Lec 7-ANS 4

Question 1

Noradrenergic transmission

Answer 1

Evidence for multiple receptor subtypes

• 1913: dale showed that adrenaline could cause vasoconstriction in some vascular beds, vasodilation in others
• 1948: Ahlquist postulated the presence of 2 subtypes of adrenoreceptors, differing in agoinst potency
• ALPHA: NorA-> Adren-> isoproterenol (isoprenaline)
• BETA: isoproterenol –> Adrenaline –> Noradrenaline

Question 2

Adrenoreceptor subtypes

Answer 2

• Adrenoreceptors classified according to order of agonists and antagonist potency: 2 subtypes of alpha-adrenoreceptors; 3 subtype Beta-adrenoreceptors
• All are G-protein-coupled receptors

Question 3

Distribution of adrenoreceptors

Answer 3

• B1= heart (increased force and rate of contraction)
• B2= Arteries and veins (dilations)/ Bronchial muscle (Relaxation)/ GI tract (Relaxation)/ Liver and pancreas (Glycogenolysis, gluconeogenesis, lipolysis)/ Uterus (Relaxation)/ Detrusor muscle (Relaxation)
• A1 = Arteroies and veins (Constriction)/ Liver and pancreas (glycogenolysis, gluconeogenesis, lipolysis)/ Uterus (Contraction)/ Bladder sphincter (Contraction)/ Pupils (Dilation)/
• A2= Arteries and veins (constrict and dilate)

Question 4

Adrenoreceptor subtypes- A1

Answer 4

• Activate phospholipase C (Increase IP3, DAG –> increase Ca2+)
• Constriction of smooth muscle in blood vessels; relaxation of smooth muscle in GI tract; Hepatic glycogenolysis
• Agonist; Phenylephrine
• Antagonist; Prazosin

Question 5

Adrenoreceptors subtypes- A2

Answer 5

• Inhibit adenylate cyclase (decrease in cAMP)
• Presynaptic at autonomic nerve terminals –> inhibition of transmitter release; decrease insulin secretion
• Agonist: Clonidine
• Antagonist: yohimbine

Question 6

Adrenoreceptors subtypes-B1

Answer 6

• Activate adenylate cyclase (increase cAMP)
• Increase heart rate and force of contraction
• Agonist: dobutamine
• Antagonist: Atenolol

Question 7

MAP kinase

Answer 7

• Beta-AR becomes phosphorylated after chronic stimulation and binds to beta-arrestin
• Beta-arrestin activates kinases
• The receptor with beta-arresting can activate the MAOK pathway which cause protein phosphorylation
• Agonist differ in there ability at stimulating the 2 pathways e.g. dobutamine stimulate adenylate cyclase but others are good at stimulating B-arrestin, this is known as agonist bias

Question 8

Adrenoreceptors subtypes-B2 adrenoceptors

Answer 8

• Activate adenylate cyclase (increase cAMP)
• Relaxation of smooth muscle in bronchi; muscle tremor
• Relaxation of vascular smooth muscle but effect masked by A1-mediated vasoconstriction
• Agonist: salbutamol
• Antagonist: butoxamine

Question 9

Adrenoreceptors subtypes-B3

Answer 9

• Activate adenylate cyclase (increase cAMP)

- B3 Lipolysis and thermogenesis

Question 10

Selectivity and specificity

Answer 10

• Ideal drug will be selective for a particular subtype of receptors
• Cardiovascular disorders- want B1-specific antagonist to slow heart rate without affecting the B2-receptors in smooth muscle of bronchi (bronchoconstriction) e.g. atenolol
• Asthma- want B2-specific agonist to relax bronchi without affecting B1-receptors in heart (tachycardia) e.g. salbutamol
• BUT: drugs are selective, not specific –> means after a certain concentration they will start affecting the other type of receptor (salbutamol in large quantities causes tachycardia)

Question 11

Synthesis of catecholamines

Answer 11

• Tyrosine (Tyrosine Hydroxylase rate limiting step)- inhibited by A-methyltyrosine used in phaeochromocytoma —>
• DOPA (DOPA decarboxylase)- methyldopa is false substrate used in hypertension) —>
• Dopamine (Dopamine B-hydroxylase) —>
• Noradrenaline (Phenylethanolamine N-methyltransferase)- mainly in adrenal medulla —>
• Adrenaline

Question 12

Noradrenaline- storage

Answer 12

Stored in vesicles in nerve terminals and chromaffin cells

• Vesicular uptake blocked by Reserpine: NA degraded by cytosolic monoamine oxidase (MAO); NA stores depleted
• Useful experimental drugs

Question 13

Noradrenaline- reuptake Uptake 1

Answer 13

The action of catecholamines is terminated by:

• Reuptake by nerve terminals ‘Uptake 1’:
• High affinity, low max rate
• Relatively selective for NA
• Blocked by: tricyclic antidepressants; phenoxybenzamine; amphetamine; cocaine

Question 14

Noradrenaline- reuptake Uptake 2

Answer 14

Uptake by non-neuronal cells ‘Uptake 2’

• Low affinity, high maximum rate
• Transport NA, adrenaline, dopamine, 5-HT, isoproterenol
• Inhibited by phenoxybenzamine, steroid hormones

Question 15

Noradrenaline- release

Answer 15

-Noradrenergic neuron blocking drugs inhibit neurotransmitter release:
-e.g. guanethidine
Concentrated in nerve terminals by uptake 1 –> impaired impulse conductance;
Accumulates in vesicles via transport –> displace NA and interferes with exocytosis
-NA release is regulated by presynaptic autoreceptors (A2): autoinhibitory feedback

Question 16

Indirectly-acting sympathomimetics

Answer 16

-For example: ephedrine; amphetamine; tyramine
-Taken up by uptake 1 and vesicular transporters in exchange for NA:
NA released via uptake 1 acts on post-synaptic adrenoreceptors;
Some NA degraded by cytosolic MOA; (actions of these agents potentiate by MOA inhibitors)
-Acts on VMAT which is the transporter that take NA from cytoplasm into vesicles
+When it interacts with VMAt it enters the synaptic vesicle and NA enters nerve terminus
-If there is a large release of NA (large amount of amphetamine) then this can cause uptake 1 to reverse so this causes even more NA to be released into synaptic cleft

Question 17

Noradrenaline- metabolism

Answer 17

MONOAMINE OXIDASE (MOA)
-The intracellular enzyme, abundant in adrenergic nerve terminals. Also in gut wall and liver
-Also metabolises dopamine and 5-HT
-Inhibition –> increase releasable store of NA
CATECHOL-O-METHYLTRANSFERASE (COMT)
-Widespread in neuronal and non-neuronal tissue
-Metabolises catecholamines and products of MOA metabolism