Circulation Flashcards
ending..
1
Q
Define vascular tone
A
describes degree of constriction of a blood vessel relative to max dilation
2
Q
What’s vascular tone controlled by?
A
contractile state of vascular smooth muscle cells (VSMCs)
Tonic sympathetic activity (constriction) + Tonic NO release (dilation)
3
Q
Which vessels have vascular tone + why?
A
arteries, arterioles, veins
containing VSMCs
4
Q
Why regulate vascular tone?
A
vital target in treating CVD
5
Q
How do the substances in blood control vascular tone?
A
Hormones - Adr, Ang II, ADH, ANP
Platelets –TXA2
Immune cells - Histamine
Blood causes stretch
6
Q
How does the endothelium control vascular tone?
A
PRODUCES:
Dilators = NO, K+, PGI2
Constrictors = ET-1
7
Q
How do VSMCs control vascular tone?
A
responds to:
substances in blood
substances released from endothelium
8
Q
How do nerves control vascular tone?
A
Sympathetic vasoconstrictor nerves: NA
Parasympathetic vasodilator nerves: NO, Ach
Sympathetic vasodilator nerves: Ach, VIP
Perivascular sensory nerves nerves: Sub P, CGRP
9
Q
Where do vasoconstrictor nerves interact at?
A
interact directly at VSMCs
10
Q
What do vasoconstrictor nerves interact with?
A
indirectly
- interact with endothelium
- endothelium interacts with VSMC
11
Q
How do metabolic factors control vascular tone?
A
Adenosine, K+, H+
12
Q
Why have intrinsic or local controls?
A
Regulate local blood flow to organs/tissues
Vital in regional hyperaemia
13
Q
eg of intrinsic or local controls?
A
endothelium, immune cells, platelets, stretch
14
Q
Why have extrinsic controls?
A
Regulate TPR to control BP for blood flow
Brain alters blood flow to organs during exercise + thermoregulation
15
Q
What are extrinsic or external controls + eg?
A
Nerves: Vasoconstrictors - NA Vasodilators - Ach, NO Hormones: Vasoconstrictor - A, Ang II, ADH Vasodilators - ANP
16
Q
What does stimulated α1 adrenoceptors do?
A
vasoconstriction
17
Q
What does stimulated β2 do?
A
vasodilation in coronary + skeletal muscle arterioles
18
Q
Describe how the brainstem control vascular tone?
A
- sense stress
- feeds into (RVLM) which receives info from CVLM, hypothalamus
- Thoraric spinal cord Intermediolateral (IML)
- short sympathetic preganglionic fibre to sympathetic ganglia/adrenal medulla
- long sympathetic postganglionic fibre
19
Q
What’s on post-synaptic membrane?
A
α1 – contraction, α2 – contraction, β2 - relaxation
20
Q
What’s on pre-synaptic membrane?
A
AT1 – increase release of NA (RAAS ↑ sympathetic)
α2 – ↓ NA release
K+, adenosine – ↓ NA release for vasodilation
21
Q
Describe what happens at post-synaptic terminal
A
- AP down postganglionic fibres
- activate vgccc
- Ca2+ influx
- vesicle release of NA
- NA hit postsynaptic membrane on VSMCs at α1, α2, β2
- α1 causes vasoconstriction
- decrease NA by : reuptake, cleared by capillaries, feedback to α2 on pre-synaptic terminal, adenosine + K+
22
Q
What’s Rostral Ventral Lateral Medulla (RVLM vasomotor centre) controlled by?
A
Caudal Ventro Lateral Medulla (CVLM), hypothalamus
23
Q
Why’s it vital that sympathetics controlled by brainstem + RVLM?
A
Provides central control of blood flow + BP
24
Q
Define tonic sympathetic nerve activity
A
sets vascular tone by firing 1 AP/s
25
What does fall in sympathetic activity cause?
vasodilation
26
Roles of sympathetic vasoconstrictor nerves?
