Physiology Kanani II

Question 1

What are the basic types of skeletal muscle fibre and mention briefly some of their differences.

Answer 1

Type I: slow twitch fibre that is also slow to fatigue. Contains a high concentration of myoglobin, e.g. soleus muscle
Type II: fast twitch that also fatigues quickly. They have large reserves of glycogen as an energy source, e.g. extraocular muscles. There are two types of fast- twitch fibre depending on their degree of activity

Question 2

What is the function of the T tubule system, and where is it located?

Answer 2

This system is an invagination of the sarcolemma (muscle cell membrane). In skeletal muscle, it is located at the junction of the A and I bands. It also lies adjacent to the sarcoplasmic reticulum (SR), so that there is rapid release of Ca2.
It is important for the transmission of the action poten- tial across the myofibril.

Question 3

List some functional differences between skeletal and cardiac muscle.

Answer 3

• Skeletal muscle is voluntary
• Cardiac muscle contracts spontaneously
  (myogenic)
• In skeletal muscle, Ca2 is released from the
  SR following spread of depolarisation through the T tubule network
• With cardiac muscle, Ca2-release from the SR is triggered by Ca2 that already been released by the SR, and by Ca2 that has influxed through membrane voltage channels. This is called Ca2- induced Ca2 release
• Mechanical summation and tetanus do not occur with cardiac muscle because of the longer duration of cardiac action potential
• In the case of skeletal muscle, increases in force are generated by recruitment of motor units and mechanical summation (see ‘Skeletal muscle’)
• The force of cardiac muscle contraction is determined by the amount of intracellular Ca2 generated. For example through the action of hormones
• Note than in both types of muscle, the initial fibre length at rest (preload) also determines the strength of contraction

Question 4

Draw the action potential curve for the sino atrial (SA) node, and a ventricular myocyte. What is the ionic basis for the shape of the ventricular myocyte action potential?

Answer 4

The ionic fluxes that are responsible for myocyte activation may be divided into a number of phases according to their timing in relation to the curve of the action potential:
Phase 0: Rapid depolarisation – when threshold is reached (around 60 mV), voltage-gated Na- channels open, permitting the influx of Na.
Phase 1: Partial repolarisation – this occurs following closure of the voltage-gated Na-channels
Phase 2: Plateau phase – this may last 200–400 ms. Occurs due to open voltage-gated Ca2 allowing a slow inward current of Ca2 that sustains depolarisation. A persisting outward current of K out that balances the influx of calcium ensures that the membrane potential keeps steady during this plateau phase
Phase 3: Repolarisation following closure of the Ca2-channels, with continued outflow of K
Phase 4: Pacemaker potential – spontaneous depolarisation due to the inherent instability of the membrane potential of cardiac myocytes

Question 5

What is the significance of the ‘plateau phase’ of myocyte depolarisation?

Answer 5

The long plateau phase caused by the slow and sustained influx of Ca2 has two important consequences on myocyte performance:
Myocytes cannot be stimulated to produce tetanic contractions
Myocytes are not fatigueable

Question 6

Why do the pacemaker cells of the heart fire

spontaneously?

Answer 6

Pacemaker cells of the SA and AV nodes have unstable membrane potentials that decay spontaneously to pro- duce an action potential without having to be stimu- lated. Other myocytes do exhibit this inherent instability, but to a lesser extent than the pacemaker cells.
This is unlike the ‘standard’ worker myocyte that has a relatively stable membrane. When the membrane potential of the pacemaker cell drifts to about 40 mV from a 60mV starting point, voltage-gated Na- channels open up as the action potential is triggered.
This instability of the membrane potential is caused by the progressive reduction of the membrane’s permea- bility to K. The resulting retention of intracellular K coupled with a continued background inflow of Na and Ca2 leads to a progressive increase in the mem- brane potential until the action potential is triggered.

Question 7

How does digoxin affect the contractility of the myocyte? What is the mechanism of action?

Answer 7

Digoxin increases the inherent contractility of the myocyte, so that the strength of contraction is higher for any given sarcomere length.
This is a cardiac glycoside that inhibits the cardiac mem- brane Na-K ATPase that normally pumps out Na in exchange for K. Therefore, there is a rise in intracellu- lar Na. This reduces the sodium gradient across the membrane, which in turn slows down the activity of the membrane Ca2-Na pump. In doing so, there is intracellular accumulation of Ca2, leading to increased contractility.

