Week 4 Flashcards
(153 cards)
1
Q
Normal end systolic volume?
A
~75 mL
2
Q
Normal end diastolic volume?
A
~150 mL
3
Q
How is TPR increased?
A
Constriction of small arteries and arterioles.
4
Q
What two factors does ventricular pressure depend on?
A
Compliance of wall (diastole) and active tension in wall (systole).
5
Q
Is the left or right ventricle more compliant?
A
Right ventricle is more compliant. Left is thicker wall (less compliant).
6
Q
Can the left or right ventricle generate more force?
A
Left ventricle can generate more force.
7
Q
How is stroke volume increased?
A
Increase EDV, or increase ventricular contractility (by SNS activation).
8
Q
Afterload
A
Load encountered by ventricle as it commences contraction.
Pressure load - imposed by arterial hypertension or LV outflow tract obstruction.
9
Q
Preload
A
Stretch on myocyte fibres before they commence contraction.
Volume (EDV) load - imposed by increased venous return.
10
Q
Left or right ventricle more compliant?
A
Right ventricle is more compliant. Left is thicker wall (less compliant).
11
Q
Left or right ventricle generate more force?
A
Left ventricle can generate more force.
12
Q
Arteries or veins more compliant?
A
Veins are more compliant than arteries. Arteries are less complaint - therefore, arterial pressure is more sensitive to changes in volume than venous pressure!
13
Q
How is blood volume of systemic arteries increased?
A
By venoconstriction! NOT by decreasing CO OR decreasing TPR!
14
Q
Blood volumes of systemic veins/arteries/capillaries?
A
Systemic veins = ~65% of total blood volume.
Systemic arteries = ~13% of total blood volume.
Systemic capillaries = ~5% of total blood volume.
15
Q
Autotransfusion
A
If BP too low, venoconstriction to increase volume to systemic arteries.
16
Q
Mean circulatory filling pressure
A
Mean vascular pressure that exists after a stop in cardiac output and redistribution of blood, so that all pressures are the same throughout the system - depends on volume of blood and compliance of vessels.
Approx. 7 mmHg.
17
Q
Pressure in great veins outside heart?
A
1 - 5 mmHg in SVC and IVC, slightly higher than right atrial pressure.
18
Q
Pressure in great veins outside heart?
A
1 - 5 mmHg in SVC and IVC (called central venous pressure - filling pressure for heart), slightly higher than right atrial pressure.
CVP increases as a result of failing heart.
CVP decreases as a result of poor venous return (e.g. blood loss, upright posture, inadequate muscle/respiratory pumps).
19
Q
Pressure in great veins outside heart?
A
1 - 5 mmHg in SVC and IVC (called central venous pressure - filling pressure for heart), slightly higher than right atrial pressure.
CVP increases as a result of failing heart.
CVP decreases as a result of poor venous return (e.g. blood loss, upright posture, inadequate muscle/respiratory pumps).
20
Q
Products of endothelium?
A
Nitric oxide (dilator), endothelin-1 (constrictor), prostaglandins (dilators or constrictors).
21
Q
Endothelium mediates actions of substances:
A
Angiotensin and thrombin - constriction.
Bradykinin - dilation via endothelium (constriction via smooth muscle directly).
22
Q
Products of white blood cells?
A
Nitric oxide, histamine and cytokines - vasodilators -> heat of acute inflammation, and migration/diapedesis of inflammatory cells.
23
Q
Products of platelets?
A
Thrombin, ADP, thromboxane A2 -> constriction to prevent blood loss.
Enhance coagulation/platelet aggregation, constriction.
24
Q
Pancytopenia
A
Generalised blood cell deficiency.
25
Anaemia
Red cell deficiency i.e. Hb below normal range for specific age and sex.
Measure Hb instead of red cell count!
26
Leukopenia
White blood cell deficiency, may be differential e.g. neutropenia, lymphopenia, etc.
27
Thrombocytopenia
Platelet deficiency.
28
Polycythaemia
Red cell excess.
