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4. Physiology and pathophysiology > Autonomic system > Flashcards

Autonomic system Flashcards

1
Q

B adrenergic R in heart

A

B1 > B2 subtype

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2
Q

Types of B adrenergic R and effects

A

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

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3
Q

Intracell signaling B-R

A

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

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4
Q

Effects of B stim on heart

A

+ inotrope
+ lusitrope
+ chronotrope
+ dromotrope

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5
Q

MOA + inotrope effect of B-R stim

A

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

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6
Q

MOA + lusitrope effect of B-R stim

A

 Phospholamban-Pi on SR + incr [Ca2+] => incr activity of Ca2+ pump
 TnI-Pi by PKA => incr rate of crossbridge detachment

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7
Q

MOA + chornotrope effect of B-R stim

A

 PM stimulation (SA node)

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8
Q

MOA + dromotrope effect of B-R stim

A

 incr conduction velocity down AV node => short PR
* Slow Ca2+ channel stimulation
 incr conduction velocity down His bundle, Purkinje fibers

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9
Q

Explain feedback mechanism after B-R stim

A

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

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10
Q

Effects of dobutamine on B adrenergic response

A

B1 R agonist => drug tolerance by desensitization + R downregulation

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11
Q

Effect of B blockers on B adrenergic response

A

o B blockers (atenolol, propanolol) => may be beneficial for decr B ARK expression → improve β adrenergic signaling

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12
Q

Effect of A stim on CV syst

A
  • Substantial vascular effects → vasoconstriction → ↑ PVR and BP
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13
Q

Intracell signaling of A-R stim

A

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

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14
Q

Cardiac effects of A-R stim

A

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

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15
Q

Types of A adrenergic R

A

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

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16
Q

Intracell signaling of muscarinic/cholinergic R

A
  • Ach (NT) => G protein coupled R => bind to GTP prot => inhibit (Gi) adenylyl cyclase => decr cAMP
    o cGMP = opposite effects vs cAMP
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17
Q

Parasymp R types in heart

A

M2 > M3 (NO linked R on endothelium)

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18
Q

Types of parasymp cholinergic R

A

 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

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19
Q

Cardiac effects of cholinergic stim

A

Bradycardia
neg inotrope
neg dromotrope

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20
Q

MOA negative chronotrope effect of Ach

A

 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

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21
Q

MOA negative inotrope effect of Ach

A

 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

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22
Q

MOA negative dromotrope effect of Ach

A

 Gi → inhibit conduction through AV node

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23
Q

Role of NO in psymp effect on heart

A
  • NO may contribute to icnr inhibitory cGMP + incr Ach release
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24
Q

How is NO released and effect

A

Release by endothelial ¢ from incr blood flow/shear stress => diffuse in vascular smooth muscle ¢ => stimulate cGMP => incr cytosolic Ca2+ => vasodilation

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25
Role of insulin and IGF
* Regulates ¢ growth * Act on tyrosine kinase => signaling system that activates nuclear transcription => promotes growth
26
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
27
Other agents that incr cAMP
Glucagon T3 Adenosine PGI Dopamine PDEi Histamine
28
MOA glucagon effect ion heart
hypoglycemia => incr glucagon secretion from pancreas => incr cAMP in liver ¢ => incr glycogen breakdown o incrHR + contractility
29
MOA thyroxine effect on heart
Bind to nuclear R => stimulate variety of RNA formation => activate adenylyl cyclase
30
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
31
MOA prostacyclin effect on heart
PG released by vascular endothelium => Gs => activate AC => incr cAMP
32
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
33
MOA PDEi effect on heart
inhibit cAMP breakdown => incr contractility, rate of relaxation, HR
34
MOA histamine effect on heart
H2 => coupled to AC => incr cAMP
35
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
36
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
37
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
38
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
39
Intracell 2nd messenger
cAMP cGMP IP3 and DAG NO
40
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
41
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
42
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
43
Role of NO
o L-arginine via nitric oxide synthase (NOS) o NO bind guanylyl cyclase → ↑cGMP o Rapid degradation
44
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
45
Vasomotor center receives signals from
autonomic control of circulation => receives signals from baroreflexes => transmit impulses to vasodilator/constrictor fibers to arterioles
46
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
47
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
48
origin of vagus nerve
Vasomotor center
49
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
50
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
51
Effects of NE
 incr HR + systolic + diastolic BP * incr CO but decr limb blood flow
52
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
53
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
54
Neuromodulators of NE
* Ang II => incr NE release * Adenosine + NO + incr psymp => decr NE release
55
Effects of cholinergic system
o Inhibit NE release => vasodilation o NO release from endothelial ¢ (if normal) o Adenosine: vasodilatory local mediator
56
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
57
Location baroR
carotid sinus + Ao arch on arterial side of circulation
58
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
59
Trigger of baroR
o Stretch R: respond to arterial distension (rather than P)  Rate of pressure induced, stretch mediated deformation, sustained BP changes
60
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
61
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
62
Location of low P R
cardiopulmonary R on venous side of circulation
63
Trigger of low P R
o Stretch R in atria, PAs, ventricular endocardium => response to volume overload
64
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
65
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
66
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
67
MOA CNS ischemic response
2nd to incr CO2 o Ischemia of vasomotor center => incr stimulation of vasoconstrictor center => incr BP
68
Cushings reaction MOA
incr pressure of CSF around brain => incr BP
69
Abdominal compression reflex
initiation of baroR or chemoR => impulse to abdominal organs => tensing of abdominal muscles => incr blood return to heart
70
Acute control of PVR
Local tissue control: blood flow according to metabolic demands Low P reflexes high pressure reflexes Local messenger
71
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
71
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
72
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
73
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
74
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
75
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
76
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
77
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
78
Effect of ions on PVR
* incr Ca2+ => vasoconstriction * incr K+, Mg2+, H+ => vasodilation * Anions (citrate, acetate) => mild vasodilation * incr CO2 => vasodilation in brain
79
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
80
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
81
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
82
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
83
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
84
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
85
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
86
MOA atropine response test
Oppose vagal stimulation: block Ach binding sites

4. Physiology and pathophysiology (19 decks)

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