Question 8

What is the relationship between the strength of contraction and the rate of contraction? Why does this occur?

Answer 8

It is known that increasing the frequency of myocyte contraction also increases the strength of contraction. This is known as the ‘Bowditch effect’. It occurs because at higher frequencies of contraction, there is less time for intracellular Ca2 to be pumped out of the cell between beats. Therefore, there is a progressive accu- mulation of intracellular calcium, leading to improved contractility.

Question 9

What are the three cell types found in the pancreas’ Islets of Langerhans, and what do they secrete?

Answer 9

a-cells: secrete glucagon
b-cells: secrete insulin
d-cells: secrete somatostatin

Question 10

Other than insulin and glucagon, which other hormones may influence the serum [glucose]?

Answer 10

There are several, but the most important are:
Catacholamines: epinephrine and norepinephrine
Glucocorticoids: most important being cortisol
Somatotrophin: a pituitary hormone
All of the above increase serum [glucose]. The only hormone that is known to decrease serum [glucose] is insulin.

Question 11

What are the possible metabolic fates for glucose molecules in the body?

Answer 11

Glycolysis: they may be metabolised by glycolysis and then to the tricarboxylic acid (TCA) cycle following the production of pyruvate
Storage: as glycogen, through the process of glycogenesis. Most tissues of the body are able to do this
Protein glycosylation: this is a normal process by which proteins are tagged with glucose molecules. This is by strict enzymatic control
Protein glycation: this is where proteins are tagged with glucose in the presence of excess circulating [glucose]. It is not enzymatically controlled unlike the above example. An example of this is glycosylated haemoglobin
Sorbitol formation: this occurs in various tissues when glucose enters the polyol pathway that ultimately leads to the formation of fructose from glucose

Question 12

Where do the body’s glucose molecules come from?

Answer 12

The diet
Glycogenolysis: following the breakdown of glycogen
Gluconeogenesis: this is the generation of glucose from non-carbohydrate precursors

Question 13

Give some examples of non-carbohydrate molecules that can be converted to glucose (by gluconeogenesis). Which tissues may generate glucose in this way?

Answer 13

Lactate, glycerol and some amino acids, such as alanine. The liver is the only tissue that can normally generate glucose in this way. However, during starvation, the kidneys may also perform gluconeogenesis.

Question 14

What is the pathophysiology of ketosis?

Answer 14

Diabetes mellitus is a state akin to starvation. There is plenty of circulating glucose, but since there is a lack of insulin, the circulating glucose cannot be taken into the cell to be utilised. This leads to increased lipolysis and increased FFA production. Ketone bodies represent readily transportable fatty acids that can be utilised by organs such as the heart and brain. When there is a lack of glucose, improper utilisation of components of the citric acid cycle leads to a continued build up of ketones, leading to metabolic acidosis. The three ketone bodies: acetone, acetoacetate and b-hydroxybutyrate.

Question 15

You are asked to examine a patient with chronic diabetes mellitus. What may you find on examination?

Answer 15

On examining the skin:
Necobiosis lipoidica diabeticorum: seen as red-yellow plaques, usually found on the shin. They may ulcerate
Leg ulcers
Areas of fat atrophy where insulin is injected
Skin infections: cellulites, carbuncles, boils or candidiasis
On examining the eyes:
Diabetic retinopathy on fundal examination Cataracts
Features of peripheral vascular disease, with ulceration: there may be evidence of limb amputation, or gangrene.
On neurological examination:
Presence of a peripheral Charcot’s joint
Features of diabetic neuropathy, such as reduced
sensation and dorsal column function
Features of chronic renal failure: such as skin pigmentation, hypertension, presence of an iatrogenic peripheral arterial fistula in the wrist (for vascular access during haemodialysis).

Question 16

What type of gland is the pancreas?

Answer 16

It is a mixed endocrine and exocrine gland.

Question 17

Microscopically, which other organ does the exocrine component of the pancreas resemble?

Answer 17

The parotid salivary gland. The functional unit of the exocrine pancreas is the acinus. Each acinus consists of a group of polygonal acinar cells that lead into a system of secretory ducts.

Question 18

Roughly, what is the daily volume of pancreatic juice produced?

Answer 18

1–1.5 l daily.

