Autonomic Nervous System Intro/SNS

autonomic nervous system (ANS)

the part of the peripheral nervous system that controls the visceral organs and involuntary movement; composed of the sympathetic division and parasympathetic division

sympathetic nervous system (SNS)

the division of the autonomic nervous system that controls the "fight or flight" response

SNS composition

short preganglionic axons located in the thoracolumbar spinal cord and long postganglionic axons located in the sympathetic ganglia

parasympathetic nervous system (PSNS)

the division of the autonomic nervous system that controls "rest and digest"

PSNS composition

long preganglionic axons located in the brainstem and craniosacral spinal cord and short postganglionic axons near or in the walls of target organs

adrenal gland

specialized SNS ganglion composed of the cortex and medulla that produces catecholamines (80% EPI and 20% NE), which are released into circulation, in the chromaffin cells of the medulla

pheochromocytoma

a benign tumor of the adrenal medulla that causes the gland to produce excess EPI/NE

two neuron system

the ANS is composed of preganglionic neurons that are part of the CNS and postganglionic neurons that synapse on visceral effector organs

ACh, nicotinic AChR's

the preganglionic neurotransmitter for both SNS and PSNS is _____ that acts on _____

ACh or NE, neuroeffector junctions

the postganglionic neurotransmitter is usually___ or ___ that diffuses at _

varicosities

sites of neurotransmitter synthesis, release, and storage in the ANS

PSNS postganglionic neurotransmission

ACh acts on metabotropic muscarinic AChRs

SNS postganglionic neurotransmission

nerves: NE, produced in and released from varicosities, acts on α and β adrenergic receptors

adrenal medulla: EPI (and some NE) acts on α and β adrenergic receptors

sweat glands: ACh acts on muscarinic AChRs

renal vasculature: DA acts on D1 receptors

neuroeffector junction

the synapse between a preganglionic autonomic neuron and its target postganglionic fiber

SNS, PSNS

in the ____, one preganglionic neuron contacts about 20 postganglionic fibers, but in the ____ one preganglionic neurons contacts 1 postganglionic fiber; therefore the effects of the SNS are more diffuse and the effects of PSNS the are more localized

autonomic tone

basal activity maintained by ANS that can be increased or decreased by changes in SNS or PSNS, allowing organs to be regulated by increasing or decreasing activity relative to baseline as needed

vasoconstriction, vasodilation

vascular tone is maintained partially by SNS activity, where increased SNS activity relative to the basal activity increases _____ and decreased SNS activity increases _____

organs only innervated by SNS

sweat glands, vascular smooth muscle, pilomotor muscles in skin, adipose tissue, kidney vasculature

SNS, PSNS (eyes)

____ produces mydriasis (pupil dilation) via α1 activation in the radial muscle of the iris, while ____ produces miosis (pupil constriction) via muscarinic receptor activation in the circular sphincter muscle of the iris

SNS, PSNS (salivary glands)

____ increases saliva protein secretion via β-adrenergic receptors and ____ increases saliva volume and release via muscarinic-AChRs

SNS, PSNS (bladder)

____ controls detrusor muscle to relax and internal sphincter muscle to contract (smooth muscle) allowing for bladder fill; ____ controls contraction of detrusor muscle and relaxation of internal sphincter muscle allowing for bladder emptying

central regulation of autonomic function

sensory info relayed to the brainstem (midbrain, pons, and medulla) and hypothalamus coordinates autonomic regulation, which can also be coordinated with voluntary reflexes and further regulated by higher brain areas

hypothalamus

brainstem region that regulates temperature, thirst, and satiety

pons

brainstem region that regulates respiration and urination

medulla

brainstem region that regulates respiration and cardiovascular function

neurotransmitter requirements

-localization at appropriate sites

-compound is released onto innervated structure following stimulation of nerve

-compound produces response identical to nerve stimulation

-antagonists block responses

catecholamine synthesis

1) tyrosine --> DOPA by TH

2) DOPA --> DA by AADC (DDC)

3) DA enters vesicles via VMAT

4) DA --> NE by DBH

5) NE --> EPI by PNMT (only in adrenal medulla and certain brainstem regions)

