Lecture 6 - PNS/Adrenergic Receptors Flashcards
Adrenal medulla?
Major organ of sympathetic NS, secretes lots of adrenaline (little NE).
Chromaffine storage cells - preganglionic sympathetic fibres release Ach and act on nAchR –> chromaffin storage depolarisation and influx of Ca2+ through VG Ca2+ channels. Ca2+ triggers exocytosis of chromaffin granules and thus release adrenaline into blood stream.
Noradrenaline synthesis in sympathetic neurones?
TYROSIN transported into sympathetic nerve axon –> converted to DOPA by TYROSINE HYDROXYLASE –> converted to DOPAMINE by DOPA CARBOXYLASE –> transported into vesicles, converted to NORADRENALINE by DOPAMINE-B-HYDROXYLASE.
Action potential –> depolarises and Ca2+ enters axon –> increase [Ca2+] causes vesicles to migrate to axonal membrane and fuse. NE –> extracellular space –> binds post junctional receptor and stimulates organ (effector) response.
Adrenaline synthesis in adrenal medulla?
NORADRENALINE –> ADRENALINE by PHENYLETHANOLAMINE-N-METHYL TRANSFERASE in adrenal medulla.
Sympathetic pre-gang fibres release Ach –> binds post junctional nicotinic receptors –> leads to adrenaline synthesis in adrenomedullary cells. Additional enzyme (PNMT) adds methyl group to NE molecule –> adrenaline. Released into blood perfusing the glands and carried throughout body.
Adrenergic receptor classification?
Two main classes (a and b) - based on potency profiles for adrenaline/noradrenaline and isoprenaline. Further divided into 3 a1, 3 a2 and 3 b receptors (based on molecular biology).
Differentially expressed in tissues and regulate diverse physiological responses.
Physiological functions of alpha adrenoreceptors?
a1 - activates PLC –> IP3 + DAG (via Gq) - generally post synaptic, results in contraction in SMCs due to increase in [Ca2+]. Causes relaxation of gut due to contraction of circular muscle.
a2 - inhibits adenylate cyclase –> decrease in cAMP production (via Gi) - generally presynaptic, inhibits release of noradrenaline from post ganglioninc neurone (-ve feedback loop).
Physiological functions of beta adrenoreceptors?
ALL ACTIVATE ADENYLATE CYCLASE –> increase cAMP (via Gq)
b1 - stimulation by adrenalne –> +ve chronotropic and inotropic effect on heart and increased conduction velocity and automaticity. In kidney causes renin release.
b2 - induces smooth muscle relaxation, induces tremor in skeletal muscle + increases glycogenolysis in liver and skeletal muscle.
b3 - induces lipolysis in fat cells.
a2 in the heart?
Presynaptic a2 receptor stimulation decreases noradrenaline release. cAMP usually acts to promote Ca2+ influx in response to membrane depolarisation –> increased noradrenaline and ATP release.
Evidence that presence of facilitatory b2 adrenoreceptors on pre-synaptic terminal may stimulate NE release (WENDELL, 2004).
Normal process in heart in absence of B-adrenergic stimulation?
- LTCCs open –> activates RyR –> CICR from SR –> contraction. Ca2+ reuptake by SERCA.
- RyR and SERCA attenuated by interaction with FKBP and PLB respectively - only work when they are not phosphorylated (i.e. when PKA is inactive)/
Overall effect = decreased rate of muscle relaxation and contractility –> decreased HR and SV.
Stimulation of B1 in the heart?
B1 (couple to Gs protein –> increased cAMP) –> activates cAMP depenent PKA, which phosphorylates mutltiple targets.
- LTCCs - increased Ca2+ entry into cell.
- FKBP - inhibits its interaction with RyR –> RyR is more active. Net result is increased Ca2+ entry during APs and enhanced Ca2+ release by SR –> more calcium binding troponin C –> POSITIVE INOTROPIC EFFECT
- PLB - inhibits interaction with SERCA, resulting in SERCA being mor active. Net result is enhanced uptake of Ca2+ into SR - increased rate of relaxation (POSITIVE CHRONOTROPC EFFECT).
a1 in blood vessels?
Stimulation –> PLC –> IP3 –> Ca2+ release from SR. Binds calmodulin and activates it –> activates myosin light chain kinase (MLCK) –> phosphorylates myosin light chain. MLC interacts with actin to form actin-myosin cross bridges –> initiates vascular contraction.
CALMODULIN = multifunctional intermediate messenger protein that transduces calcium signals by binding Ca2+ and modifying its interactions with proteins.
b2 in blood vessels?
Stimulation –> *AC –> cAMP –> *PKA, which phosphorylates target proteins and the following happens:
- INCREASED SERCA ACTIVITY - resultng in Ca2+ being stored in the SR.
- INCREASED PMCA* ACTIVITY - resulting in Ca2+ being transported outside the cell.
NET RESULT = decreased Ca2+ conc –> decreased activation of MLCK –> SM relaxation. - DECREASED MLCK AFFINITY FOR Ca2+-CaM BINDING - through direct phosphorylation.
NET RESULT = decreased MLCK activity –> decreased MLC phosphorylation –> SM relaxation.
Clinical uses of beta agonists?
Salbutamol - (B2 agonist) - for asthma
Adrenaline - (a/b agonist) - asthma, anaphylaxis, cardiac arrest.