Question 19

What is the juice basically composed of?

Answer 19

There are two main components to the juice:
An aqueous component: containing water, bicarbonate and other ions
An enzymatic component: containing digestive enzymes

Question 20

What are the most important ions found in the

secretions of the exocrine pancreas?

Answer 20

HCO3: at basal secretion, pancreatic juice contains more than twice the concentration of bicarbonate ions as the plasma
Cl: at basal secretion, this is slightly at lower concentration than the plasma
Na: similar concentration to the plasma
K: similar concentration to the plasma
Note that it has a high pH

Question 21

Why is there a reciprocal relationship between bicarbonate and chloride ions?

Answer 21

This is because the two ions are exchanges at the acinar cell membrane, so that chloride is absorbed into the cell from the lumen of the ducts in exchange for increased bicarbonate output into the secretions.

Question 22

List the enzymes secreted by the pancreas. Which molecules are they responsible for the digestion of?

Answer 22

Proteases
 Trypsinogen
 Chymotrypsinogen
 Procarboxypeptidase
 Proelastase  Lipolytic
Lipase
 Phospholipase A2  Starch digestion:
 ’-amylase
Note that the proteases are secreted as the inactive zymogen forms that require activation.

How are they activated?
Trypsinogen is activated by enteropeptidase (also called enterokinase) that is secreted by the mucosa of the duodenum. The trypsin released is then able to activate the other enzymes.

Question 23

Which factors stimulate pancreatic secretion?

Answer 23

Vagal stimulation
Secretin: a hormone produced by the duodenal mucosa following the appearance of acid. Predominantly stimulates the aqueous component
CCK: released from the duodenum following the appearance of fatty food
Gastrin: causes less pronounced stimulation

Question 24

Taking all of this into account, outline the effects

of a total pancreatectomy.

Answer 24

Development of diabetes mellitus
Reduced fat absorption: leading to steatorrhoea together with malabsorption of the fat-soluble vitamins A, D, E, and K
Reduced protein absorption: leading to a negative nitrogen balance
Reduced absorption of Fe and Ca2: this is due to the loss of alkalinisation of the chyme from the stomach that normally promotes the absorption of these ions. Therefore leads to iron-deficiency anaemia and osteoporosis/rickets

Question 25

Can you think of why those who have been rendered diabetic by pancreatectomy are very sensitive to exogenous insulin therapy?

Answer 25

This is because there is also an absolute lack of glucagon (also secreted by the pancreatic islets). This hormone normally counteracts insulin and places a negative feed- back on its metabolic effects.

Question 26

Which ECG changes may you see with hyperkalaemia?

Answer 26

Tall and tented T-waves
Small P-waves
Wide QRS complex

Question 27

Which ECG changes might you see in hypokalaemia?

Answer 27

Small or inverted T-waves
Prolonged PR-interval
S–T segment depression

Question 28

What is the principle function of the proximal convoluted tubule (PCT)?

Answer 28

This structure is the kidney’s major site for reabsorption of solutes – in fact, 70% of filtered solutes are reab- sorbed at the PCT.

What kinds of solute?
The most important are sodium, chloride and potas- sium ions. In addition, nearly all of the glucose and amino acids filtered by the glomerulus are reabsorbed here.
The first half of the PCT also absorbs phosphate and lactate.

Question 29

Which membrane pump system is key to the PCT reabsorptive abilities?

Answer 29

The Na-K ATPase pump.

Question 30

What are the basic functions of the loop of Henle?

Answer 30

Solute reabsorption: about 20% of filtered sodium, chloride and potassium ions are absorbed in the thick ascending limb of Henle
Water reabsorption: about 20% of filtered water is absorbed at the thin descending limb of Henle
Formation of the counter current multiplication system: this is an efficient way of concentrating the urine over a relatively short distance along the nephron with minimal energy expenditure

Question 31

5. Why there is no water reabsorption at the ascending limb of Henle?

Answer 31

This portion of the loop of Henle is impermeable to water.

Question 32

What is the basic function of the DCT and collecting duct?

Answer 32

Reabsorption of solute: about 12% of filtered sodium and potassium are absorbed here
Secretion: variable amounts of potassium and protons are secreted here
Reabsorption of water: this occurs only at the most distal portions of the DCT and collecting duct, since the more proximal areas are impermeable to water

Question 33

Once released, what is the effect of ADH on the kidney?