-Contract resistance arterioles : produces vascular tone for vasodilatation for increased blood flow
-Distinct RVLM neurones-sympathetic pathways innervate diff tissues : Increased sympathetic nerve stimulation to GI (less blood flow) whilst reduce to skin (more blood flow, cool down)
-Pre-capillary vasoconstriction : ↓capillary pressure due to pressure drop
absorption of interstitial fluid into blood plasma
to maintain blood volume (important in hypovolemia)
Control TPR - maintains arterial blood pressure and blood flow to brain/myocardium since Pa = CO x TPR and BF = Pa / TPR
Controls venous blood volume (at rest 2/3rd blood in veins)
Venoconstriction venous blood volume Venous return
stroke volume via Starling’s law
27
Roles of sympathetic vasoconstrictor nerves + eg?
- Contract resistance arterioles : produces vascular tone for vasodilatation for increased blood flow
- Distinct RVLM neurones-sympathetic pathways innervate diff tissues : Increased sympathetic nerve stimulation to GI (less blood flow) whilst reduce to skin (more blood flow, cool down)
- Pre-capillary vasoconstriction : ↓capillary pressure due to pressure drop so reabsorption of interstitial fluid into blood plasma maintaining blood volume (vital in hypovolemia)
- Control TPR : maintains arterial BP + flow to brain/myocardium as Pa = CO x TPR and BF = Pa /TPR
- Controls venous blood volume : venoconstriction ↓ venous blood volume for venous return by increasing SV via Starling’s law
28
eg of vasoconstrictors hormones
Adrenaline, Angiotensin II, Anti-Diuretic Hormone, Endothelin-1 (EN1), Thromboxane (TXA2)
29
eg of vasodilator hormones
Atrial natriuretic peptide (ANP)
30
Physiological role of hormonal control of VSMCs?
Controls BP + flow during activity
| Maintain BP + flow to brain, heart during haemodynamic crisis (haemorrhage, dehydration)
31
Pathological role of hormonal control of VSMCs?
Excess production, associated with excess vasoconstriction + vascular disease – hypertension, heart failure
32
What's adrenaline?
Released due to sympathetic nerve stimulation
From adrenal glands
Acts on α1-adenoceptors on VSMCs
33
What's Angiotensin II (Ang II)?
Formed from RAAS
Potent vasoconstrictor
Acts on AT1 receptors on VSMCs
34
What's ADH (Vasopressin/Anti-Diuretic Hormone)
Released from posterior pituitary
| Acts on V1-receptors on VSMCs
35
What's Endothelin-1 (ET1)?
Released from endothelium
| Acts on ET1 receptors on VSMCs
36
What's Thromboxane (TXA2)?
Released from aggregating platelets
Acts on TP receptors on VSMCs
Vital vasoconstriction alongside clotting process
37
How is Ang II produced by RAAS system during drop in CO?
- low CO
- low renal blood flow
- sympathetic nerves β1
- low NaCl load
- produce renin
- produce angiotensinogen in liver
- produce Ang I (decapeptide)
- Angiotensin Converting Enzyme (ACE) on lung vascular endothelium
- produces Ang II (octapeptide)
38
How much blood does kidney receive?
25% of CO
39
Why do lungs have ACE?
lungs receive total CO
40
Effects of Ang II?
- ↑sympathetic - central effect
- ↑Blood volume - adrenal glands release aldosterone NaCl+ H2O Retention
- ↑TPR - vasoconstriction, stimulates sympathetic nerves
41
What is ADH produced during a haemorrhage?
- drop in blood volume detected by arterial baroceptors + left atrial receptors
- switches off Nucleus Tractus Solitarius (NTS)
- inhibitory pathway switches off CVLM
- switches on positive pathway of hypothalmic nerves
- stimulates magnocellular neurons in SON + PVN
- drives ADH release from posterior pituitary
42
Effects of ADH?
- ↑blood volume : at kidney V2 receptors, insertion of aquaporin channels in collecting duct so ↑H2O reabsorption
- vasoconstriction : at VSMCs V1 receptors during hypovolemia
43
Importance of myogenic response?
Maintains local blood flow during changes in local blood pressures
Protective mechanism – BP drops, still good flow – BP high, less flow/damage
44
What's the myogenic response?
As pressure increases, more distension, more vasoconstriction but blood flow remains the same
45
How do vasoconstrictors increase vascular tone?
by activating same G-protein-coupled pathway in VSMCs
46
What does receptor does NA work on?
α1
47
What does receptor does Adrenaline work on?
