Quiz #2 (1/11-1/13) Flashcards
NE
transmitter for most post-ganglion sympathetic neurons (not sweat glands)
Synapses: Released by Ca2+-dependent exocytosis.
EPSP: Causes depolarization of postsynaptic membrane
IPSP: Causes hyperpolarization of postsynaptic membrane
E
major hormone of the adrenal medulla
NE is methylated in the cytoplasm to produce E. E is then transported back into vesicles
80:20 E:NE in adrenal medulla
released by Ca2+-dependent exocytosis
DA
transmitter in the CNS, carotid body, and superior cervical ganglion
Biosynthesis
tyrosine (rate limiting step)–> DOPA –> Dopamine –> NE then in the adrenal medulla NE –> E
VSM innervation and propagation
Innervation: cells are in the medial layer of the blood vessel. Adrenergic nerves ramify at the adventitia-medial junction, the adventitia contains a lot of connective tissue. NE is released at the terminal effector plexus, which is the outermost muscle layer. No localization of adrenergic receptors, but it also shows de-innervation super-sensitivity
Propagation: NE diffuses down the media of the smooth muscle. Electric current goes from one cell to the next to propagate the signal. Slightly different neuro-effector junction than NMJ.
Termination of NE and E
- Main pathway: re-uptake into the cytoplasm and ultimately into the granules or vesicle.
- Secondary: Monoamine oxidase (MAO) in the mitochondria.
NE: oxidized to aldehyde –> alcohol or carboxylic acid
E: oxidized to a ketone - Secondary: metabolized by catecholamine-O- methyl transferase (COMT), which is extra-neuronal, e.g. liver and kidney
transfers a methyl group onto one of the hydroxyls of the aromatic ring - End products of metabolism are excreted into the urine and there are diagnostic tests for their detection
Parkinson’s Disease
Etiology: degeneration of the nigrostriatal pathway with a reduction in DA, 5HT, and NE
Treatment: increase DA levels using its precursor DOPA. DOPA is usually supplemented with an inhibitor of peripheral DOPA decarboxylase, carbidopa, which does not enter the CNS and allows lower doses of DOPA to be given.
Alternative treatment: tolcapone which inhibits COMT and is given with carbidopa.
Presynaptic receptors
some adrenergic terminals contain presynaptic receptors (e.g. muscarinic or alpha-adrenergic receptors) that are coupled to inhibition of NE release. Presynaptic receptors are often coupled to Gi and inhibition of AC. Presynaptic cAMP normally enhances NT release
Alpha adrenergic receptors
Alpha-1: mediates contraction of vascular smooth muscle. Activation of PLC, liberates IP3 and mobilizes free calcium, which stimulates muscle contraction by stimulating PKC and MLCK. NE > E»_space; Iso
Alpha-2: located presynaptically on adrenergic terminal and act to modulate the release of NT, they are coupled to inhibition of AC through Gi. Provide a negative feedback on release of NE into the synaptic cleft. E = NE»_space; Iso
Beta adrenergic receptors
Beta-1: present in the heart and mediates cardiac stimulation. Coupled to stimulation of AC through Gs. Concentrations of receptors increase in the presence of thyroid hormones causing tachycardia. Iso > E = NE
Beta-2: present in smooth muscle and mediate relaxation of smooth muscle. Coupled to stimulation of AC through Gs, cAMP activates PKA which in turn inhibits the activity of myosin light chain kinase (MLCK). NE is ineffective at beta-2 receptors. Iso > E»_space; NE
Beta-3: expressed in high levels in brown fat cells and is thought to mediate lipolysis. Iso = NE > E
Response to Stimulation: Heart, Skeletal muscle vasculature, bronchial smooth muscle
Heart: Iso > NE in stimulation of heart rate therefore effects are through the beta-1 receptor
Skeletal Muscle Vasculature: vasodilation or vasoconstriction because there are both alpha-1 (primary) which cause contraction and beta-2 which causes relaxation.
Bronchial smooth muscle: Relaxation of smooth muscle primarily through beta-2 receptors
Epinephrine and Cardiovascular Effects
Low Dose E: preferentially activate the Beta-2 receptors over the alpha-1 in VSM leading to vasodilation and net result is decrease in peripheral resistance
High Dose: beta-1 receptors in the heart, increases the rate and force of contraction of the heart, leading to increased cardiac output. You would expect an increase in systolic BP. Would cause peripheral vasoconstriction through alpha-1 receptors
AC3
calcium inhibited AC. It explains why low epinephrine cause vasodilation (Beta-2 decreased Ca2+ levels) and higher concentrations cause vasoconstriction (Alpha-1 to increase Ca2+ and calcium inhibits AC3).
Baroreceptors
stretch receptors in the carotid sinus and aortic arch send fibers to the CNS, to regulate activity of the ANS:
If blood pressure is “too high”: decreases sympathetic activity, increases parasympathetic activity
If blood pressure is “too low”: increases sympathetic activity - increase heart rate and contraction force and decreases parasympathetic activity
NE and Cardiovascular Effects
VSM: activation of alpha-1 receptors to increase peripheral resistance and cause vasoconstriction
Heart: Activation of beta-1 receptors expected to increase heart rate
Reflex: Because of the increased BP from peripheral resistance you actually find a decrease in HR because of the parasympathetic reflex through baroreceptors. Net effect is a slight increase in BP. Atropine and hexamethonium block this parasympathetic reflex.