29
Leukocytosis
White cell excess.
30
Thrombocytosis
Platelet excess.
31
Dyserythropoiesis
Red cell dysfunction.
32
Tissue oxygen delivery equation
Tissue Oxygen Delivery = CO x Hb x %Sat x 1.34
| Note CO = SV x HR
33
Pressure in great veins outside heart
1 - 5 mmHg in SVC and IVC (called central venous pressure - filling pressure for heart), slightly higher than right atrial pressure.
CVP increases as a result of failing heart.
CVP decreases as a result of poor venous return (e.g. blood loss, upright posture, inadequate muscle/respiratory pumps).
34
Products of endothelium
Nitric oxide (dilator), endothelin-1 (constrictor), prostaglandins (dilators or constrictors).
35
Endothelium mediates actions of substances
Angiotensin and thrombin - constriction.
| Bradykinin - dilation via endothelium (constriction via smooth muscle directly).
36
Products of white blood cells
Nitric oxide, histamine and cytokines - vasodilators -> heat of acute inflammation, and migration/diapedesis of inflammatory cells.
37
Products of platelets
Thrombin, ADP, thromboxane A2 -> constriction to prevent blood loss.
Enhance coagulation/platelet aggregation, constriction.
38
Tissue oxygen delivery equation
Tissue Oxygen Delivery = CO x Hb x %Sat x 1.34
| Note CO = SV x HR
39
Effects of anaemia
Reduced oxygen delivery to tissues (UNLESS increased CO to compensate).
40
Clinical signs of anaemia
```
Pallor
Lethargy
Failure to thrive
Hypoxia e.g. as dizziness
Ischaemia
Tachycardia e.g. if acute blood loss (but if chronic e.g. due to iron deficiency, may be normal HR due to compensation by SV).
```
41
Causes of anaemia
1 Failure of production.
2 Increased destruction/loss.
3 Inappropriate production.
42
Blood film features
Morphology of RBCs, WBCs and Plts.
Size (normocytic, macrocytic, microcytic).
Shape (different types).
Colour (normochromic, hypochromic, polychromatic).
43
Classifications of anaemia
Regenerative or aregenerative.
44
Regenerative anaemia
Blood loss/destruction - bone marrow generates new blood cells and Hb is depleted RAPIDLY.
Rapid reduction in Hb -> rapid reduction in O2 delivery -> patient rapidly deteriorates!
45
Aregenerative anaemia
Bone marrow does not generate new blood cells and Hb is depleted SLOWLY
Slow reduction in Hb -> compensation and slow progression.
46
Signs of increased blood cell production
Reticulocytes, polychromasia.
47
Signs of increased blood cell destruction
Jaundice (increased serum bilirubin), haptoglobins, LDH.
48
Signs of increased blood cell destruction
Jaundice (increased serum bilirubin), haptoglobins, LDH.
Important to detect! - Capacity for rapid reduction in Hb and rapid reduction in O2 delivery, with limited time to compensate.
49
Life spans of RBCs, WBCs and Plts
RBCs - replace every 120 days.
WBCs - replace every 3-5 days.
Plts - replace every 10 days.
50
Sites of haemopoiesis
Initial weeks in yolk sac.
6-7 months in liver and spleen.
After 7 months in bone marrow:
Infant = all bone marrow; adult = axial skeleton and proximal femur bone marrow.
51
Haematopoietic growth factors
Glycoprotein hormones.
| IL-3, GM-CSF, IL-6, EPO.
52
Haematinics
Nutrients required for formation and development of blood cells in bone marrow - iron, vitamin B12 and folate.
Vitamin B12 and folate important for all cell production, but esp. rapidly proliferating cells.
53
Haematinics
Nutrients required for formation and development of blood cells in bone marrow - iron, vitamin B12 and folate.
Vitamin B12 and folate important for all cell production, but esp. rapidly proliferating cells.
54
Stages of injury (vascular)
```
Primary haemostasis (seconds-minutes) - vasoconstriction, platelet adhesion, platelet aggregation.
