Autonomic system Flashcards
B adrenergic R in heart
B1 > B2 subtype
Types of B adrenergic R and effects
o B1-R subtype: concentration => SA node (7x) > ventricles > atrial + AV node
o B2 R subtype: non cardiac = bronchodilation
Inotropic + lusitropic effects from terminal neurons of cardiac ∑ nerves (NE release)
o B3 R subtype: adipose tissue > heart
Mediate breakdown of fat
Negative inotropic effect: might contribute to poor fct in CHF
Intracell signaling B-R
o Adrenergic stim → release Epi (adrenal gland) + NE (nerve terminal) → β-R
o G protein coupled R => bind to GTP prot => activate (Gs) adenylyl cyclase => incr cAMP → activate PKA => intra¢ signals
Effects of B stim on heart
+ inotrope
+ lusitrope
+ chronotrope
+ dromotrope
MOA + inotrope effect of B-R stim
incr rate of contraction + force developed
PKA → Pi L-type Ca2+ channels → incr Ca2+ entry through ¢ membrane => incr Ca2+ induced Ca2+ release from RyR=> incr intra¢ Ca2+
* incr Myosin ATPase activity => incr rate of development of contractile force
* incr Ca2+ interaction w TnC => incr force developed
* Calmodulin activation => incr PDE activity => incr cAMP breakdown
MOA + lusitrope effect of B-R stim
Phospholamban-Pi on SR + incr [Ca2+] => incr activity of Ca2+ pump
TnI-Pi by PKA => incr rate of crossbridge detachment
MOA + chornotrope effect of B-R stim
PM stimulation (SA node)
MOA + dromotrope effect of B-R stim
incr conduction velocity down AV node => short PR
* Slow Ca2+ channel stimulation
incr conduction velocity down His bundle, Purkinje fibers
Explain feedback mechanism after B-R stim
o Desensitization: physiological decr response w/i minutes
Uncoupling: Sustained stimulation => B agonist R kinase (B ARK) => Pi of COOH tail of R => uncouples from Gs prot and ↑ affinity for arrestin → configuration change
* B ARK expression/activity: major regulator of cardiac contractile function
o Long term B stimulation => incr mRNA expression for B ARK
o Long term B blockade => decr B ARK
Desensitization also accentuated by Pi of β-R by PKA
* Prevent adverse effects of intracell ↑cAMP
o Internalization: long term inhibitory mechanism: prolonged desensitization B R sequestration and internalization
Can participate in growth signaling => formation of complex
* B-R/arrestin/tyrosine kinase
* Arrestin change molecular conformation of R
Reversible: resensitization → phosphatase release P group => R can be linked to G prot again
o Digestion: via intracell proteolytic enzymes
Irreversible
Effects of dobutamine on B adrenergic response
B1 R agonist => drug tolerance by desensitization + R downregulation
Effect of B blockers on B adrenergic response
o B blockers (atenolol, propanolol) => may be beneficial for decr B ARK expression → improve β adrenergic signaling
Effect of A stim on CV syst
- Substantial vascular effects → vasoconstriction → ↑ PVR and BP
Intracell signaling of A-R stim
o Release of NE (vascular nerve terminal) => bind to A-R (G protein) => activate adenylyl cyclase => incr cAMP => PKC => IP3 + DAG => incr cytosolic Ca2+
IP3 = phosphatidyl inositol system
* Stimulates release of Ca2+ from SR
DAG = diacyglycerase
* Lipophilic => stays in ¢ membrane => activate PKC
* Sustained vasoconstriction
Cardiac effects of A-R stim
o Small positive inotrope via post synaptic A1-R =
> IP3 => icnr Ca2+
Not major impact in normal myocardium
May have an effect in CHF: downregulation of B adrenergic response
Types of A adrenergic R
o Post synaptic A1-R: inhibited by prazosin
o Presynaptic A2-R: inhibited by Yohimbine
o Other R coupled to phospholipase C: Ang II-R
Intracell signaling of muscarinic/cholinergic R
- Ach (NT) => G protein coupled R => bind to GTP prot => inhibit (Gi) adenylyl cyclase => decr cAMP
o cGMP = opposite effects vs cAMP
Parasymp R types in heart