TH (tyrosine hydroxylase)

enzyme that converts tyrosine to DOPA; rate-limiting enzyme in catecholamine synthesis

AADC (aromatic amino acid decarboxylase)

enzyme that converts DOPA to DA

DBH (dopamine β-hydroxylase)

enzyme that converts DA to NE

PNMT (phenylethanolamine N-methyltransferase)

enzyme in the adrenal medulla and certain brainstem regions that converts NE to EPI

NET (norepinephrine transporter)

co-transporter that uses secondary active transport to couple Na+ movement down electrochemical gradient (maintained by Na+/K+-ATPase pump) with movement of NE back into neuron (sodium symoport)

VMAT, MAO

____ has a higher affinity for NE than ____, resulting in most NE being recycled as opposed to degraded

cocaine

NET inhibitor, resulting in blocking of reuptake of NE which leads to increased NE levels in the synapse or junction which allows for continued postsynaptic signaling of NE

amphetamine

drug that is transported into nerve terminal by NET and subsequently VMAT, resulting in displacement of NE from vesicle into the cytosol which results in reversal of NET and release of NE into junction, producing increased blood pressure and heart rate, contraction of bladder sphincter, headache, and other sympathetic effects

VMAT (vesicular monoamine transporter)

actively transports monoamines from cytosol into vesicles against concentration gradient using a proton electrochemical gradient generated by vesicular H+-ATPase in membranes of vesicles (antiporter)

reserpine

VMAT blocker that prevents loading of NE into vesicles, resulting in NE being metabolized by MAO over time (irreversible depletion)

NE/EPI metabolism

___ --> dihydroxymandelic acid by MAO, then --> into VMA by COMT; alternatively can be metabolized first by COMT then MAO with different metabolites

MAO (monoamine oxidase)

enzyme involved in catecholamine metabolism located in the outer mitochondrial membrane

MAO-A

MAO isoform primarily located in the brain, gut, liver, placenta, and skin that metabolizes both NE and DA

MAO-B

MAO isoform primarily located in the brain, platelets, and lymphocytes that metabolizes DA

MAO inhibitors

drugs that inhibit MAO, which increases levels of NE, DA, and 5-HT; have been used as antidepressants

false transmitter effect

inhibition of MAO prevents metabolism of tyramine taken into varicosities, so it gets converted into octopamine in vesicles, resulting in dilution of NE's effect upon exocytosis

tyramine effect

consumption of foods high in tyramine with MAOI administration results in excessive tyramine that is not metabolized and gets transported into varicosity where it displaces NE from vesicles; excess NE in cytosol reverses direction of NET transport resulting in NE transport to junction producing increased sympathetic activity (increased blood pressure and heart rate)

COMT (catechol-O-methyltransferase)

enzyme that breaks down catecholamines located in the cytosol

sympathomimetics

drugs that mimic the actions of NE and EPI

direct sympathomimetics

compounds that act directly on one or more of the adrenergic receptors

EPI

catecholamine that can be used to treat anaphylaxis and allergic reactions; must be given via injection because it is subject to first-pass metabolism

how EPI treats anaphylaxis

-increases blood pressure by stimulating the heart via increasing strength of ventricular contraction, increasing heart rate, and vasoconstriction of veins

-relieves airway constriction directly via bronchodilation

inotropic effect

effect of a drug to change the strength or contractility of the heart

chronotropic effect

effect of a drug to changing heart rate

chromaffin cells

the cells in the adrenal medulla that secrete EPI and NE

alpha-methyltyrosine

competitive TH inhibitor used to treat high blood pressure caused by pheochromocytoma

renal vasculature

DA in the SNS binds to D1 receptors in the _, producing vasodilation of smooth muscle at low concentrations to cause diuresis