Secondary haemostasis (minutes) - activation of coagulation factors, formation of fibrin.
Fibrinolysis (minutes-hours) - activation of fibrinolysis and lysis of thrombus.
```
55
Virchow's triad
Factors that contribute to thrombosis:
| Altered vessel wall, abnormal blood flow and abnormal composition of blood.
56
Features of coagulation system
Redundancy - deficiency of some factors may not affect coagulation!
Initiated by tissue factor.
Thrombin - positive and negative feedback loops (control thrombosis).
Thrombin -> formation of fibrin clot.
57
Initiation phase of coagulation
Injury of vessel wall -> contact between blood and subendothelial cells.
Tissue factor is exposed, binds to FVIIa or FVII -> converted to FVIIa.
TF and FVIIa complex activates FIX and FX.
FXa binds FVa on cell surface.
58
Amplification phase of coagulation
FXa/FVa complex converts small amounts of prothrombin to thrombin.
Small amount of thrombin - activates FVIII, FV, FXI and platelets locally.
FXIa converts FIX to FIXa.
Activated platelets bind FVa, FVIIIa, FIXa.
59
Propagation phase of coagulation
FVIIIa/FIXa complex activates FX on surface of activated platelets.
FXa associated with FVa - converts large amounts of prothrombin to thrombin (thrombin burst).
Thrombin burst leads to formation of stable clot.
60
Thrombin
Converts fibrinogen into fibrin.
| Deficiency of thrombin = bleeding; excess of thrombin = thrombosis.
61
Thrombin inactivation
Binding to thrombomodulin-APC downregulates ability to activate fibrinogen to fibrin.
Irreversible inhibition by antithrombin - heparin accelerates this inhibition by 1000-fold!
Binding to heparin co-factor II, dermatan sulphate.
Binding to alpha-2 macroglobulin.
62
Actions of thrombin outside of coagulation pathway
Activation of protease-activated receptors.
| Important in embryonic development, tumour metastasis and vascular disease.
63
Haemostatic tests for blood vessel wall
No effect tests.
| Formerly, skin bleeding time.
64
Haemostatic tests for platelets
Number, function and appearance.
65
Haemostatic tests for coagulation system
Risk of bleeding: use global tests, specific assays and genotype (specific disorders).
Risk of clotting: NO global tests; use specific assays, genotype (specific disorders).
Monitor anticoagulant drugs: use global tests, specific assays, genotype (predict responsiveness?).
Note - at present, NO effective test to measure combined coagulation system.
66
Why do we need an oxygen carrier in blood?
Oxygen diffuses slowly, not enough O2 in solution for metabolic demands and oxygen is reactive (oxidation).
67
Oxygen carriers
Hb (tetramer) and Mb (monomer):
Hb transports O2 in blood.
Mb stores O2 in muscle.
68
Haem moieties bind ___
Haem moieties bind O2.
69
Haem structure
Fe(II) = 6 coordinating bonds:
4 bonds - nitrogens in porphyrin ring.
1 bond - histidine (F8), proximal histidine.
1 bond - unbound in deoxyHb (in oxyHb, O2 binds).
Oxygen binds to Fe at 120 degree angle - easily unbound!!!
70
Other functions of haem (Fe2+-porphyrin) prosthetic group (i.e. not O2 transport)
Electron transport e.g. cytochrome C.
| Enzymes involved in redox reactions e.g. catalase - reduce H2O2 to H2O.
71
Colours of haem
Depends on redox state (Fe2+ Fe3+) AND bound ligand.
HbO2 - "scarlet red".
Hb deO2 - "dark red".
HbCO - "cherry red".
MetHb (Fe2+ irreversible oxidised to Fe3+) - "dark brown".
72
Binding of CO to Hb c.f. O2
CO binds 200x more tightly than O2 e.g. at straight angle c.f. 120 degree angle of O2.
73
Function of globin component of Hb
Cooperativity!
| Sigmoidal curve - weak-binding state at low pO2 and strong-binding state at high pO2.