M2 > M3 (NO linked R on endothelium)
Types of parasymp cholinergic R
Nicotinic R: autonomic ganglia
* Respond to nicotine
* Inhibited by ganglion blocking agents (hexamethonium)
Muscarinic: in tissues
* Inhibited by atropine
* M2: associated w vagal nerve activity negative inotrope
Cardiac effects of cholinergic stim
Bradycardia
neg inotrope
neg dromotrope
MOA negative chronotrope effect of Ach
G dependent K+ channel opening => inhibit rate of spontaneous depol => slow SA node
Negative Treppe effect mediated by NO => decr HR
Ach directly inhibits SA node
MOA negative inotrope effect of Ach
Ventricles < atrial response to muscarinic agonists despite similar R density
* Shorten atrial AP
NO => activate guanylyl cyclase => incr cGMP => negative inotrope
* Also inhibit cAMP production
MOA negative dromotrope effect of Ach
Gi → inhibit conduction through AV node
Role of NO in psymp effect on heart
- NO may contribute to icnr inhibitory cGMP + incr Ach release
How is NO released and effect
Release by endothelial ¢ from incr blood flow/shear stress => diffuse in vascular smooth muscle ¢ => stimulate cGMP => incr cytosolic Ca2+ => vasodilation
Role of insulin and IGF
- Regulates ¢ growth
- Act on tyrosine kinase => signaling system that activates nuclear transcription => promotes growth
Effects of incr cAMP
Organelles influences by cAMP
* Activation of PK => Pi of
o Sarcolemmal prot of Ca2+ channel
o Phospholamban on SR
o TnI => Pi of inhibitory subunit = decr sensitivity to Ca2+ + promotes crossbridge detachment => incr relaxation
* PK: 2 subunits => regulatory or catalytic
o PK activity ratio proportional to cAMP levels
o PKA : predominates in cardiac ¢
o PKC: in response to A adrenergic, ET-I, Ang II
Other agents that incr cAMP
Glucagon
T3
Adenosine
PGI
Dopamine
PDEi
Histamine
MOA glucagon effect ion heart
hypoglycemia => incr glucagon secretion from pancreas => incr cAMP in liver ¢ => incr glycogen breakdown
o incrHR + contractility
MOA thyroxine effect on heart
Bind to nuclear R => stimulate variety of RNA formation => activate adenylyl cyclase
MOA adenosine effect on heart
formed by breakdown of ATP => couples to Gi
o Open K+ channel (IK-Ach) => hyperpolarization => inhibit Ca2+ entry → decr HR
o ↓ contractility from ↓ Ca2+
o Regulate apoptosis and protect from reperfusion injury
MOA prostacyclin effect on heart
PG released by vascular endothelium => Gs => activate AC => incr cAMP
MOA dopamine effect on heart
catecholamine NT => stimulate pre/post dopamine R
o Low [dopamine] → peripheral DA1-R → vascular SM relaxation → vasodilation
o High [dopamine] → central DA-R → ↑ NE release in nerve ending → activate β1-R → incr contractility
o ↑↑↑ High [dopamine] → cross reaction w/ α1-R → vasoconstriction
MOA PDEi effect on heart
inhibit cAMP breakdown => incr contractility, rate of relaxation, HR
MOA histamine effect on heart
H2 => coupled to AC => incr cAMP
Effect of CHF on autonomic system
- decr myocardial fct => hypotension => stimulate baroR => symp activation
o B mediated tachycardia
o A mediated vasoconstriction - Receptors: decr # of B1-R, more prominent B2-R
o decr inotropic response to catecholamines
Negative inotropic effect of β3-R
o Inhibit formation of cAMP via Gi signaling - incr plasma [NE]: degree of inrc proportional to severity of HF => related to px
B1-R downregulation
* Chronic/high exposure to catecholamines => decr myocardial responsiveness = desensitization
o B adrenergic R kinase => Pi-B1-R => inactivation
* Role of B2-R: become more prominent as B1-R # decr
o Not full expected inotropic result
o May be linked to Gi protein => negative inotropic antiapoptotic effect
B adrenergic blockers in HF
- Anti-arrhythmic effects
- Reverse remodelling
- Improve internal Ca2+ cycling