β1 receptors (DA)

intermediate DA concentrations activate _, resulting in increased contractile force of the ventricle

alpha receptor (DA)

high DA concentrations produce general vasoconstriction via _ activation

fendolopam

Dopamine D1 receptor agonist that produces renal, coronary, peripheral, and splanchnic vasodilation, while also decreasing blood pressure and increasing natriuresis

indirect sympathomimetics

compounds that enhance the actions of endogenous catecholamines by displacing stored catecholamines, inhibiting NET (decreasing NE clearance) or preventing metabolism (MAO and COMT inhibitors)

mixed-action sympathomimetics

compounds that have agonist effects at both α and β receptors and enhance release of NE from sympathetic neurons (ex: ephedrine)

ephedrine

mixed-action sympathomimetic derived from the ephedra plant that is used as a nasal decongestant but is also used recreationally as a mild stimulant; can produce hypertension and insomnia

structure of sympathomimetic amines

phenyl ring, ethyl side chain, and terminal amine

2 carbon atoms, 3 and 4

Greatest sympathomimetic activity comes when _____ separate ring from amine group and when their are hydroxyl groups on both positions _____ of phenyl ring

larger, smaller

____ alkyl substituents on the amino group generally increases β receptor activity while _____ alkyl substituents on amino group increases α receptor activity

β2 selective

_ compounds have large amino substituents and OH groups on positions 3 and 5 (ex: terbutaline)

beta-hydroxyl side chain

indirect sympathomimetics lack ____ as well as OH group on phenol ring, whereas direct sympathomimetics (except DA) do have this

MAO, COMT

α-carbon substitution blocks oxidation by ____ and lack of OH on ring decreases metabolism by ____

7 general actions of sympathomimetics

-peripheral excitatory action: excitation of smooth muscle of blood vesicles, as well as salivary and sweat glands

-peripheral inhibitory action: inhibition of bronchioles and blood vessels supplying blood to skeletal muscle and smooth muscle of gut

-cardiac: excitatory action to increase heart rate and force of contraction

-metabolic: increased glycogenolysis in liver and increased fatty acid breakdown in adipose tissue

-endocrine: modulates insulin and renin secretion

-CNS: increases SNS outflow, wakefulness, and psychomotor activity; decreases appetite

-prejunctional: prejunctional α2 activation decreases neurotransmitter release, but prejunctional β activation enhances neurotransmitter release

α1 receptor

EPI ≥ NE >> ISO; Gq-coupled receptor whose activation produces contraction of smooth muscle, including vascular smooth muscle, pupillary dilator muscle, pilomotor muscles, GI and bladder sphincters, etc. and increases blood pressure; also involved in temperature regulation (vasoconstriction decreases blood flow to skin to reduce heat loss)

α2 receptor

NE > EPI >> ISO; Gi-coupled receptor that can be presynaptic (autoreceptor or heteroreceptor) or postsynaptic

presynaptic α2 autoreceptors

adrenergic receptors on adrendergic nerve terminals that inhibit NE release via negative feedback

presynaptic α2 heteroreceptors

adrenergic receptors on non-adrenergic nerve terminals that inhibit release of ACh from PSNS postganglionic nerves (ex of SNS indirectly inhibiting PSNS)

postsynaptic α2 receptors

activation of these receptors produces vascular smooth muscle contraction, inhibits lipolysis, etc.; in the CNS, activation inhibits sympathetic outflow to produce sedation and analgesia

nonselective α adrenergic agonists

drugs often used in topical preparations to produce vasoconstriction in local areas such as in the nasal mucosa as a decongestant or reduce eye redness; reduced efficacy following repeated administration, possibly due to receptor desensitization or tissue damage, and a rebound effect after discontinuation

nonselective α adrenergic antagonists

drugs that nonselectively antagonize α adrenergic receptors, producing primarily cardiovascular effects, but outcomes largely depend on SNS status when administered

α2 receptor agonists

drugs that decrease heart rate and contractility and decreases sympathetic vascular tone to cause vasodilation and decreased blood pressure and additionally causes PSNS activation through α2 heteroreceptors to regulate baroreceptors (ex: clonidine, xylazine)

sympatholytics

drugs that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the SNS

α2 receptor antagonists

drugs that increase blood pressure and heart rate by increasing sympathetic outflow via autoreceptor binding to potentiate NE release from nerve terminals, thus activating α1 and β1 (ex: yohimbine)

