective response switches the original stimulus off, so the factor oscillates very slightly around the set point rather than running away. Contrast this with positive feedback (e.g. the spread of an action potential, or oxytocin in labour), where the response amplifies the change — not used for routine homeostasis.

Excretion is the removal of the waste products of metabolism from the body. The main excretory products are carbon dioxide (from respiration, removed by the lungs), urea (from excess amino acids, removed by the kidneys) and bile pigments (from the breakdown of haemoglobin, lost in faeces). Do not confuse this with egestion — the removal of undigested food, which was never part of metabolism.

The liver and excess amino acids. Amino acids cannot be stored, and any in excess of need cannot simply be kept. In the liver they are deaminated: the amino group (—NH₂) is removed and converted to ammonia (NH₃). The remaining carbon-containing keto acid can be respired or converted to carbohydrate/fat.

Ammonia is very toxic and very soluble, so it cannot be allowed to accumulate. In the liver it is combined with carbon dioxide in the ornithine cycle (urea cycle) to form urea, which is far less toxic and is carried in the blood to the kidneys for excretion:

$2\text{NH}_3 + \text{CO}_2 \rightarrow \text{CO(NH}_2)_2 + \text{H}_2\text{O}$

In outline the ornithine cycle works as a loop: ornithine + ammonia + CO₂ → citrulline, citrulline takes up a second ammonia → arginine, and arginine is hydrolysed to release urea, regenerating ornithine to begin again. (You are expected to know the overall reactants and product, and that ornithine is regenerated, rather than every intermediate enzyme.)

Detoxification. The liver also breaks down toxins — for example hydrogen peroxide (by catalase) and alcohol (ethanol), which is oxidised to ethanal and then to ethanoate by enzymes including alcohol dehydrogenase. This protects the rest of the body, and explains why liver damage is so serious.

Blood enters each kidney through the renal artery and leaves by the renal vein; processed fluid (urine) leaves down the ureter to the bladder. In section the kidney shows an outer cortex, an inner medulla and a central pelvis.

The functional unit is the nephron (about one million per kidney). Trace the fluid through it:

1. Bowman's (renal) capsule in the cortex surrounds a knot of capillaries, the glomerulus — the site of ultrafiltration.
2. Proximal convoluted tubule (PCT) in the cortex — the site of most selective reabsorption (all the glucose, most ions and water).
3. Loop of Henle, which dips into the medulla and back — sets up the water-potential gradient in the medulla.
4. Distal convoluted tubule (DCT) in the cortex — fine adjustment of ions and pH.
5. Collecting duct, running back down through the medulla to the pelvis — the site of ADH-controlled water reabsorption.

The blood supply is unusual and worth knowing: the afferent arteriole (which brings blood in) is wider than the efferent arteriole (which takes it out). This difference builds up a high hydrostatic pressure in the glomerulus, which drives ultrafiltration. The efferent arteriole then forms a second capillary network wrapped around the tubule, allowing reabsorbed substances to be carried away.

Ultrafiltration is filtration under pressure. Because the afferent arteriole is wider than the efferent, the blood in the glomerulus is at high hydrostatic pressure. This pressure forces water and small solutes out of the blood and into the Bowman's capsule, across three layers:

• gaps (fenestrations) between the capillary endothelial cells;
• the basement membrane — a mesh of glycoproteins that is the true molecular filter;
• the slits between podocytes (the cells of the capsule wall, which have foot-like projections).

Small molecules — water, glucose, amino acids, urea, ions — pass through to form the glomerular filtrate. Plasma proteins and blood cells are too large to cross the basement membrane, so they stay in the blood.

Using water-potential language: the high hydrostatic pressure works against the water potential of the blood. Because proteins remain behind, the blood has a low (very negative) water potential, which opposes filtration; but the hydrostatic pressure is greater, so there is a net outward movement of water into the capsule. The net filtration pressure is the hydrostatic pressure minus the opposing oncotic (water-potential) pull of the plasma proteins.

Selective reabsorption in the PCT. About 180 dm³ of filtrate is made per day, but almost all is reabsorbed — only ~1.5 dm³ becomes urine. In the proximal convoluted tubule essentially all the glucose and amino acids, and most of the ions and water, are returned to the blood. The mechanism is a beautiful synoptic link to membrane transport:

1. Sodium–potassium pumps (active transport, using ATP) on the membrane facing the blood pump Na⁺ out of the tubule cell, keeping the cell's Na⁺ concentration low.
2. This creates a steep Na⁺ gradient, so Na⁺ diffuses into the cell from the filtrate through a co-transporter protein, dragging glucose (or an amino acid) with it — secondary active transport (co-transport), against glucose's own gradient.
3. Glucose then leaves the cell into the blood by facilitated diffusion.
4. The reabsorption of all these solutes lowers the water potential of the blood beside the tubule, so water follows by osmosis, down the water-potential gradient.

