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Flashcards in Physiology Kanani Deck (31):

What is meant by the ‘resting membrane potential’ for a cell?

This is the potential difference across the cell membrane. This occurs due to the ionic fluxes of Na, K, and Cl across the membrane, the sizes of which are determined by their electrochemical gradients. It is calculated by the Goldman equation, which takes into account the contribution of the equilibrium potentials of each species of ion that crosses the membrane.


What is the typical value of the resting membrane potential for a neurone?

A typical value is 70 mV. The value is negative because the interior of the cell is negatively charged with respect to the exterior.


What is the importance of the Na/K pump for the equilibrium potential?

This pump, which is ATPase-driven, transports 3 Na out of the cell for 2 K pumped in. It helps to maintain the internal and external ionic environment that pro- gressively alters as ions naturally flow down their elec- trochemical gradients. In doing so, it maintains and sustains the potential difference across the cell (Resting membrane potential).


Briefly describe the ionic basis for the action potential.

The changes in the fluxes of ions that account for depolarisation may be summarised in the following

Once the threshold potential is reached by the stimulus, the voltage-sensitive Na-channels open, causing a rapid influx of Na into the cell. This causes depolarisation, and the membrane potential becomes positive. Once open, the Na-channel closes again within milliseconds

During the initial opening of the Na-channels, a positive feedback loop is initiated; so more channels open up, leading to rapid depolarisation
 The cell would remain depolarised if it were not for the rapid closure (inactivation) of the Na-channels

At the same time there is a constant background movement of K out of the cell. This has the effect of placing a limit on the change of membrane potential during the depolarisation phase of the action potential

During repolarisation, there is the opening of the voltage-sensitive K-channels, leading to loss of K from the cell. These react more slowly than the Na-channels, and are open for longer. Thus, repolarisation, with a return to the resting membrane potential is a slower process than depolarisation

After lots of action potentials, when there is the exchange of many ions, the ionic environment is returned to the steady state by the continued and persistent action of the Na/K pumps


What types of nerve fibres are there?

Peripheral nerve fibres may be classified in the follow- ing way:
 Group A: These are the largest (up to 20 ’m):
 ’ (Ia and Ib): Motor and proprioception fibres
 ’ (II): Touch, pressure and proprioception fibres
 ’ (II): Muscle spindle fusimotor fibres
 ’ (III): Touch pain and pressure fibres
 Group B: Myelinated fibres which are autonomic preganglionic (up to 3 ’m)
 Group C (type IV): Unmyelinated fibres which carry postganglionic fibres, and fibres for touch and pain (up to 2’m)


Briefly list some drugs that may alter the conduction along a neurone.

Some agents which can modify the activation and propagation of the action potential include:
 Tetrodotoxin: a neurotoxin that is a selective blocker of Na-channels
 Tetraethylammonium: a selective K-channel blocker, which prolongs the action potential
 Local anaesthetic agents: composed of an amine group connected to an aromatic side chain via an ester or amide bond. They are selective blockers of the voltage-dependent Na-channels


What are the anatomic layers of the adrenal cortex, and which hormones do they produce?

 Zona glomerulosa: the superficial layer. Mineralocorticoid production occurs here
 Zona fasiculata: the middle layer
 Zona reticularis: the deepest layer
 The deepest two layers are for the production of glucocorticoids, androgens, and oestrogens. Progestogens are also produced, but they act mainly as precursors in the production of the other hormones


What are the physiological effects of aldosterone?

 Sodium balance: stimulation of sodium reabsorption in the distal convoluted tubule (DCT) and collecting duct of the kidney, sweat glands, salivary glands and gut
 Potassium balance: through the active exchange with sodium ions at the membrane, leading to the loss of serum potassium

 Acid-Base balance: H may also be exchanged with Na, leading to loss of H from the plasma. Therefore, aldosterone excess may lead to a metabolic alkalosis

 Water balance: as a consequence of increasing the serum [Na], there is stimulation of pituitary osmoreceptors, leading to increased release of arginine vasopressin (AVP) (also known as antidiuretic hormone (ADH)). This leads to water retention, and so a return of the [Na] back to normal at the expense of increased circulating volume


Describe the principle mechanisms controlling aldosterone release

Aldosterone release is stimulated by
 Increased renin secretion: this increases the serum aldosterone through increasing serum angiotensin II. Important stimuli for the release of renin is reduction of renal perfusion and reduced presentation of sodium to the kidney’s macula densa
 Decrease of plasma [Na]
 Increase of plasma [K]
Aldosterone secretion is reduced by the opposite of the above together with
 Increased circulating atrial natriuretic peptide (ANP): this has an inhibitory effect on renin release, and so acts indirectly to inhibit aldosterone release


What are the most common causes of Cushing’s
syndrome of cortisol excess?