α1
48
What does receptor does Ang II work on?
AT1
49
What does receptor does Vasopressin (ADH) work on?
V1
50
What does receptor does Endothelin-1 (ET-1) work on?
ETA
51
What does receptor does Thromboxane A2 (TXA2) work on?
TP
52
Describe how vasoconstrictors increase vascular tone?
- Stretch activates these receptors – myogenic response
- receptors are Gq
- linked to PLC
- hydrolysis of PIP2 -> DAG + IP3
- IP3 acts on SR to cause release of Ca2+
- DAG increases excitability, gets more depolarised, activates vgcc, release of Ca2+
- influx of Ca2+ from external fluid
- Ca2+ activates Calmodulin
- drives myosin light-chain kinase
- phosphorylation of myosin heads
- interaction between myosin-actin
- contraction
53
Effects of Atrial Natriuretic Peptide (ANP)?
- systemic vasodilatation : opposes NA, A, Ang II, ADH, ET-1, TXA2
- ↓blood volume : dilation of renal afferent arteriole, increase glomerular filtration rate, increased Na+ + H2O excretion by the kidney -
- ↓release+actions : aldosterone, renin, ADH
54
How vasodilater hormone ANP produced when excess vasoconstriction?
- increase blood volume, too much vasoconstriction
- more blood returns to heart
- detected by stretch receptors in atrium
- release ANP by specialised atria myocytes
- act at NP receptors on VSMCs - ↑cGMP pathway
55
What's Atrial Natriuretic Peptide (ANP)
Biomarker for poor heart function/congested circulation – e.g. heart failureom atria
-acts on VSMC
56
What receptor does Atrial Natriuretic Peptide (ANP) work on?
NP
57
What are the diff vasodilator responses?
Nerves
Endothelium Derived Relaxation Factors (EDRF)
Endothelium Derived Hyperpolarisation Factors (EDHF)
58
What's sympathetic vasoconstrictor nerves inhibited by?
Parasympathetic vasodilator nerves
Sympathetic vasodilator nerves
Sensory (nociceptive C fibres) vasodilator nerves
59
Where are parasympathetic vasodilator nerves + what do they release?
Salivary glands – release Ach / VIP
| Pancreas + intestinal mucosa – release VIP
60
Why do salivary glands, pancreas, intestinal mucosa need high blood flow?
- need fluids to produce salivia, enzymes, pancreatic juices for excretion
- maintains parasympathetic-mediated fluid secretion
- releases juices
61
How does vasodilation happen in salivary glands, pancreas, intestinal mucosa?
parasympathetic nerves release Ach/VIP act on endothelium to cause release of NO
62
What does receptor does Ach work on?
M3
63
How does vasodilation happen for erection?
- erectile tissue releases NO by parasympathetic nerves
- causes production of cGMP
- vasodilation
64
How does Sildenafil (Viagra) work?
enhances NO by blocking breakdown of cGMP by phosophodiesterase 5
65
Where are sympathetic vasodilator nerves + what do they release?
Skin (sudomotor fibres) – release Ach, VIP
66
Effect of Ach + VIP on sudomotor fibres?
cause release of sweat + vasodilation
67
Importance of sympathetic vasodilator nerves for skin?
-need more blood flow, to make more sweat,
-need more blood flow to skin
helps to cool down
68
What's blushing?
Head, face, upper chest blush by stress (sympathetic) response
69
What causes redness in trauma + infection?
stimulation of sensory axon reflex (C-fibres)
70
Describe how redness happens in trauma + infection
-C fibres (pain fibres) stimulated + releases CGRP
-pain pathway stimulus to dorsal root ganglion in spinal cord + brain perceives pain
-axon collaterals come of C fibres goes to blood vessels + localised immune cells (mast cells):
releases substance P acts at endothelium + VSMC
stimulates mast cells that produce histamine
-vasodilation
71
How does NO cause vasodilation?
- shear stress in endothelium (or IF) stimulates Nitric Oxide Synthase (eNOS)
- produces NO
- NO diffuses from endothelium cell into VSMC
- stimulates G pathway
- stimulates Guanulate Cyclase (GC)
- produces cGMP from GMP
- cGMP activates PKG
- PKG causes vasodilation
72
Why's there constant release of NO?
