Adrenergic transmission in the ANS

Question 1

Main processes regulated by the ANS

Answer 1

Contraction and relaxation of visceral and smooth muscle.
All exocrine and certain endocrine functions.
Heartbeat
Energy metabolsim, particularly in liver and skeletal muscle.

Question 2

Parasympathetic

Answer 2

Rest and digest, slows HR, increases gut motility.
Preganglionic neuroness (ACh nic) located in sveral cranial nuclei, the brainstem and sacral segments of the spinal cord.
Post ganglionic neurons (ACh Mus)located within or near target organ.

Question 3

Sympathetic

Answer 3

Fight or flight, increase HR, only innervation to sweat glands.
Preganglionic neurons (ACh) lie in the lateral horn of the grey mattef of thoracic and lumber segments of the spinal cord.
Preganglionic neuronsexit the spinal cord via the ventral root and synapse onto postganglionic (NA) cell bodies located within the paravertbral chain (sympathetic trunk) on either side of the spinal cord.
NA acts on alpha and beta adrenoceptors.
Adrenal medulla is exception as it is really controlled by the CNS.

Question 4

NA

Answer 4

A major transmitter released by sympathetic nerve termimals.
Synthesized from L-tyrosine, as shown on flashcard

Question 5

NA storage

Answer 5

Mostly within vesicles, very little free in the cytoplasm.
Transported into vesicles by vesicular monoamine transporter (VMAT)
Co-transmission of ATP and protein chromgranin A with NA.
Within the vesicle cotransmitters have two functions - to reduce leakage of NA and reduce osmolarity of contents.

Question 6

NA release

Answer 6

Calcium mediated exocytosis

One AP leads to release of many vesicles

Question 7

Modulation of NA release

Answer 7

Autoregulation by action on presynaptic alpha2 adrenoceptors.
Inhibiting Calcium entry into the nerve terminal inhibits the release of NA.
Adensine and 5HT both decrease NA release.
Angiotensin II increases NA release.
NA inhibits the release of ACh presynaptically and vice versa.
NA terminals also repsond to high levels of cotransmitters by inhibiting NA release.

Question 8

Degradation of NA

Answer 8

By monoamine oxidase (MAO) in the nerve terminal.
By catechol-o-methyl transferase in many tissues (adrenal medulla) but not nerve terminals.

MAO is bound to the surface membrane of mitochondria and is abundant in nerve terminals, liver and intestjnal epithelium.it converts catecholamines to aldehydes and then carboxylic acid.

Question 9

Reuptake of NA

Answer 9

Uptake 1 - NA transporter, presynaptic, high affinity and relative specificity for NA.
Uptake 2 - found on cell membranes of non-neuronal cells. Low affinity for NA, also trasports Adr and isoproterenol. Used to limit the spread of NA, clean-up from bloodstream.

The electrochemical gradient of sodium, created by sodium/chlorine transporters provides the energy for movjng NA from the synaptic cleft to nerve terminal.

Question 10

Adrenoceptors

Answer 10

All are G-protein coupled.
Alpha1 potency NA>Adr>Iso
Alpha2 potency Adr>NA>Iso
Alpha1 receptors are postsynaptic only, and increase cAMP formation (vasoconstriction).
Alpha2 receptors are post- and pre-synaptic, and decrease cAMP formation (relaxation and autoregulation of NA).

Beta adrenoceptor potency Iso>Adr>NA (Adr=NA in B3)
Beta receptors stimulate adenylate cyclase and increase cAMP.

Question 11

NA in CNS

Answer 11

NA cell bodies occur in discrete clusters, mainly within the pons and medulla.
NA has a primary inhibitory role in the CNS.
Important in wakefulness (arousal), BP regulation and mood control.
Psychotropic drugs acting on NA transmission in the CNS include cocaine and amphetamine.

Question 12

Drugs that effect NA storage

Answer 12

Reserpine - blocks VMAT, decreasing NA stores, leading to decreased transmission. Anti-hypertensive but causes depression as it depletes dopamine from neurones in the brain, no longer used clinically.

Methyl-dopa - used rarely in the teatment of high BP (pre-eclampsia). Taken up by NA neurones, converted into false transmitter (alpha-methylnoradrenaline), and displaces NA within synaptic vesicles. Released in the same way as NA but is a potent agonist for alpha2 receptor, further decreasing NA release. Less affinity to alpha1 than NA so less vasoconstriction.