In their order of frequency:
 Iatrogenic steroid administration
 Cushing’s disease: due to an adenoma of the pituitary leading to over secretion of adrenocorticotrophic hormone (ACTH)
 Ectopic ACTH secretion: such as a peripheral tumour, often in the lung
 Adrenal adenoma: leading to hypersecretion of cortisol. Note that unlike the above two cases, cortisol excess here is autonomous and independent of ACTH
 Adrenal carcinoma


What are the principle causes of adrenal insufficiency?

 Auto-immune adrenalitis: leading to Addison’s disease
 TB: of the adrenal glands
 Less commonly due to tumours, amyloid or other bacterial infection of the glands


What is the most common cause of congenital adrenal hyperplasia?

21-hydroxylase deficiency. This leads to ACTH excess following reduced glucocorticoid and mineralocorti- coid synthesis. Can produce congenital hyperkalaemia and an Addisonian crisis with vomiting and dehydra- tion. Since the path of hormone production goes down that of androgen synthesis, leads to developmentally ambiguous genitalia.


How does the embryonic origin of the adrenal cortex differ from that of the medulla?

The adrenal cortex is mesodermal in origin, whereas the medulla is derived from neuroectoderm. This deter- mines the pattern of innervation of the adrenal gland.


How is the adrenal medulla innervated?

Preganglionic sympathetic fibres synapse directly onto the chromaffin cells of the adrenal medulla. As with other preganglionic autonomic synapses, the neuro- transmitter at this point is acetylcholine (ACh).
ACh release from the preganglionic sympathetic fibre stimulates the release of catecholamines by exocytosis, just in the same manner as any other synapse.
Therefore, in effect, the chromaffin cells are specialised postganglionic sympathetic neurones that secrete their transmitter directly into the circulation. The origin of this arrangement arises from the neuroectodermal ori- gin of the adrenal medulla.


What biochemical tests may be performed to make the diagnosis?

A number of tests can be performed to establish the diagnosis, predominantly based on measuring catecholamine metabolites:
 24 urinary measurement of vanillyl mandelic acid: the traditional investigation, but misses 30% of cases of phaeochromocytoma
 Metadrenaline: more sensitive than the above
 Plasma or urinary epinephrine or norepinephrine:
best measured during hypertensive episodes


Which drug is used in the management of this condition?

Phenoxybenzamine: this is an ’-adrenoceptor antagonist.


How are the multiple endocrine neoplasia (MEN)
syndromes classified?

These conditions essentially occur in three groups:
 Type I: adenomas of the parathyroid, pancreatic and anterior pituitary glands
 Type IIa: hyperparathyroidism, phaeochromocytoma, medullary carcinoma of the thyroid
 Type IIb: phaeochromocytoma, medullary carcinoma of the thyroid, with multiple cutaneous neuromas and neurofibromas


Where are the locations of the cell bodies of the neurones that make up the SNS?
Sympathetic nervous system

 Preganglionic cells: cell bodies are located at the lateral horns of the spinal grey matter. This extends from T1 to L2 (thoraco-lumbar outflow)
 Postganglionic cells: cell bodies are located in the sympathetic chain


Other than their location, how else do pre and postganglionic cells of the SNS differ?

 Preganglionic fibres are myelinated: therefore, their diameter is larger with more rapid transmission of the action potential
 Differences in the neurotransmitter: the transmitter substance secreted by preganglionic cells is ACh (acting on nicotinic receptors), and by postgan- glionic cells is noradrenaline


What is special about the mode of sympathetic supply to the adrenal medulla?

The chromaffin cells of the adrenal medulla receive direct innervation from preganglionic sympathetic fibres arising from the lateral horn of the spinal cord. Stimulation leads to secretion of catacholamine from the chromaffin cells, so these cells are akin to postgan- glionic cells of the SNS.


How does the origin of the PNS differ from the SNS?

 Preganglionic parasympathetic: these neurones take origin from specific cranial nerve nuclei and from sacral segments 2–4 of the spinal cord (cranio-sacral outflow vs. thoraco-lumbar origin of the SNS)
 Parasympathetic ganglia: unlike the sympathetic chain, the PNS ganglia are located at discrete points close to their respective target organs


Which cranial nerves have a parasympathetic outflow?