74
Hb saturation in lungs and venous blood
Hb in lungs is 90% saturated, Hb in venous blood is 64% saturated (transfer O2 to Mb).
75
Mb structure
8 alpha helices (A-H).
Transient "breathing" of alpha helices allows O2 to access haem in buried hydrophobic pocket.
Monomer - NO cooperativity!
76
Hb structure
2 alpha and 2 beta chains.
| Alpha and beta subunits bind more strongly than subunits of same type.
77
Affinity of Hb for O2 depends on ___
Affinity of Hb for O2 depends on: [O2], pH, CO2 and 2,3-BPG concentration.
78
Allosteric interaction
Binding of a ligand at one site affects binding properties at another site.
O2 is both a ligand and homotropic (same ligand) allosteric modulator of Hb.
79
2,3-BPG
2,3-bisphophoglycerate is a heterotropic (different ligand i.e. different to O2) allosteric modulator of Hb.
BPG synthesised esp. in RBCs - glycolysis!
2,3-BPG binding to Hb decreases affinity for O2 - helps release of O2 in tissues!
80
Effects on altitude on 2,3-BPG
At high altitude, pO2 decreases -> cannot deliver enough O2 to tissues -> 2,3-BPG level increases -> more efficient unloading of O2 in tissues.
81
Before transfusion, during storage of RBCs, 2,3-BPG is ___
Depleted! -> Temporary but clinically significant impairment of O2 transport.
82
Hb in transport of CO2
Hb carries ~15% of CO2 formed in tissues to lungs (on amino terminal groups of deoxyHb as carbamate).
(Note - O2Hb binds CO2 LESS readily than deO2Hb.)
Rest of CO2 is converted to HCO3- by carbonic anhydrase.
BOTH REACTIONS -> decreased pH (Bohr effect).
83
Hb in transport of CO2
Hb carries ~15% of CO2 formed in tissues to lungs (on amino terminal groups of deoxyHb as carbamate).
(Note - O2Hb binds CO2 LESS readily than deO2Hb.)
Rest of CO2 is converted to HCO3- by carbonic anhydrase.
BOTH REACTIONS -> decreased pH (Bohr effect).
84
Bohr effect
Example of a different allosteric interaction in Hb.
Binding of protons to Hb lowers its affinity for O2.
(Two histidines that salt bond become more positively charged in acid - stabilises T state).
Stimulates HbO2 to release more O2 in tissues.
85
Foetal HbF
Alpha2Gamma2 - binds O2 with greater affinity than maternal HbA (adult Hb).
86
HbF binds 2,3-BPG ___ avidly than HbA
Less avidly!
| Decreased binding of 2,3-BPG relative to HbA = increased affinity for O2 relative to HbA.
87
Loewi's experiment
Evidence for chemical transmission:
Perfused donor heart and stimulated vagus nerve -> decrease in HR.
Perfuse recipient heart with perfusate from donor heart -> decrease in HR (i.e. without vagus nerve stimulation).
88
Loewi's experiment
Evidence for chemical transmission:
Perfused donor heart and stimulated vagus nerve -> decrease in HR.
Perfuse recipient heart with perfusate from donor heart -> decrease in HR (i.e. without vagus nerve stimulation).
89
Organisation of peripheral NS
Autonomic and somatic.
Autonomic = SNS and PNS.
Two fibres - pre-ganglionic (from CNS) and post-ganglionic (from autonomic ganglia).
```
Somatic = voluntary.
Single fibre (one neuron) - innervates skeletal muscle.
```
90
General autonomic NS fibre lengths
PNS - extended pre-ganglionic and short post-ganglionic (heart, glands and smooth muscle).
SNS - short pre-ganglionic and extended post-ganglionic (heart, glands and blood vessels).
91
Major peripheral NS neurotransmitters
Acetylcholine and noradrenaline
| Note - other neurotransmitters e.g. NO, ATP, VIP, NPY.
92
ACh synthesis
Choline converted to acetylcholine by choline-acetyltransferase (needs molecule of acetyl-CoA).
