Lec 7-ANS 4 Flashcards
Noradrenergic transmission
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
Adrenoreceptor subtypes
- 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
Distribution of adrenoreceptors
- 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)
Adrenoreceptor subtypes- A1
- 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
Adrenoreceptors subtypes- A2
- Inhibit adenylate cyclase (decrease in cAMP)
- Presynaptic at autonomic nerve terminals –> inhibition of transmitter release; decrease insulin secretion
- Agonist: Clonidine
- Antagonist: yohimbine
Adrenoreceptors subtypes-B1
- Activate adenylate cyclase (increase cAMP)
- Increase heart rate and force of contraction
- Agonist: dobutamine
- Antagonist: Atenolol
MAP kinase
- 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
Adrenoreceptors subtypes-B2 adrenoceptors
- 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
Adrenoreceptors subtypes-B3
- Activate adenylate cyclase (increase cAMP)
- B3 Lipolysis and thermogenesis
Selectivity and specificity
- 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)
Synthesis of catecholamines
- 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
Noradrenaline- storage
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
Noradrenaline- reuptake Uptake 1
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
Noradrenaline- reuptake Uptake 2
Uptake by non-neuronal cells ‘Uptake 2’
- Low affinity, high maximum rate
- Transport NA, adrenaline, dopamine, 5-HT, isoproterenol
- Inhibited by phenoxybenzamine, steroid hormones
Noradrenaline- release
-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
Indirectly-acting sympathomimetics
-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
Noradrenaline- metabolism
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
