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Flashcards in L6- Catecholamines Deck (36)
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What are the catecholamines?







How are endogenous catecholamines made and what is the rate-limiting step?

Tyrosine + Tyrosine Hydroxylase (RLS) to make DOPA

DOPA + Da Decarboxylase to make Da that is taken up into storage vesicles

DA + Da-beta-Hydroxylase to make NE


How is DA taken up into vesicles? What inhibits this mechanism?

Vesicular monoamine transporter VMAT2 exchanges monoamines for protons

need acidic vesicles so need proton pump of V-ATPase

RESERPINE depletes NE from storage Vesicles as a selective VMAT2 blocker


Where and How is Epinephrine made?

Adrenal Medulla Chromaffin cells express enzyme PNMT to methylate cytosolic NE to Epi and then both can accumulate into storage vesicles for release


How is NE signaling inactivated or turned off?

Primarily through REUPTAKE via the NE -Transporter (NET) into terminal that released it

Secondarily signal ends via fascilitated diffusion into tissues with polyspecific Organic Cation Transporter (OCT3)


Where does Cocaine act in the peripheral nervous system?

Cocaine inhibits NET - NE Transporter and so potentiates sympathetic activity by allowing excess NE at nerve terminal (acts on Da transporter in the CNS for effects)


What are mechanisms of Adrenergic Receptor Regulation?

Desensitization (seconds) via PKA phosphorylation of intracellular tail

Sequestration (minutes) via aggregation of receptors and internalization

Down-regulation (hours) with decreased mRNA

Beta-Arrestin with Ligand Bias for desensitization and acts as a chaperone to mediate internalization into clathrin-coated pits into endosome where receptors can be recycled or degraded


What are the enzymes that degrade NE/Epi and where are they found?

Monoamine Oxidase - MAO - pre-synaptic and mitochondrial - found in BBB, GI tract, Liver

Catechol-O-Methyl-Transferase (COMT) - found in most tissues EXCEPT pre-synaptically - found in adrenal medulla


Adrenal-Medullary Pathway for breakdown of Ne/Epi?

COMT inactivates and makes the "metas" in the adrenal medulla and then they leak out

MAO acts on the Metas to make MHPG MHPG gets oxidated in the liver to VMA and excreted in urine


Sympathoneuronal Pathway for breakdown of Ne/Epi?

NE from nerve terminals made into DHPG by MAO

DHPG circulates and turned into MHPG by COMT

MHPG oxidized to VMA in the liver and excreted in urine


Alpha 1 Receptor Agonists


Tissues and Responses

Agonists: = EPINEPHRINE > NE >> Iso = Phenylephrine

Antagonists = Prazosin

Tissues and Responses

- SM of vasculature, Iris, GU and activation = contraction

- Salivary and Sweat Glands and activation = secretions

-Liver and activation = K+ Secretion from liver


What is Isopreterol significance?

Synthetic Adrenergic agonist that's only really effective at Beta-receptors!


Alpha 2 Receptor Agonists Antagonists Tissues and Responses

Agonist:s: = Epinephrine > NE >> Isopreterol = Clonidine Antagonists = Yohimbine Tissues and Responses - Vascular SM contraction - Pancreatic Beta cells = decreased insulin secretion - Platelets = aggregation - Nerve Terminals acts as an Autoreceptor and lowers NE release


Beta 1 Receptor Agonists Antagonists Tissues and Responses

Agonists: = Iso > Epi = Ne = Dobutamine

Antagonists = Metoprolol and Atenolol Tissues and Responses - Heart - Activation increases HR, Force, and CV - JG cells in Kidney and activation increases Renin release


Beta 2 Receptor Agonists Antagonists Tissues and Responses

Agonists: = Iso> Epi >>>>>> Ne - Albuterol

Antagonists - none Tissues and Responses - Smooth Muscle of vasculature, Pulmonary and Uterine and activation leads to relaxation - Skeletal Muscle and activation leads to increase Glucose and K+ uptake and tremors -Liver and activation increases glucose from liver - Mast cells to decrease granule release


Beta 3 Receptor Agonists Antagonists Tissues and Responses

Agonists: = Iso = NE > Epi = Mirabegron Antagonists = none Tissues and Responses - Adipose Tissue activation leads to thermogeneration and lypolysis - Urinary bladder activation leads to relaxation of bladder


Which beta receptor is NE a weak agonist on ?

Beta 2


Which beta receptor does NE = Epi agonism?

Beta 1


Which beta receptor is NE better agonist than Epi?

Beta 3


What does a solution that of catecholamines that is pinkish/brown mean?

Inactivated!! Catecholamines are very unstable and can be readily oxidized to colored products in presence of alkaline pH, heat and light


How are catecholamines administered and why?

Injection or topically NOT by mouth Very hydrophillic and so poor penetration of membranes


What receptors does NE act on?

A1, A2 B1, B3 NOT B2


What receptors does Epi act on?

A1, A2 B1, B2 Not B3


What receptors does Isoproteranol act on?

NOT alphas B1, 2, 3


What receptors does Dopamine act on?

Beta 1 MOSTLY on D1 in the sympathetic vasculature / capillary beds of kidney and mesentary Activation of D1 receptors in those vascular beds leads to relaxation and dilation


What receptors does Dobutamine act on?

Beta 1!!!


What is the cellular effect of Epinephrine at the SA Node?

Beta-1 (and B2) activation increases the amplitude and rate of currents for: 1) L type calcium channels - slow inward current for upstroke of AP 2) K+ channels for repolarization and outward current to mediate RMP 3) If Current - funny cation channels turned on by hyperpolarization and bring cell back to trigger point for AP ALL MEDIATED BY cAMP!!! PLA phosphorylation of channels to activate currents


What is the clinical effect of Beta-AR activation in the heart?

Chronotropy - increased HR by pacemaker Automaticity - recruitment of latent pacemaker cells Increased conduction velocity and decreased Refractory Period Arrhythmogenicity increased!!! ionotropy - increased contractility BUT ALSO increased oxygen consumption Lusitropy - increased re-polarization and shortened systole


What happens with adrenergic stimulation in the vasculature?

Vasoconstriction with A1/A2 activation to increase TPR and get more blood back to heart


What are the effects on TPR, BP, and HR with low-dose IV infusion of NE in humans?

NE has little effect on Beta2 in heart but large effect on Beta1 - increased force of contraction!! Increase in BP from Beta-1 induces Vagal Reflex and Baroreceptor firing causes decreased HR and overrides Beta stimulation to the pacemaker Increased TPR and Increased Contractility = increased BP Vagal Response to decrease HR BP = CO x TPR