o Inhibit hyperphosphorylation of RyR => decr excessive release of Ca2+ and Ca2+ overload - decr uptake/use of free fatty acids
Types of R
- G protein coupled R: GTP binding prot → Gi or Gs
- Ion channel linked R: open channel when bind to ligand
- Direct binding of intracell targets: bind to guanylyl cyclase
- Enzyme linked R: enzyme/kinase activated when bond to ligand
o Tyrosine kinase R
o Sernine/threonine kinase R
o Receptor guanyly cyclase
o Phosphatases - Nuclear R: bind to hormones
o Thyroxine, aldosterone
G protein coupled R: structure, activation
o Major type in cardiovascular system
o G-prot have 3 subunits: Gα, Gβ, Ggamma
Gαs → activate adenylyl cyclase → ↑cAMP
Gαi → inhibit adenylyl cyclase → ↓cAMP
Gαo → open K+ channels
Gαq → activate PLC cascades
Gβgamma → can activatite PLA, PLC, IK-Ach
o Activation: ligand bind to R → activation of Gα
Gα-GTP dissociate from Gβ → intracell targets
Intrinsic GTPase → Gα-GDP → bind to Gβgamma → reform basal state of R
Intracell 2nd messenger
cAMP
cGMP
IP3 and DAG
NO
Effect of cAMP
o Mediates most cardio response to ∑ stimulation
o Gαs → adenylyl cyclase → cAMP → cAMP dependent prot kin
o Gαi → inhibits cAMP formation
o cAMP degradation by PDE
Role of cGMP
o Opposite actions to cAMP (couterregulatory)
o Respond to NO and natriuretic peptides → guanylyl cyclase → cGMP → cGMP dependent prot kin
o cGMP degradation by PDE
Role of IP3 and DAG
o Synthetized from PIP2 in cell membrane → phospholipase C
o IP3: release Ca2+ from IP3 gated Ca2+ release channels → ↑ intracell [Ca2+] → vascular SMcell vasoconstriction (no effect on contractility)
o DAG: weak effect on contractility
Role of NO
o L-arginine via nitric oxide synthase (NOS)
o NO bind guanylyl cyclase → ↑cGMP
o Rapid degradation
Signaling enzymes
- Protein kinases
o Transfer Pi from ATP
o PKA: cAMP activated
o PKG: cGMP activated
o PKC: phospholipid activated
o CAM: Ca2+ activated
Vasomotor center receives signals from
autonomic control of circulation => receives signals from baroreflexes => transmit impulses to vasodilator/constrictor fibers to arterioles
Areas of vasomotor center
o Located in reticular substance of the medulla and lower pons: areas
Vasoconstrictor area: continuously transmit signals => symp tone
Vasodilator area: inhibit vasoconstrictor area
Sensory area: nucleus solitarius
* Terminal site of afferent stimuli
o From baroR in response to incr or decr pressure
o Glossopharyngeal and vagal nerves
o Reflex activation of vasodilator/constrictor area
* BaroR => vagus/glossopharyngeal nerve => adrenergic/cholinergic vagal systems
Structure of symp system innervation
o Symp fibers leave spinal chord through thoracic spinal nerves + 1-2 lumbar
symp chain on each side of vertebral column => enter circulation (all vessels except capillaries)
Adrenal medulla => NE/Epi release
origin of vagus nerve
Vasomotor center
Control of vasomotor center
o Control by higher centers: can be inhibited/stimulated
Neurons in reticular substance of pons, mesencephalon, diencephalon
* Excitation: lateral + superior portions of reticular substance
* Inhibition: medial + inferior portions
Hypothalamus
* Excitation: posterolateral portions
* Inhibition: anterior portions
Cerebral cortex
Effects of Epi/catecho infusion
incrHR + systolic BP
decr diastolic BP => stable mean BP
* Stimulates vascular vasodilatory B2-R
* Presynaptic R => promote NE release
2 majors effects: incr CO + incr limb blood flow
o Vascular A-R vasoconstriction tend to offset B-R vasodilation
Effects of NE
incr HR + systolic + diastolic BP
* incr CO but decr limb blood flow
Difference in effects of Epi vs NE
NE stimulates both vascular A-R and cardiac B-R
* incr HR is transient => will decr 2nd to baroR response to vasoconstriction
Formation of NE
Formed by dopa + dopamine + tyrosine (A.A)