PCT cells are perfectly adapted for this: a brush border of microvilli (huge surface area), many carrier proteins, and many mitochondria to supply the ATP for the pumps. Normally all glucose is reabsorbed, so there should be no glucose in the urine — its presence signals diabetes.

Osmoregulation is the control of the water potential of the blood — itself a homeostatic, negative-feedback process. To reabsorb water from the collecting duct, the kidney first has to make the surrounding medulla 'salty' (a low/very negative water potential). That is the job of the loop of Henle, acting as a countercurrent multiplier.

In outline:

• The ascending limb actively pumps Na⁺ and Cl⁻ out into the medulla but is impermeable to water, so the medullary tissue fluid gains a lower (more negative) water potential the deeper you go.
• The descending limb is permeable to water, so as filtrate flows down past this increasingly negative water potential, water leaves by osmosis and the filtrate becomes more concentrated.
• Because the two limbs run in opposite directions and exchange continuously, the gradient is multiplied down the medulla. The longer the loop, the steeper the gradient and the more concentrated the urine a mammal can make (desert mammals have very long loops).

The collecting duct then runs back down through this gradient. As the filtrate passes the low water potential of the medulla, water can leave the duct by osmosis — but only if the duct wall is permeable to water. That permeability is controlled by ADH (antidiuretic hormone).

The ADH negative-feedback loop (osmoregulation):

1. Blood water potential falls (dehydration, salty meal, sweating).
2. Osmoreceptors in the hypothalamus detect the lower water potential.
3. The hypothalamus signals the posterior pituitary gland to release more ADH into the blood.
4. ADH makes the collecting-duct cells insert more aquaporins (water channels) into their membranes, so the walls become more permeable to water.
5. More water is reabsorbed by osmosis into the blood → a small volume of concentrated urine is produced.
6. Blood water potential rises back to the set point → osmoreceptors detect this → less ADH is released. (Negative feedback.)

When blood water potential is too high (after drinking a lot), the reverse happens: less ADH, fewer aquaporins, the duct stays relatively impermeable, less water is reabsorbed, and a large volume of dilute urine is produced.

Thermoregulation. Mammals keep core temperature near a set point (~37 °C) so that enzymes work efficiently. Thermoreceptors in the skin and the hypothalamus detect temperature change and the hypothalamus coordinates the response, with the skin as the main effector.

When too hot:

• Vasodilation — arterioles supplying the skin capillaries widen, so more warm blood flows near the surface and more heat is lost by radiation.
• Sweating — sweat glands secrete sweat; its evaporation takes latent heat from the skin, cooling it.
• Hairs lie flat (erector muscles relax), reducing the insulating air layer.

When too cold:

• Vasoconstriction — skin arterioles narrow, so less blood (and less heat) reaches the surface.
• Shivering — rapid involuntary muscle contraction releases heat from respiration.
• Hairs stand erect, trapping an insulating layer of air; sweating stops; the liver may raise the metabolic rate.

Note: vasodilation and vasoconstriction act on the arterioles, not on the capillaries themselves; blood is not 'moved up and down' in the skin.

Control of blood glucose. Blood glucose is held near ~5 mmol dm⁻³ by two antagonistic hormones from the islets of Langerhans in the pancreas. This is another textbook negative-feedback system, with the liver as the main effector.

	After eating (glucose too high)	Fasting/exercise (glucose too low)
Detected by / hormone	β-cells release insulin	α-cells release glucagon
Effect on liver	glycogenesis (glucose → glycogen)	glycogenolysis (glycogen → glucose)
Other effects	more glucose uptake by cells (more carriers); more respiration	gluconeogenesis (glucose from amino acids/glycerol)
Net result	blood glucose falls to set point	blood glucose rises to set point

• Glycogenesis = making glycogen from glucose (storing it).
• Glycogenolysis = breaking glycogen down to glucose (releasing it).
• Gluconeogenesis = making new glucose from non-carbohydrate sources.

Diabetes mellitus occurs when this control fails. In Type 1 the β-cells are destroyed (often an autoimmune response), so little or no insulin is made; it usually appears in childhood and is treated with insulin injections. In Type 2 the β-cells make insulin but the target cells become resistant to it (receptors respond poorly); it is linked to obesity, diet and age and is managed first by diet, weight loss and exercise. Both raise blood glucose so high that the PCT cannot reabsorb it all — hence glucose in the urine.