Stored in synaptic vesicle.
93
NAd synthesis
Tyrosine converted to L-DOPA by tyrosine hydroxylase. L-DOPA converted to dopamine by DOPA decarboxylase. Dopamine converted to NAd by dopamine beta-hydroxylase.
Stored in synaptic vesicle.
94
Adrenaline synthesis
Noradrenaline converted to adrenaline by PNMT
95
Inactivation of ACh in synapse by ___
Degradation.
ACh esterase on post-junctional membrane converts ACh to choline and acetate.
Choline is recycled.
96
Inactivation of NAd in synapse by ___
Uptake NAd in synapse.
| High-affinity uptake 1 in pre-junctional neuron or low-affinity uptake 2 on post-junctional neuron.
97
Main neurotransmitters in somatic, PNS, SNS and ganglionic transmission
Somatic = ACh
PNS = ACh
SNS = NAd (EXCEPT ACh at sweat glands and adrenal glands).
Ganglionic transmission = ACh.
98
Receptors for ACh and NAd
ACh - nicotinic (ligand gated ion channel) AND muscarinic (GPCR) receptors.
NAd - alpha AND beta adrenoceptors (GPCR).
99
Antagonists of ACh receptors
Atropine (muscarinic receptor antagonist), curare.
100
Antagonists of ACh receptors
Atropine (muscarinic receptor antagonist), curare.
101
Effects of botox
Inhibits ACh vesicle exocytosis - no release of ACh to synapse.
Botox is endocytosed and cleaves SNARE proteins, preventing vesicle fusion.
Selective for cholinergic nerves.
102
Effects of anticholinesterases (e.g. edrophonium, neostigmine, donepezil)
Inhibit acetylcholine esterases, and therefore increase level and duration of ACh in synapses.
103
Edrophonium
An anticholinesterase of short duration, used to diagnose myasthenia gravis.
104
Neostigmine/pyridostigmine
An anticholinesterase, used to reverse effect of neuromuscular blockers and treat myasthenia gravis.
105
Donepezil
An anticholinesterase with CNS access (via BBB), used to treat Alzheimer's disease.
106
Myasthenia gravis is an autoimmune disease to ___
Nicotinic cholinergic receptors (specifically on skeletal muscle)!
Reduced expression of nicotinic receptors - use anticholinesterase to inhibit ACh degradation -> increase ACh level and duration -> normal skeletal muscle function.
107
Tensilon test
To diagnose myasthenia gravis: use edrophonium - a short acting anticholinesterase - to see if skeletal muscle function is restored.
108
Neostigmine/pyridostigmine
An anticholinesterase, used to reverse effect of (non-depolarising) neuromuscular blockers and treat myasthenia gravis.
109
Tensilon test
To diagnose myasthenia gravis: use edrophonium - a short acting anticholinesterase - to see if skeletal muscle function is restored.
110
Effects of muscarinic ACh receptor agonists
Salivation, lacrimation, urination, defecation (SLUD).
| Sweating, bradycardia, bronchoconstriction, vasodilation.
111
Effects of muscarinic ACh receptor antagonists
Depends on level of parasympathetic tone.
Reduced salivation, lacrimation, urination, defecation (SLUD).
Reduced sweating, tachycardia, bronchodilation.
112
Effects of cocaine
Cocaine is an inhibitor of NAd reuptake from synapses (by high-affinity uptake 1 or low-affinity uptake 2).
Increased NAd in synapse, increased NAd and dopamine in CNS, and peripheral effects of increased NAd (increased HR and BP).
113
Effects of monoamine oxidase inhibitors (MAO inhibitors)
MAO metabolise and degrade NAd that leaks from vesicles. MAO inhibitors block metabolism of NAd that leaks from vesicle -> increase NAd in nerve terminal -> increase NAd released from terminal.
114
Effects of monoamine oxidase inhibitors (MAO inhibitors)
MAO metabolise and degrade NAd that leaks from vesicles. MAO inhibitors block metabolism of NAd that leaks from vesicle -> increase NAd in nerve terminal -> increase NAd released from terminal.