* Released from terminal varicosities
* Some interact w R, some go into circulation
o Stimulate post synaptic A1-R = vasoconstriction
o Stimulate pre synaptic A2-R = feedback inhibition of its own release
Neuromodulators of NE
- Ang II => incr NE release
- Adenosine + NO + incr psymp => decr NE release
Effects of cholinergic system
o Inhibit NE release => vasodilation
o NO release from endothelial ¢ (if normal)
o Adenosine: vasodilatory local mediator
Baroreflexes influencing psymp and symp syst activation
BaroR
Low P R
Brainbridge
Chemo R
CNS ischemic response
Cushing reflex
Abd compression reflex
Contraction of skeletal muscles
Location baroR
carotid sinus + Ao arch on arterial side of circulation
Role baroR
o 1st defense line against acute hypo/hypertension
o Short term regulation of BP
Rapid response to acute BP variation
Maintain BP in normal range during normal daily activity
Not importance in chronic regulation: will reset to new “normal” BP
Trigger of baroR
o Stretch R: respond to arterial distension (rather than P)
Rate of pressure induced, stretch mediated deformation, sustained BP changes
MOA baroR hypertension
Hypertension: incr signals => vasomotor center => vagal nucleus => incr psymp outflow, incr vagal tone => decr HR, contractility => decr CO => decr BP
* Carotid sinus massage = induce same response
MOA baroR hypotension
Hypotension: decr signal frequency => vasomotor center => incr symp outflow, decr vagal
* B mediated response: incr HR + contractility => incr CO
* A mediated vasoconstriction => incr PVR => incr BP
Location of low P R
cardiopulmonary R on venous side of circulation
Trigger of low P R
o Stretch R in atria, PAs, ventricular endocardium => response to volume overload
MOA low P R
Respond to alterations of filling volumes on venous side of heart
icnr blood volume => incr signals from vagal afferent fibers => brain => decr symp outflow, decr renin release
Brainbridge reflex
o Stretch R at jct of LA and PVs => directly activate SA node
o incr atrial pressure => incr HR/contractility
Mediated by vagus afferent, symp efferent
Chemo R MOA
o Chemosensitive ¢: decr O2, incr CO2/H+
o Respond to decr BP => excite vagus nerves => vasomotor center
Not much activity in normal pressure range
o Important role in control of respiration
MOA CNS ischemic response
2nd to incr CO2
o Ischemia of vasomotor center => incr stimulation of vasoconstrictor center => incr BP
Cushings reaction MOA
incr pressure of CSF around brain => incr BP
Abdominal compression reflex
initiation of baroR or chemoR => impulse to abdominal organs => tensing of abdominal muscles => incr blood return to heart
Acute control of PVR
Local tissue control: blood flow according to metabolic demands
Low P reflexes
high pressure reflexes
Local messenger
What local tissue control incr tissue blood flow
Vasodilator theory: stimulate adenosine release +/- other vasodilators
O2 demand theory: O2 needed for vasoconstriction
* decr O2 availability => vasodilation
Other nutrients deficiencies => vasodilation
* decr glucose
* decr A.A or fatty acids
* decr Thiamine, niacin, riboflavin
Autoregulation of blood flow
blood flow will return to normal after BP changes
Metabolic theory: incr arterial pressure => incr nutrient delivery => incr vasoconstriction
Myogenic theory: reflex constriction 2nd to wall stretch
Tubuloglomerular feedback:
* Composition of fluid in early distal tubule => macula densa
* If incr fluid filtered => signals => vasoconstriction of afferent arteriole => decr renal blood flow and GFR
Brain: excess CO2 => vasodilation
Low pressure reflexes for PVR regulation
o Stimulation of renin release by => renal artery pressure
o A1 mediated vasoconstriction by baroreflex activation
o B1 mediated response
Low pressure reflexes for PVR regulation