Clinical uses of alpha-1 blockers?
DOXAZOSIN, PRAZOSIN, TERAZOSIN
Treatment of hypertenson. Inhibit peripheral vasomotor tone by blocking post-synaptic a1 receptors -> decreased vasoconstriction and systemic vascular resistance.
Clinical uses of non-selective alpha-adrenergic antagonists?
PHENOXYBENZAMINE, PHENTOLAMINE
Used in short term management of phaeochromocytoma (rare catecholamine secreting tumour derived from adrenal chromaffin cells - catecholamine release not precipiated by neural stimulation - mechanism unclear. Secrete noradrenaline predominantly, whereas normal tissue secretes 85% adrenaline).
Result is reflex tachycardia due to inhibition of presynaptic a2 adrenergic receptor. Can be controlled by careful titration of cardioselective beta-blocker. NOT GOOD for treating hypertenson due to tachycardia, cardiac dysrhythmias and increased GI activity.
Clinical uses of B-adrenergic receptor blockers?
PROPANOLOL, ATENOLOL, TIMOLOL, BISOPROLOL…
Angina, hypertension, tachyarrhythmias and HF.
Block effect of sympathetic nerve distribution or circulating catecholamines at B-adenoreceptors.
Predominant in heart + kidney (B1) and lung, liver, GI tract, blood vessels and skeletal muscle (B2).
What does B1 blockade do in the heart and kidney?
HEART - B1 blockade in SAN causes -ve chronotropic effect +blockade in myocardium causes -ve inotropic effect.
Kindey - Inhibits release of renin from juxtaglomerular cells and decreases activity of RAAS.
What are the 5 classifications of beta blockers?
- Non-selective B antagonists
- Non-selective B and a-1 antagonists
- B1 selective (cardioselective)
- B2 selective
- Partial agonist activity.
Non-selective B-antagonists?
PROPANOLOL and TIMILOL
Bind equally to B1/B2. Used in treatment of HF and angina.
Non-selective B and a-1 antagonists?
CARVEDILOL and LABETALOL
Post-synaptic a-1 receptor blockade results in vasodillation. Cardiac b1 blockade prevents reflex sympathetic increase in HR. Net result = decrease in BP. Used in treatment of HT in patients with increased peripheral vascular resistance.
B1 selective antagonists?
Cardioselective - ATENOLOL, METOPROLOL, BISOPROLOL
Selectivity = dose related. Increased doses produce progressively more B2 receptor blockade. Little effect on pulmonary function, peripheral resistance and carb metabolism.
HYPERTENSION and ANGINA
B2 selective antagonists?
Not clinically useful
Partial agonist activity Beta blockers?
PINDOLOL, ACEBUTOLOL
Apart from blocking some sympathetic activity it provides some stimulation (acts as B-stimulant when background adrenergic activity is low i.e. at rest) but B-blockade occurs when adrenergic activity is high i.e. during exercise.
- Hypertension/diabetes.
Use of B blockers in IHD?
Treatment is based on either decreasing O2 demand or increasing supply.
STABLE - decrease BP and cardiodepressive –> decreased O2 demand of heart –> decreased O2/demand ratio and pain.
VARIANT - NOT USED. Due to unopposed a1-adrenergic constriction of catecholamines. Instead Ca2+ blocker is used (peripheral arteriolar dilatation).
UNSTABLE - high risk of MI. Need PCI and long term treatment with aspirin, B blocker and ACEi.
V. important in treatment of MI. Decreased mortality not just due to improved O2/demand ratio and decreased arrhythmias, but also inhibits cardiac remodelling.
B blockers in hypertension?
Decreased BP by decreasing CO. Chronic treatment –> decreased renin secretion and has effects on B blockade in CNS/PNS (blockade of presynaptic B receptors and central effect - lipophilic B blockers).
B blockers in HF?
Seems counter intuitive - but several studies have show B blockers increase cardiac functon and improve mortality.
Decrease deleterous cardiac remodelling. Mechanism not understood but thought to be due to blockade of excessive chronic sympathetic influences on heart.
3 B blockers licensed for HF - CARVEDILOL (non selective), BISOPROLOL (b1 selective), NEBIVOLOL (b1 selective).
B blockers in cardiac dysrhythmias?
Act by inhibiting sympathetic input to SA/AV nodes. Effect of sympathetic nerve activation (by B1 receptors) = increased pacemaker currents, therefore increased sinus rate and conduction velocity at AV node. BOTH EFFECTS ARE BLOCKED BY BETA BLOCKERS.
Adverse cardiovascular effects of B blockers?
EXCESSIVE SYMPATHETIC BLOCKADE
Cardiac failure- may depend on sympathetic drive to maintain CO.
Bradycardia - in patients with defects in AV conduction.
Exacerbation of IHD - abrupt discontinuation of long term treatment - increased angina and SCD.
Other adverse effects of B blockers?
Bronchoconstriction - sympathetic nerves innervating bronchioles activate B2 receptors –> bronchodilation.
Diabetics - mask warning signs for impending hypo, prolong hypoglycaemia (blockade of B2 normally stimulates glycogenolysis and pancreatic glucagon release).
Fatigue - decreased CO and muscle reperfusion.
Cold extremities - blockade of vasodilatory B2 receptors
CNS effects - sleep disturbaces, vivid dreams .
