1 Flashcards
where are the kidneys located?
posterior to the peritoneum in the abdominal cavity
the left kidney is slightly higher than the right
function of the kidney
homeostasis
blood ionic composition blood pH (7.38-7.42) blood volume and pressure blood osmolarity (conc. of solutes) excretion of waste hormone production - locally or long distance glucose levels - dip test on urine
hypovolaemia
blood fluid volume too little so dehydrated
thirst, postural hypotension (dizzy), low jugular venous pulse/pressure (JVP), weight loss, dry mucous membranes, reduced skin turgor, reduced urine
hypervolaemia
too much blood fluid volume
oedema (tissue swell), breathlessness, raised JVP, weight gain, hypertension
what contributes to blood pressure?
sodium and water
water follows sodium
interstitial fluid
surrounding capillaries
intracellular fluid
in cells
extracellular fluid
vasculature and interstitial fluid so in blood and around tissues
osmolarity
number of active solutes in fluid
osmoles (osmol/L, Osm/L, mOsm/L)
osmolality
like osmolarity but per kg instead of L so weight not volume
but can interchange the words
osmotic pressure
pressure applied to prevent inward fluid movement across semi-permeable membrane
high osmotic pressure means high osmolarity
oncotic pressure
osmotic pressure exerted by proteins in plasma which attract water
hydrostatic pressures (P)
force exerted by fluid against capillary wall
tonicity
effective (relative) osmotic pressure gradient, relative concentration of solutes dissolved, diff tonicities of compartments to allow movemet
hypotonic solution
high osmotic in cell
low in interstitial fluid
water moves hypo to hyper so into cell
isotonic solution
high in cell and fluid so no net movement but freely back and forth
hypertonic solution
high osmotic in cell but very high in fluid so water move out cells to fluid (from high water to low water)
what movement occurs if Pc (hydrostatic pressure of capillaries) is bigger than osmotic pressure?
fluid leaves capillary - filtration of plasma
diameter affects P
high P from large diameter e.g. large diameter of afferent arteriole and small diameter of efferent so filtrates water out capillary
2 different lengths of nephron
cortical - shorter less important
juxtamedullary - focus on this, role in conc.
function of nephron
filtration
tubular reabsorption
tubular secretion
urine excretion
mesangial cells
around afferent arteriole and vasculature
smooth muscle cells so affect diameter and surface area of filtration so change P
parietal outer layer of Bowman’s capsule
squamous cells
podocytes of visceral layer of Bowman’s capsule
fingers make another filtration layer
macula densa
wall of ascending limb
cells act as chemoreceptors to detect sodium chloride in filtrate
juxtaglomerular cells
wall of afferent arteriole
mechanoreceptors detect stretch in capillary walls
3 main layers for glomerular filtration
fenestration (pores) prevent filtration of RBCs and platelets
basal lamina (basement membrane) prevent large proteins, -vely charged
pedicels - filtration slits (allow less than 0.006-0.007um, water, glucose, vitamins, ammonia, urea)
NFP (details on paper notes lecture 1-2)
net filtration pressure
total P that promotes filtration
= GBHP-CHP-BCOP
GFR
glomerular filtration rate
amount filtrate formed per min
control of GFR
renal autoregulation - myogenic and tubuloglomerular feedback
neuronal regulation
hormonal regulation
renal autoregulation (myogenic and tubuloglomerular)
maintain constant renal blood flow and GFR
myogenic mechanism: increases BP and GFR means BP stretches walls of afferent A which is detected by JG cells so smooth muscle fibres contract and narrow lumen of afferent so reduces renal flow and GFR
tubuloglomerular feedback: -ve feedback by macula densa cells, increased filtration rate sensed by macula densa from solutes and JGA so decrease NO release (vasodilator) so afferent constrict and decrease blood flow and GFR
change water levels in nephron
most reabsorbed in PCT and Loop of Henle
fine tuning in LoH and collecting duct
thick ascending limb is impermeable to water
countercurrent system in LoH keeps gradient
how is glucose reabsorbed from PCT?