β1 receptor

ISO > EPI = NE; Gs-coupled receptor whose activation increases heart rate (via SA node) and force of contraction (via AV node and ventricle) as well as blood pressure; also increases release of free fatty acids from adipose tissue into circulation, increases salivary protein secretion, and promotes secretion of renin

renin

enzyme that converts angiotensinogen to angiotensin I, which increases blood volume and pressure by constricting vascular smooth muscle and increases sodium and water reabsorption in the kidney

dobutamine

β1 receptor agonist

β2 receptor

ISO > EPI > NE; Gs-coupled receptor whose activation dilates smooth muscle of the skeletal muscle vasculature, bronchioles, uterus, bladder detrusor muscle, and ciliary muscle of eye

How different EPI concentrations effect skeletal muscle vasculature

normal physiological concentrations of EPI produce vasodilation because it is more potent at β2 receptors, but higher concentrations of EPI activate both α and β receptors and the α-receptor response (vasoconstriction) predominates due to the higher expression level of α-receptors

β2 agonists

drugs that causes bronchodilation and is used for treatment of asthma and COPD (ex: terbutaline)

β2 antagonists

drugs that can be used to decrease secretion in the eye and reduce intraocular pressure (glaucoma)

β3 receptor

ISO = NE > EPI; Gs-coupled receptor expressed mostly in adipose tissue, the gallbladder, and the detrusor muscle of the bladder

mirabegron

β3 receptor agonist used to treat overactive bladder syndrome that relaxes the detrusor muscle of the bladder to expand bladder capacity/inhibit detrusor muscle contraction before bladder is full

Nonselective β agonists

drugs that stimulate the heart and produce systemic vasodilation without markedly changing blood pressure, can be used for heart failure; long-term administration can β receptor desensitization or downregulation and tolerance

GPCR desensitization

the process of uncoupling of a GPCR to its G-protein, resulting in decreased signalling; β-arrestin binds to phosphorylated GPCR, which marks it for endocytosis at which point the receptor can be degraded by lysosomes or recycled to the plasma membrane

nonselective β receptor antagonists (β blockers)

drugs that attenuate heart rate when it is increased, but have little effects on heart rate at rest; this occurs due to reduction in HR and contractility, decreased renin secretion, decreased CNS sympathetic outflow, and inhibition of presynaptic β receptors (enhances NE release); adverse effects can include worsening of asthma (via β2 antagonism), peripheral vasoconstriction, diabetes, and CNS symptoms

β receptor supersensitivity

long-term β receptor antagonist treatment can produce a compensatory increase in β receptors that may result in rebound hypertension if abrupt withdrawal occurs; can be reduced with use of partial agonist instead

reciprocal actions of α and β receptors

α1 activation produces vasoconstriction and increases blood pressure, whereas β2 activation produces vasodilation and decreased blood pressure

cooperative actions of α and β receptors

α1 activation and β2 activation both activate downstream effectors that eventually activate glycogen phosphorylase to break down glycogen so it can be converted to glucose

tachyphylaxis

attenuation of a drug response due to cellular neurotransmitter depletion or rapid desensitization of the receptor

tolerance

attenuation of drug response due to cellular adaptations, such as receptor downregulation

blood pressure

cardiac output x total peripheral resistance; determined by the effects of the heart and the effects of the vasculature

β1 receptors, M2 receptors

SNS increases heart rate via _____ by increasing heart rate in the SA node, conduction velocity in the AV node, and contractility in the left ventricle, while the PSNS decreases heart rate via _____

α1 receptors, β2 receptors

SNS constricts vascular smooth muscle and skeletal muscle vasculature via _____ to increase total peripheral resistance and dilates skeletal muscle vasculature via _____

baroreceptor reflex

mechanoreceptors in the internal carotid artery and in the aorta detect increased stretching of cardiac muscle which signals to the brainstem to adjust ANS input to the heart and vessels in order to maintain a homeostatic blood pressure

SNS, PSNS; PSNS, SNS

if baroreceptors sense a loss of pressure then there will be a compensatory increase in ____ activity and decrease in ____activity, but if baroreceptors are stretched then there will be a compensatory increase in ____ activity and decrease in ____ activity

α1 agonists

_ elicit a compensatory baroreceptor reflex because the baroreceptors stretch as muscle contracts, resulting in sympathetic tone being reduced and vagal tone being enhanced to slow heart rate