Cranial nerves III, VII, IX and X.


Can you name the four main types of receptor involved in cellular signalling? Give some examples.

 Ion channel linked receptor: e.g. nicotinic cholinoceptors at the neuromuscular junction
 G-protein coupled receptor: e.g. muscarinic cholinoceptors and adrenoceptors
 Tyrosine kinase linked receptor: e.g. various growth factors, insulin receptor
 Intracellular receptor: steroid hormone receptors


What basically happens when a ligand binds to a
G-protein coupled receptor?

Receptor stimulation by the ligand causes binding of the receptor to its G-protein. This causes the G-protein to release (inactive) guanosine diphosphate (GDP) and uptake (active) guanosine triphosphate (GTP). Depending on the type of G-protein that the receptor is coupled to, the G-protein may then activate the enzyme adenylyl cyclase, or inhibit it, or it may stimulate the enzyme phospholipase C.


What are the components of the G-protein?

This is composed of ’, ’ and ’ subunits:
 ’ subunit: variation in this determines the type of
G-protein. This component binds to GDP and GTP
 ’ and ’ components bind reversibly to the ’ subunit


What is the functional significance of the ’ subunit?

This determines the type of G-protein and therefore its function. There are several types of ’ subunit, each linked to a particular type of G-protein. Three exam- ples are:
 Gs: receptor binding to this system leads to activation of adenylyl cyclase, e.g. occurs with
’1- and ’2-adrenoceptor stimulation and glucagon signals through this pathway
 Gi: receptor binding to this system leads to inhibition of adenylyl cyclase, e.g. with ’2-adrenoceptor stimulation
 Gq: binding produces activation of phospholipase C, e.g. ’1-adrenoceptors


What is the result of activation or inhibition of adenylyl cyclase by the activated G-protein?

This leads to an increase or decrease in intracellular cAMP, respectively. This molecule is termed a second messenger, since it is an intermediary product following G-protein coupled receptor stimulation. It stimulates molecules within the cell, such as protein kinases, leading to activation of many intracellular reaction cascades.


Can you give some more examples of other second messengers generated through G-protein receptor stimulation? What effects do these have within the cell?

DAG: this is produced when activated phospholipase C (generated from Gq-protein linked receptor stimulation) hydrolyses inositol triphosphate (IP3). DAG stimulates various cellular protein kinases
 IP2: this is also generated by hydrolysis of IP3 by activated phospholipase C. IP2 has the effect of causing Ca2 release from the endoplasmic reticulum, such as occurs during activation of smooth muscle cells
 Cyclic guanosine monophosphate (cGMP): leads to activation of protein kinase G
 Arachidonic acid and eicosanoids: these are produced by G-protein linked receptors that activate phospholipase A2. These have numerous effects following production of prostaglandins


Outline the events that occur during defecation.

The defecation reflex is triggered by the distension of the rectal walls by faeces entering from a mass contraction proximally
 The intra-rectal pressure has to reach 18 mmHg before the reflex is triggered
 Afferent impulses pass to sacral segments 2, 3 and 4. This leads to stimulation of the efferent reflex pathway, together with stimulation of the thalamus and cortical sensory areas producing the conscious desire to defecate
 Efferent impulses pass back to the myenteric plexus of the rectum, activating postganglionic PNS neurones
 This leads to contraction, propelling the faeces forward
 PNS stimulation also leads to relaxation of the internal anal sphincter
 The external sphincter relaxes, reducing the pressure in the anal canal. Further peristalsis in the rectum pushes the faeces out
 This is augmented by voluntary contractions of the pelvic floor muscles when performing the Valsalva manoeuvre


What happens to the reflex pathway when there is conscious desire not to defecate?

When faecal material enters the upper anal canal, there is stimulation of S1, 2 and 3, as mentioned. If the desire to defecate is resisted, then this leads to activation of the pudendal nerve, which sends signals to the external anal sphincter, increasing its tone. There is also acti- vation of ascending pathways to the sensory cortex, enabling the subject to distinguish between solid and gaseous material in the rectum. If there is solid, descending pathways reinforce the external sphincter. If the content is gas, the descending pathways lead to relaxation of the sphincter and expulsion of the gas.


When does involuntary defecation occur?

This occurs when the rectal pressure is greater than 55 mmHg. This may occur either because of a volumin- ous content, or in the presence of colonic spasm and diarrhoea.
The reflex defecation triggered by this pressure rise also occurs in the spinal patient.