Blood flow (via shear stress)
73
What's Nitric oxide (NO)?
lipophilic, soluble gas, freely diffusible
| Stimulates GC
74
eg of inflammatory factors?
Sub P, histamine, bradykinin, Ach
75
How does Prostacyclin (PGI2) cause vasodilation?
- shear stress (or IF/Ach) on endothelium
- membrane lipids into PGI2 via cyclooxygenase (COX)
- PGI2 acts at Prostanoid receptor (PGI2) on VSMC's
- drives A pathway
- Gs -> AC -> cAMP -> PKA
- PKA causes vasodilation
76
Importance of Prostacyclin (PGI2)?
- tonic PGI2 production
- vasodilates renal arterioles
- maintain glomerular filtration rate (GFR) + kidney function
77
Why shouldn't you give NSAIDs to people with kidney failure?
- COX inhibition
- reducing PGI2
- vasoconstriction
- dangerous in kidney failure
78
Why do PKA + PKG produce vasodilatation?
- ↑Ca ATPase (SERCA) – increase uptake into SR + exclusion from cell
- ↑K channel activity->hyperpolarisation->VGCCs switched off
- Inhibits myosin light chain kinase (MLCK)
79
How does endothelium-derived hyperpolarisation factors eg K+ cause vasodilation?
- K+ is 4mmol outside cell
- shear stress (or IF) activates K+ channels on endothelium
- release K+ to local external fluid
- high K+ in local external fluid
- switches on K+ channels
- more K+ go out
- switches on Na/K-ATPase
- 3Na+ out, 2K+ in
- hyperpolarisation of VSMC
80
How does endothelium-derived hyperpolarisation (EDH) cause vasodilation?
- shear stress (or IF) activates K+ channels on endothelium
- conduction of hyperpolarisation from endothelium to VSMCs via gap junctions
- less VGCCs and Ca entry
81
How does stimulation of β2-adrenoceptors cause vasodilation?
increases PKA activity so:
- ↑Ca ATPase (SERCA) – increase uptake into SR + exclusion from cell
- ↑K channel activity->hyperpolarisation->VGCCs switched off
- Inhibits myosin light chain kinase (MLCK)
82
Other functions of endothelium?
- Blood–tissue interactions, production of Ang II, endothelium surface contains ACE
- Blood clotting, Inflammatory pathway, Angiogenesis, Atheroma
83
How endothelium dysfunction happens?
Breakdown of endothelium function by hypertension, diabetes, cigarette smoking
Reduce NO/PGI2 production, enhance vasoconstriction
84
Why's regulation of BP + BF vital when treating sepsis?
BP too low – systolic <60 mmHg
| poor drive for end organ perfusion
85
Why's regulation of BP + BF vital when treating hypertension?
BP too high – damage blood vessels, afterload which reduces CO, increasing O2 demand of heart - alters end organ perfusion
86
Darcy’s law equations?
```
Blood flow (CO) = BP / TPR
BP= CO x TPR
```
87
Poiseuille’s law equations?
TPR ∝ r⁴
88
What controls BP + BF?
Regulation of vascular tone (controlling blood vessel radius)
89
Effect of increasing vascular tone?
increase blood vessel constriction + BP
90
Effect of reducing vascular tone?
induce blood vessel dilation + reduce BP
91
When do you increase vasoconstriction?
when a drop in BP in these conditions:
| sepsis, anaphylaxis, HF
92
What's sepsis?
-systemic infection --> excessive vasodilatation
-decreases TPR
-drop in BP
-no drive for end organ perfusion
-end organ damage
very serious, ITU (Intensive Treatmeant Unit)
93
What's anaphylaxis?
- hypersensitivity reaction --> systemic vasodilatation,
| - poor end organ perfusion
94
What's HF?
- poor CO
- poor BP
- poor end organ perfusion
95
Which stimulated receptors cause vasoconstriction?
α1, AT1, V1, ETA, TP
96
Which pathways are vasoconstrictor receptors?
Gq
97
What does Adrenaline act as at GI tract + skin?
vasoconstrictor
98
What does NA act as at GI tract + skin?
vasoconstrictor
99
What does Adrenaline act as at skeletal muscle + coronary circulation?
vasodilator
100
What does NA act as at skeletal muscle + coronary circulation?
vasodilator
101
Why are there diff between NA + A?