Question 13

Drugs that effeft NA reuptake

Answer 13

Uptake 1 - inhibition increases sympathetic transmission, by keeping NA in the synaptic cleft.
Inhibited by tricyclic antidepressants (desipramine) has major effect on CNS,peripheral effects cause tachycardia/dysrhythmia.
Cocaine also inhibits uptake 1, causing tachycardia and increased arterial BP.

Uptake 2 - inhibited by corticosteroids.

Question 14

Drugs can affect NA release in many ways

Answer 14

Directly block NA release.
Evoke NA release in the abscence of an AP.
Interact with presynaptic receptors to inhihit or enhance NA release.
Increase or decrease NA stores (reserpine)

Question 15

Drugs that directly block NA release

Answer 15

Guanethidine - taken up by uptake 1 and concentrated in nerve terminal. Inhibits NA release by blocking nerve impulse conduction, and deplacing NA in vesicles. NA stores are gradualy depleted leading to decreased transmission. Anti-hypertensive but severe side effects (postural hypotension, neurotoxicity).

Question 16

Drugs that evoke NA release in the abscence of an AP

Answer 16

Indirectly acting sympathomimetic amines. (amphetamine, tyromine).
Weak actions on adrenoceptors but resemble NA so taken up by uptake1. Displaces NA in vesicles, NA is released into cytosol where it is either degraded by MAO or escapes into synaptic cleft via uptake1 an exerts effect on postsynaptic receptors. No specific actions.
MAO inhibitors potentiate sympathomimetic actions by inhibiting degradation of displaced NA.
MAO inhibitors prevent degradation of tyramine, ingestion of tyramine rich food (brie) can evoke sudden increased BP in patients on MAO inhibitors - cheese reaction.
Amphetamine used as CNS stimulant in narcolepsy, ill effects on pns.
Ephedrine (nasal decongestant) - little CNS action, can cause hypertension and tachycardia but not used long-term.

Question 17

Drugs that act on presynaptic receptors to enhance NA release

Answer 17

Yohimbine - alpha2 antagonist, increase NA release by decreasing reducing inhibition.
Angiotensin II - increases NA release.
Beta2 stimulation increases NA release.
Beta2 agonists - salbutamol, terbutaline, salmeterol.

Question 18

Drugs that act on presynaptic receptors to decrease NA release

Answer 18

Clonidine - alpha2 agonist, decreases NA release.
Adenosine and 5-HT decrease NA release.

Partial agonists produce submaximal effects and are used in Hypertension.

Question 19

Beta-Adrenoceptor agonists in the heart

Answer 19

Catecholamines stimulate beta1 adrenoceptors in the heart.
This increases HR and force of contraction.
It does this by stimulating adenylate cyclase which leads to increased calcium concentration and therefore contraction.
Can disturb cardiac rhythm and cause ventricular fibrillation.
Non specific beta1 agonists -
Dobutamine is used to treat cardiogenic shock
Adrenaline is used to treat cardiac arrest

Question 20

Adrenoceptor agonists in smooth muscle

Answer 20

Catecholamines stimulate alpha1 receptors in vascular smooth muscle, resulting in contraction.
Arteries and veins constrict, there is decreased vascular compliance, a rise in central venous pressure and total peripheral resistance. Overall increased arterial BP and cardiac output.
Alpha1 agoninst - phenylephrine.

Alpha2 agonists lead to relaxation and are anti-hypertensives (clonidine).

Catecholamines also stimulate beta2 receptors in bronchial smooth muscle resulting in relaxation and dilation.
Beta2 agonist - salbutamol.

Question 21

Alpha adrenoceptor antagonists

Answer 21

Non-selective alpha antagonists (phenoxybenzamine) also antagonise actions of ACh, 5HT, and histamine. Long lasting effects due to covalent bonds with receptor. Decreases arterial BP by blocking alpha mediated vasoconstiction.

Alpha1 selective antagonists (prazosin) result in vasodilation and a fall in arterial BP. High selectivity means they do not bind alpha2 presynaptically thus do not stimulate NA release.

Alpha2 selective antagonists (Yohimbe) result in vasodilation but also act on NA presynaptically.

Ergot derivatives act on alpha adrenoceptors but are not used clinically.

Question 22

Beta adrenoceptor antagonists

Answer 22

Beta blockers have greatest effect on CVS and bronchial smooth muscle.
Used for treatment of angina, myocardial infarction, dysrhythmia and heart failure.
Slight increase in airway resistance, not suitable for asthmatics.
Non-selective - propanolol
B1 selective - atenolol.
Side effects - cardiac depression, bradycardia and hypoglycemia.