115
Effects of monoamine oxidase inhibitors (MAO inhibtors)
MAO metabolise and degrade NAd that leaks from vesicles. MAO inhibitors block metabolism of NAd that leaks from vesicle -> increase NAd in nerve terminal -> increase NAd released from terminal.
116
Indirectly-acting sympathomimetics do not need ___ for NAd release from nerve terminals.
Calcium.
| Indirectly-acting sympathomimetics cause non-exocytotic (calcium independent) release of NAd.
117
Indirectly-acting sympathomimetic action
Uptake into nerve terminal where it can enter synaptic vesicles and displace NAd from vesicle into terminal.
Some will be degraded by MAO but some will be released into synaptic cleft -> activate adrenoceptors.
118
Examples of indirectly-acting sympathomimetics
Amphetamine, ephedrine (pseudoephedrine), tyramine (in diet, may cause CV side effects e.g. hypertension in patients on MAO inhibitors e.g. for depression).
119
Subtypes of beta adrenoceptors
B1 - heart.
| B2 - airways.
120
B1 AND B2 adrenoceptor agonist and antagonist
```
Agonist = isoprenaline.
Antagonist = propranolol.
```
121
B1 adrenoceptor (heart) agonist and antagonist
Activation of B1 -> increase HR and contractility.
Agonist = dobutamine (e.g. in HF).
Antagonist = atenolol (e.g. in hypertension).
122
B2 adrenoceptor (smooth muscle) agonist
Activation of B2 -> relaxation of bronchial smooth muscle.
Agonist = salbultamol (e.g. in asthma).
Specific to B2, so no CV side effects on B1 adrenoceptors.
123
A1 adrenoceptor (blood vessel) agonist and antagonist
Activation of A1 -> vasoconstriction!
Agonist = phenylephrine (e.g. nasal decongestant).
Antagonist = prazosin (e.g. in hypertension).
124
A1 adrenoceptor (blood vessel) agonist and antagonist
Activation of A1 -> vasoconstriction!
Agonist = phenylephrine (e.g. nasal decongestant).
Antagonist = prazosin (e.g. in hypertension).
125
Examples of local mediators: ___, ___, ___
Histamine, bradykinin and nitric oxide.
126
Histamine is mainly stored in and released from ___ and ___
```
Mast cells (tissues - mainly mucosal surfaces/skin) and basophils (blood).
(Also stored and released from enterochromaffin-like cells (GIT) and peripheral/central histaminergic neurons.)
```
127
Histamine release from mast cells is stimulated by ___ (many stimuli)
Antigen via IgE, complement, neuropeptides, cytokines/chemokines, bacterial components and physical trauma.
128
Histamine receptors are ___ (type of receptor)
GPCRs
| Many subtypes e.g. H1, H2, H3, H4
129
Histamine causes a "triple response": ___, ___ and ___
Redness - vasodilation at initiating site (capillary).
Flare - redness surrounding area (arteriolar dilation).
Wheal - increase in vascular permeability -> exudate from capillaries and venules.
130
Histamine causes a "triple response": ___, ___ and ___
Redness - vasodilation at initiating site (capillary).
Flare - redness surrounding area (arteriolar dilation).
Wheal - increase in vascular permeability -> exudate from capillaries and venules.
131
Action and uses of H1 receptor antagonists
Antihistamines!
Competitive, reversible antagonists of H1 receptors.
Useful in hayfever, atopic dermatitis, anaphylaxis, motion sickness, etc.
NOT effective in asthma!
132
Classes of H1 receptor antagonists (three classes)
Sedative (e.g. chlorpheniramine, promethazine) - effective but cause drowsiness.
Non-sedative (e.g. terfenadine, astemizole) - poor entry to CNS (no drowsiness) but may cause rare, sudden ventricular arrythmia.
New non-sedative (e.g. cetirizine, loratadine) - reduced risk of unwanted cardiac effects.