Answer 33

This leads to an increase in the reabsorption of solute- free water by the collecting duct.
Also leads to NaCl reabsorption by the thick ascending limb of Henle. By increasing the concentration of the interstitium around the loop of Henle, this enhances the nephron’s ability to reabsorb water.

Question 34

Loop of Henle

Answer 34

1. Fluid enters the descending limb of Henle that is isotonic with the plasma. The tubular fluid that leaves the PCT is always isotonic with the plasma
2. The descending limb of Henle is permeable to water (and only slightly permeable to salt and urea. Therefore, water is progressively absorbed down the limb, becoming more and more concentrated (up to 1,200 mOsmol1)
3. The ascending limb of Henle is impermeable to water, but permeable to sodium chloride. There is passive diffusion of NaCl down its concentration gradient, when travelling up the limb. This dilutes the tubular fluid
4. When the thick ascending limb is reached, NaCl is actively pumped out, further diluting the tubular fluid. ADH increases the pumping of NaCl into the interstitium
5. By the time that the tubular fluid reaches the collecting duct, it is hypotonic compared to the interstitium. Therefore, in the presence of ADH (which increases the water-permeability of the collecting duct), water is rapidly reabsorbed
6. By the time that urine is excreted, it has a very high osmolality (up to 1,200 mOsmol1)

Question 35

If the normal CO at rest is said to be 5–6 Lmin1, what is the output of the right side of the heart?

Answer 35

This is also 5–6Lmin1 since under normal circum- stances; the outputs of both sides of the heart are the same.

Question 36

PVR and the lung volume

Answer 36

This shows that at very low lung volumes, the PVR is relatively high, but soon falls following distension of the lungs. After this initial fall, with increasing volumes, the PVR rises again. This rise in the PVR following the initial dip is virtually exponential
Much of these changes can be explained in terms of the elastic forces generated by the collagen and elastin of the lung parenchyma (see ‘Mechanics of breathing IV’). At increasing lung volumes, the elastic recoil forces of the lung increase. This produces a circumferential radial traction force that pulls small airways (i.e. those without cartilaginous walls) and blood vessels open; thus reducing their resistance to the flow of air and blood respectively
At very small lung volumes, due to little radial traction, pulmonary vessels are collapsed. This has the effect of increasing the overall PVR
As the lung expands, radial traction forces on the blood vessels increase, increasing their calibre. This causes a progressive fall in the PVR
At increasing volumes, radial traction overstretches the pulmonary vessels, reducing their calibre. Thus, once again, the PVR rises, and blood flow falls

Question 37

factors controlling the PVR, and hence the pulmonary blood flow.

Answer 37

Pulmonary arterial and venous pressure
Lung volume
Pulmonary vascular smooth muscle tone: this is affected by various mediators, such as the catacholamines, histamine, 5-HT, and arachidonic acid metabolites
Hypoxia: this also has an effect on the smooth muscle tone, but is listed separately due to its importance. This leads to pulmonary vasoconstriction, with an increase in the PVR. The result of this is to improve the ventilation-perfusion ratio in the lung in the face of a fall in the PaO2.
It can therefore be considered to be a defence mechanism against the deleterious effects of hypoxia, e.g. in situations of COPD. However, chronic hypoxia, can lead to irreversible pulmonary hypertension with progressive right heart failure (cor pulmonale).

Question 38

Nitric oxide (NO) is the main method by which many of these mediators act. It is also often used in the management of pulmonary hypertension in the critically ill. What is its mode of action?

Answer 38

It has a very short duration of action, and functions through stimulation of intracellular Guanylate cyclase, which produces cGMP from GTP. This in turn stimulates cGMP-dependant protein kinases that are involved in causing vessel wall smooth muscle cell relaxation
Bradykinin and 5-HT are examples of mediators that act through NO

Question 39

Under normal circumstances, how is the blood flow in the lungs distributed?

Answer 39

In the standing position, the lowest parts of the lungs receive the greatest blood flow. In fact, a linear decrease in the blood flow distribution can be seen from apex to base
This is because the hydrostatic pressure of the most dependent portions is greater

Question 40

How does this alter with exercise?

Answer 40

During mild exercise, the blood flow to the upper and lower portions of the lung increases, but the overall dis- tribution of the flow is more even than during rest.