NA has higher affinity for α > β
A has higher affinity for β > α
and skeletal muscle + coronary arteries have more β2 than α1
102
What does A mostly do?
dilates vessels at β2
103
What does NA mostly do?
constricts vessels at α1
104
What happens if you give Adrenaline via IV?
```
Acts at β1 heart to:
-increase HR, CO, force of contractility to increase SV
- CO = HR X SV
-increases BP slightly as TPR is reduced
- BP = CO X TPR
Acts at β2 skeletal muscle to:
-dilates vessels reducing TPR
```
105
What happens if you give NA via IV?
Acts at α1 to:
- increases vasoconstriction + TPR
- BP increases
- baroceptors switches off HR, contractility, drop CO
- protects heart
106
Pharmacological vasoconstrictors agents + eg of when it's given?
NORAD (NA) = sepsis, severe HF
A = epipen for anaphylaxis
ADH (Vasopressin) = sepsis
107
Effects of NORAD?
acts at α1-adrenoceptors on VSMCs to increase TPR --> increased BP
cardiac protective
108
How's NORAD cardiac protective?
No sig actions on heart (β1) so doesn’t make heart work hard to increase BP, blood flow
109
Why's Adrenaline given in high conc?
to have an action on both β1 on the heart and α1 on VSMCs to raise BP (also β2 in lungs to give bronchodilation)
110
When do you increase vasodilation?
when hypertension is a risk factor in:
| angina, HF
111
Effects of hypertension?
- causes endothelium dysfunction
- reducing tonic vasodilatation processes (NO, PGI2)
- poor end organ perfusion
- increases afterload
- poor CO
- heart has to work much harder
112
What causes raised BP?
Imbalance of vasoconstrictor + vasodilator mechanisms
| Excessive vascular tone in arterioles suppling end organs
113
Why does greater BP not mean greater drive?
greater pressure drop across arterioles since higher pressure upstream, lower pressure (lower blood flow) downstream of excessive constriction
114
Diff vasoconstrictor mechanisms?
- Stretch of receptors (myogenic response)
- Activate vgcc
- Increase membrane depolarisation
115
Diff vasodilator mechanisms?
-Block receptors
-Open K+ channels hyperpolarisation
-Block vgcc
-Increase Ca ATPase SERCA:
more Ca into SR + more Ca exclusion from cell
-Decreased MLCK
-Increased MLCP (myosin light chain phosphatase)
116
eg of Gq receptor blockers?
AT1 antagonist : ARB
ACE inhibitor
α1 antagonist
ETA1 antagonist
117
Effect of ARB + eg?
```
Block AT1 (Angiotension II) receptors to reduce vasoconstriction in hypertension, HF
Losartan
```
118
Effect of ACE inhibitor + eg?
Reduce Ang II levels in hypertension, HF
| Enalapril
119
Effect of α1 antagonist + eg?
Competitive receptor antagonists – drug-resistance hypertension
Prazosin
120
Effect of ETA1 antagonist + eg?
Block ETA receptors which are upregulated in pulmonary artery hypertension
Bosentan
121
What type of drugs prevent increase in membrane excitability?
Nitrates
| K channel openers
122
How do drugs prevent increase in membrane excitability?
Hyperpolarisation
| Inhibit VGCCs
123
eg of Ca influx blockers?
```
VGCC blockers (CCB)
K Channel Openers
```
124
Effect of VGCC blockers (CCB) + eg?
Dihydropyridine subtype, vascular selective, block influx of Ca2+ to reduce vasoconstriction in hypertension, angina
Amlodipine
125
Effect of K Channel Openers + eg?
Hyperpolarisation, less VGCC activation/Ca influx, vasodilatation for angina
Nicorandil
126
eg of contractile mechanism relaxants?
Nitrates
| PDE5 inhibitors
127
Effect of nitrates + eg?
```
NO donors, PKG-mediated vasorelaxations for angina, pulmonary oedema
Glyceryl trinitrate (GTN)
```
128
Effect of PDE5 inhibitors + eg?
GMP breakdown, PKG-mediated vasodilatation for erectile dysfunction
Sildenafil