o decr symp outflow => decr renin release => decr angiotensin mediated vasoconstriction
o Endothelial regulation of BP (local messengers)
Normal endothelium: incr shear forces => release of NO
Diseased: ET-1 release
Local messenger influencing PVR
o Endothelial NO
NO is a gas, free radical that acts only locally where it is formed
Synthetized in normal vascular endothelium, nerve terminals of NO releasing nerves
* Released 2nd to shear stress, incr blood flow
Actions
* Inhibit symp outflow
* decr NE release
* incr relapse of Ach
o Adenosine: formed from ATP breakdown
incr when rate of breakdown > resynthesis (ie. exercise)
Actions
* Adenosine R on vascular SM¢ => direct vasodilation
* Neuromodulator => decr NE release
o Endothelin: vasoconstrictor
Released by damaged endothelium
Long term control of PVR
- incr vascularity of tissues
o Vascular remodeling
o incr # of vessels => incr in O2 deprivation - Growth of new vessels: 4 factors
o Vascular endothelial growth factor
o Fibroblast growth factor
o Platelet derived growth factor
o Angiogenin
o Inhibitors: angiostatin, endostatin, steroids - Collateral circulation
Humoral regulation of PVR: vasoconstrictors
- NE/epi: released from adrenal medulla + NE from symp nerve terminal
- Angiotensin
- Vasopressin: incr H2O reabsorption from renal tubules + powerful vasoconstrictor
o Produced by hypothalamus
o Stored in posterior pituitary
Humoral regulation of PVR: vasodilators
- Bradykinin
o A2-macroglobulin => protease (kallikrein) released from tissues split into kallidin => form bradykinin
Powerful vasodilation
incr vascular permeability - Histamine
o Released from basophils in blood/mast ¢ in tissues
Vasodilation
incr vascular permeability
Effect of ions on PVR
- incr Ca2+ => vasoconstriction
- incr K+, Mg2+, H+ => vasodilation
- Anions (citrate, acetate) => mild vasodilation
- incr CO2 => vasodilation in brain
Psymp system organization
- Medulla oblongata: vagal nuclei => nerves from originate from cranial and sacral locations => preganglionic fibers => cardiac branches of vagal nerve => synapse in heart w ganglionic neurons
o Post ganglionic neurons distributed to atria and to a lesser degree to ventricles
Effect of vagal stimulation
NO release => Ach release
Ach bind M2 R => activate Gi => inhibit cAMP prod
* decr Pi of L type Ca2+ channels
* Activates IKACh => hyperpolarize ¢
* Negative dromotropic and chronotropic
Effect of vagal tone on SA node
o Autonomic tone have > influence on SA node because of denser innervation
fibers from ganglia in PV fat pad (btw CrVC and CaVC, adjacent to RPV)
More affected by R vagal nerve
decr rate of SA nodal d/c => decr rate of diastolic depol
* Inhibit effects of adrenergic stimulation: decr probability of opening If and ICa-L
Effect of vagal tone on AV node
fibers from ganglia in fat pad at entry of coronary sinus into caudal interatrial septum, at jct of CaVC and caudal LA
More affected by L vagal nerve
Slow AV nodal conduction => inhibitory stimuli
* Stimulation/inhibition of L type Ca2+ current
Effect of vagal tone on atrial myocytes
decr contractility by shortening AP and refractory period (activation of IKAch)
o decr probability of channel opening in plateau phase
o decr Ca2+ levels contibuting to decr contractility
Effect of vagal tone on ventricular myocytes
intramural/subendocardial fibers => rise to epicardium in AV groove => very little supply to ventricles
o decr ventricular contractility by decr cAMP production
MOA vagal maneuver
Stimulation of carotid BaroR => stimulates nerve of Hering (branch of 9th cranial nerve) => afferent impulse to vasomotor center => vagus nerve stimulation => decr SA node d/c and AV node conduction
MOA atropine response test
Oppose vagal stimulation: block Ach binding sites
