Adrenergic Transmission and Adrenoceptors

• adrenergic transmission


  neurotransmitter release and termination of action.
• Sympathetic nervous system Organization

  Sympathetic nervous system consists of paravertebral ganglia with pre & post ganglionic fibers & adrenal medulla.

  • Organs receiving only sympathetic innervation: –Most of the blood vessels, Adrenal medulla, Kidney

  • Functioning of cardiovascular system & regulation of BP is mainly a sympathetic activity.

  • The sympathetic and parasympathetic systems produce opposite effects & are in equilibrium. e.g.: CVS, RS etc.
• Sympathetic activity increases in

  • stress - fight or flight response in emergency.

  • many stressful situations such as trauma, fear, hypoglycemia, cold, exercise etc.

  • adaptation to postural changes, exercise or variations in temperature.
• Sympathetic neurotransmitters 


  • Noradrenaline (Norepinephrine) is the primary transmitter at post-ganglionic sympathetic nerves (except those supplying sweat glands) and in adrenal medulla.

  • Adrenaline (Epinephrine) is secreted by the adrenal medulla.

  • Dopamine – secreted by sympathetic dopaminergic fibers in blood vessels (renal & splanchnic) & in brain (basal ganglia etc).
• Norepinephrine Synthesis and Storage

  norepinephrine is formed from dopamine in the synaptic vesicles where it is stored till release following an impulse.

  • In the adrenal medulla, part of NE is methylated into epinephrine & is stored.

  • released NE is taken back into the adrenergic neuron, then into synaptic vesicles, known as reuptake of NE & is essential for

  1. to remove and terminate the action of NE
  2. to replenishes the stores.
• Norepinephrine Release 


  In sympathetic neurons, arrival of an action potential leads to influx of calcium resulting in fusion of the synaptic vesicles with the cell membrane & release of NE into the synaptic cleft.

  • Adrenal medulla releases about 80% of Epinephrine & 20% of NE directly into circulation.

  
• Receptor binding of Norepinephrine

  Adrenergic receptors are G protein-coupled receptors.

  • NE released into the cleft binds either to the

  • presynaptic receptors on the nerve ending – which by a negative feedback mechanism decrease the release of NE.
  • postsynaptic receptors on the effector organ which results in formation of intracellular second messengers :
  • c-AMP
  • the phosphatidylinositol (IP3)leading to action.
• Termination of action of NE

  .

  • Some NE diffuses out of the synapse & is metabolized in plasma or liver.
  • Neuronal Uptake (NET/Uptake 1): about 80% of the released NE is taken up into the neuron, major mechanism of termination of action. - Partly stored in intracellular vesicles for further release - partly metabolized in neuron by MAO. 3. Extraneuronal uptake (Uptake 2): Metabolized in the synapse by COMT in the postsynaptic cell membrane.

  
• Enzymes in the metabolism of Norepinephrine : Monoamine oxidase (MAO)


  
  

  Monoamine oxidase (MAO)-

  • Mitochondrial enzyme present in sympathetic neurons, liver, intestinal epithelium etc.

  • Metabolizes – NE, epinephrine, dopamine, serotonin.

  • MAO plays an important role in regulating the levels of neurotransmitters in CNS also.
• Enzymes in the metabolism of Norepinephrine : Catechol-O-Methyl Transferase (COMT)


  Catechol-O-Methyl Transferase (COMT)

  • Cytoplasmic enzyme.

  • Not present in sympathetic nerve endings.

  • Present in many tissues (smooth muscle, cardiac muscle, endothelium etc.).

  • Inactivates NE, epinephrine, DA.

  • COMT in intestinal wall and liver is responsible for ‘first Pass

  metabolism’ of NE & epinephrine.
• Enzymes in the metabolism of Norepinephrine - MAO & COMT metabolize both

  : endogenous & exogenous NE, epinephrine, dopamine, 5HT.
• Types of adrenergic receptors

  .

  
• Adrenoceptors - Classification Adrenergic receptors are G protein-coupled receptors. 


  Based on selective antagonists they are classified into alpha and beta receptors.

  
• Adrenergic receptors - Classification

  a Receptors

  • a1 & postsynaptic a2 – Excitatory,

  Present in blood vessels of skin and mucosa etc.

  • Presynaptic a2 – Inhibitory. Decrease NE release

  B Receptors: ▪ B1 receptors – Excitatory - Heart

  B2 receptors – Inhibitory – Lungs, Blood vessels, Uterus
• α Adrenergic Receptors Stimulation of

  α1 receptors: Excitatory

  • mydriasis

  • vasoconstriction

  Presynaptic α2 receptors: Inhibitory

  Stimulation results in decrease of NE release.

  E.g. stimulation of α2 receptors decreases sympathetic activity
• β Adrenergic Receptors

  Stimulation of

  β1 receptors : Excitatory

  Increase in heart rate

  Increase in force of contraction of heart. β2 receptors : Inhibitory

  Bronchodilatation (bronchial asthma)

  Vasodilatation

  hepatic glycogenolysis

  Muscle tremor

  
• Terminology in Cardiovascular actions

  Vasoconstriction : Increase in Peripheral resistance (PR)

  → Increase in BP

  Vasodilatation: Decrease in Peripheral resistance (PR)

  → Decrease in BP

  +ve inotropic : Increase Force Of Contraction (FOC)

  → Increase in COP

  +ve chronotropic : Increase in Heart Rate (HR)

  →Increase in COP

  COP : Cardiac output
• Distribution & Effects of α receptor stimulation

  α1 & α2

  
• Distribution & Effects of β receptor stimulation

  β1 & β2

  
• Dopamine Receptors

  Location & effect

  
• Major effects mediated by α- and β-adrenoceptors (Summary)

  .

  
• Regulation of sympatheic activity

  • Pre-synaptic regulation – Immediate – by α2 receptors
• Regulation of sympatheic activity

  • Post-synaptic regulation – follows prolonged drug use by either increasing or decreasing the receptor number.

  – Up-regulation (Increased response)

  – Down regulation (Decreased response)
• Up-regulation & Down regulation

  Up-regulation - Prolonged exposure to an antagonist (deprivation of stimulation by agonist) results in increase in no. of receptors. This leads to supersensitivity to the agonist when the antagonist is discontinued. Down regulation - Prolonged exposure to agonist results in decrease in the no. of receptors & decreased response.
• Post synaptic Receptor regulation

  Don't stop certain drugs after prolonged use (eg: B-blocker)

  
• Presynaptic regulation


  Presynaptic α2 receptor stimulation by NE at the synapse results in inhibition of further release of NE thereby regulating the sympathetic activity.
• Post-synaptic regulation - Receptor up-regulation 


  Up-regulation - increase in no. of receptors which leads to supersensitivity to the agonist when the blocker is discontinued.
• Why beta blockers should not be stopped abruptly?

  Clinical implication: Following abrupt withdrawal of β blockers eg. Propranolol (for Hypertension) - angina & myocardial infarction (ischemic heart disease) may be precipitated due to increased no. of sympathetic receptors & activity. When the antagonist is withdrawn, the endogenous catecholamines act on the receptors (increased in no. due to the antagonist) & produce enhanced action. Hence, beta blockers should not be stopped abruptly
• Post-synaptic regulation - Receptor down-regulation

  Down-regulation:

  Prolonged exposure to β receptor agonists n bronchial asthma results in decrease in no. of receptors & decrease in response,

  i.e. tolerance
• Post-synaptic regulation - Receptor down-regulation

  Clinical implications:

  development of tolerance to bronchodilatory action of Salbutamol during long term treatment of asthma.