Pharmacology 1 - Asthma (1) Flashcards
What neurotransmitter do all preganglionic fibres of the sympathetic and parasympathetic division use?
Acetylcholine
Where are cell bodies of the preganglionic fibres of the parasympathetic division located?
In the brainstem (this is where they synapse onto the post-synaptic fibre)
Where are the cell bodies of the postganglionic fibres located (parasympathetic) in the respiratory system?
In the walls of the bronchi and bronchioles
What does stimulation of postganglionic cholinergic fibres cause in terms of bronchial smooth muscle?What is this mediated by?
Bronchial smooth muscle contractionM3 muscarinic ACh receptors on airway smooth muscle cellsIncreased mucus secretion mediated by M3 muscarinic ACh receptors on goblet cells
What does stimulation of postganglionic noncholinergic fibres cause (parasympathetic division)?
Bronchial smooth muscle relaxation mediated by NO and VIP (instead of ACh which would cause contraction)
What are nitric neurones?
nerve cells where transmission is mediated by NO
What 2 effects can the parasympathetic system have on airway smooth muscle and what is each mediated by?
Contraction = cholinergic post-synaptic neurone (uses ACh)Relaxation = nitrergic post ganglionic neurone (uses NO and VIP)
Does the sympathetic nervous system supply the lungs?
Post-ganglionic fibres supply submucosal glands and smooth muscles of blood vesselsThere is NO innervation of bronchial smooth muscle
What does stimulation of the sympathetic nervous system cause in terms of the lungs? (4)what is each mediated by?
Bronchial smooth muscle relaxation via B2-adrenoceptors on airway smooth muscle cells activated by adrenaline released from the adrenal glandDecreased mucus secretion mediated by B2 adrenoceptors on goblet cellsIncreased mucociliary clearance (mediated by B2 adrenoceptors on epithelial cells)Vascular smooth muscle contraction mediated by alpha1-adrenoceptors on vascular smooth muscle
How does airway smooth muscle contract at the cellular level - G-protein-coupled receptor mechanism?
The transmitter or hormone activated the G-protein coupled receptor (in lungs this is M3)This activates the membrane bound enzyme PLC PLC degrades PIP2 to IP3 which is a secondary messengerIP3 diffuses through the cytoplasm until it encounters the IP3 receptor on the sacroplasmic reticulumIP3 opens the channel and calcium diffuses out of the reticulum and into the cytoplasm which causes contraction
What is the sarcoplasmic reticulum?
The main calcium ion store in the cell
How many ways can smooth muscle be stimulated to contract (cellular level)?
Either by the activation of G protein coupled receptors (most important)Depolarisation activating a calcium channel on the cell surface
How does airway smooth muscle contract at the cellular level - calcium channel mechanism?
Depolarisation activates a Ca2+ channel on the cell surfaceCalcium moves down the concentration gradient into the cell This is an amplification stopCalcium binds to the calcium activated calcium channel (ryanodine receptor) on the sarcoplasmic reticulum membrane which causes the channel to open and calcium to leave the internal Ca2+ store causing contraction
How does the release of calcium from the sarcoplasmic reticulum initiate contraction of smooth muscle?
Increase in intercellular calcium concentration is sensed by a calcium binding molecule within the cytoplasm called Calmodulin (this is a regulatory protein - not an enzyme)When Calmodulin binds to Ca2+, it undergoes a conformational change and becomes an active complex which can integrate with downstream targetsCa2+-Calmodulin wraps itself around inactive MLCK activating itActive mLCK tips the terminal phosphate from ATP = ADP and Pithis Pi phosphorylates the myosin cross bridge forming an actin myosin cross bridge which can bind actin
What does MLCK stand for?
Myosin light chain kinase
In terms of the regulatory myosin light chain, what causes contraction of smooth muscle cells?
phosphorylation of MLC in the presence of elevated intracellular Ca2+
How does smooth muscle relax?
Due to dephosphorylation fo MLC by myosin phosphatase (MLCK and myosin phosphates activity opposes each other)
What does myosin light chain kinase do?
Phosphorylates (adds a phosphate) to the myosin light chain causing contraction
What does myosin phosphatase do?
Dephosphorylates the myosin light chain = relaxation
What happens to the enzymes in the presence of elevated intracellular Ca2+
the rate of phosphorylation exceeds the rate of dephosphorylationTherefore for relaxation the intracellular Ca2+ concentration must return to basal level (achieved by primary and secondary active transport)
What happens when B2 adrenoceptor is stimulated by adrenaline in terms of phosphorylation?
B2 adrenoceptor is coupled to Gs which activates adenyl cyclase (AC)AC causes the conversion of ATP to cAMP which binds to protein kinase A (PKA) activating it (cAMP is degraded by Phosphodiesterase (PDE))PKA phosphorylates the myosin light chain kinase inhibiting it and phosphorylates myosin phosphatase stimulating itThis results in relaxation of bronchial smooth muscle
What happens to vascular smooth muscle due to release of adrenaline and through what receptors?
Activation of B2 = vasodilation at lungsActivation of alpha 1 = vasoconstriction in rest of body
What is asthma?
Recurrent and reversible (in the short term) obstruction of the airways in response to substances (or stimuli) that are not necessarily noxious and normally do not affect non-asthmatic subjects