133
H2 receptor antagonists
Selective H2 receptor antagonist.
Used in treatment of peptic ulcers (e.g. cimetidine, ranitidine) -> reduced gastric acid secretion.
Mechanism - neuronal stimulation -> histamine release from enterochromaffin-like cell -> histamine -> H2 receptor on parietal cell -> increase cAMP -> activate proton pump -> protons secreted into stomach lumen (acid).
134
Bradykinin
A local mediator in pain and inflammation.
| Plasma exudation during inflammation -> production of bradykinin.
135
Bradykinin
A local mediator in pain and inflammation.
| Produced during plasma exudation during inflammation.
136
Bradykinin may be inactivated by ___ and ___
Kininase I and kininase II - inactivation by cleavage of terminal residues.
Kininase II is angiotensin converting enzyme (ACE)!!!
137
Bradykinin receptors are ___ (type of receptor)
GPCRs
| B1 and B2 receptors.
138
ACh on endothelium causes ___ and on vascular smooth muscle causes ___
ACh on endothelium -> causes relaxation of vascular smooth muscle.
ACh directly on vascular smooth muscle -> causes contraction.
139
ACh on endothelium causes ___ and on vascular smooth muscle causes ___
ACh on endothelium -> causes relaxation of vascular smooth muscle.
ACh directly on vascular smooth muscle -> causes contraction.
140
Production of NO in endothelial cells
ACh/bradykinin/mechanical shear stress -> increase intracellular calcium -> activate NOS -> production of NO and citrulline from arginine.
NO diffuses from endothelial cells to underlying vSMC.
141
Action of NO in vSMC
NO activates guanylate cyclase (GC). GC converts GTP to cGMP. Increased cGMP causes relaxation.
(Note - cGMP can be converted to GMP by phosphodiesterase - reduce relaxation.)
142
Isoforms of NOS
nNOS - nerves, epithelial cells.
iNOS - inducible in macrophages, smooth muscle.
eNOS - endothelial.
143
Inhibitors of NOS
E.g. L-NAME - causes vasoconstriction and hypertension.
| Important - basal release of NO regulates vascular tone!!!
144
Inhibitors of NOS
E.g. L-NAME - causes vasoconstriction and hypertension.
| Important - basal release of NO regulates vascular tone!!!
145
Structure of arachidonic acid
C20:4 i.e. 20 carbons and 4 double bonds.
An eicosatetraenoic acid.
Omega 6 - double bond is 6 carbons from non-functional end.
146
Source of arachidonic acid
From polyunsaturated fatty acids (PUFA).
Diet - mainly omega-6 PUFAs.
Indirectly as linoleic acid C18:2 or directly as arachidonic acid C20:4.
147
Storage of arachidonic acid
Bound to albumin in circulation, and uptake into cells and esterified (at C2 position) in membrane phospholipids (plasma AND nuclear membranes).
148
Release of arachidonic acid
Activation of phospholipase A2 (by increase in intracellular calcium, acute) -> free arachidonic acid produced.
Phosphorylation of extracellular regulated kinase (ERK, acute) -> increase phospholipase A2 activity.
Chronic = increase number of phospholipase A2.
149
Release of arachidonic acid
Activation of phospholipase A2 (by increase in intracellular calcium, acute) -> free arachidonic acid produced.
Phosphorylation of extracellular regulated kinase (ERK, acute) -> increase phospholipase A2 activity.
Chronic = increase number of phospholipase A2.
150
Types of stable prostaglandins
```
PGE2 - relax vascular smooth muscle -> vasodilatory and natriuretic -> decrease BP.
And hyperalgesia (sensitises to pain, does not cause pain), pyrogenic and angiogenic.
PGF2a - bronchoconstrictor.
PGD2 - bronchoconstrictor.
```
151
Targets of NSAIDs
COX1 and COX2 enzymes.
152
Indications of NSAIDs
Anti-inflammatory, analgesia, antipyretic.
153
Adverse effect of ALL NSAIDs
Gastric irritation or ulceration.