through SGLTs (sodium glucose transporters) so cotransported with Na
normally all reabsorbed by PCT
sodium ions at PCT
Na/H antiporter gets H into tubule to get rid of it and helps buffering, and Na out
ions and urea in PCT
passive reabsorption in distal part of PCT
leaky cells so pericellular movement and transcellular in leak channels
Loop of Henle absorption and secretions
thick ascending limb with Na/K/Cl symporters in apical membrane
potassium pumped out
chloride leaks out
distal convoluted tubule and collecting duct function
fine tuning depending on what body needs
water affected by ADH
what causes ADH release?
cellular dehydration causes increase plasma osmolarity which triggers osmoreceptors in hypothalamus
OR
extracellular dehydration decreases fluid volume and causes hypovolaemia detected by pressure sensors in peripheral volume receptors in atria/carotid sinuses/aortic arch/afferent arteriole
where is ADH produced?
supraoptic and paraventricular nuclei of hypothalamus
where is ADH released?
posterior lobe pituitary
mechanisms of ADH
vasopressin receptor for ADH on collecting duct activates PKA so phosphorylation of proteins and AQP2 export to apical membrane of cell so inserts aquaporins so water absorbed to blood
what is the point of the countercurrent multiplier in the Loop of Henle?
to increase osmotic gradient in medullary interstitial fluid
how does the countercurrent multiplier in the Loop of Henle work?
hairpin arrangement
symporters in thick AL transport Na and Cl into medulla
continued movement through tubules supplies ion for this
thin DL permeable to water and no active reabsorption/secretion occurs, water moves out due to high conc. ions in medulla
thin AL impermeable to water and no active movement of solutes
thick AL impermeable to water but active reabsorption
ions pumped out on right so water from left comes out and concentrated fluid flows from left to right in tube so high concentration on right again and pumped out again etc.
only pump out difference of 200
urea helps with gradient as well
renin-angiotensin-aldosterone system
low blood pressure/volume causes afferent arteriole to be less stretched so JGA secrete renin enzyme which causes angiotensin II (vasoconstrictor) release
so lower GFR and more Na/Cl reabsorption and adrenal cortex releases aldosterone which acts on kidneys to reabsorb water and Na so increase BP/volume
how is angiotensin II made?
angiotensinogen made by liver makes angiotensin I + ACE (angiotensin converting enzyme) which converts it to angiotensin II and acts on adrenal cortex
where is ACE produced
from renal and lung epithelia
ACE inhibitors
hypertension drugs, stop vasoconstriction, stop high BP
e.g. benazepril, captopril (more on lecture 1-2 slide 48)
diuretics
promote loss of Na and water
loop diuretics most powerful and inhibit medullar gradient
thiazide diuretics act on DCT and reduce Na reabsorption
Spironolactone - aldosterone receptor antagonist, acts because K in urine from aldosterone tubular secretion into late DCT/CT
atherosclerosis
precursor of all CVD (cardiovascular disease) apart from rheumatic
plaques
reduced lumen
reduced elasticity of vessels
clots
normal BP
120/70 or 80
120 is systolic P in artery when ventricle contract
70/80 is diastolic P
lipid transport in body
insoluble so require specific transport
apolipoproteins and lipoproteins definition and types
apolipoproteins bind lipids to form lipoproteins - 1 layer lipid membrane with proteins inside, acts as receptor
e.g. chylomicrons, VLDL (very low density lipids), IDL (intermediate), LDL, HDL (high), Lipoprotein A
(more dense means more protein)
diff densities transport diff things
relationships between lipoproteins and CVD
positive relationship between LDL-C and CVD
inverse relationship between HDL-C and CVD
what does LDL transport
cholesterol to tissues
similar to lipoprotein A but A has extra protein on outside
lipoprotein mechanism and function
chylomicron picks of triglyceride (TG) from diet to transport to liver, skeletal muscle, adipose tissue for energy or storage so smaller chylomicron remnant
VLDL made in liver carries new TG from liver to tissues so becomes IDL then LDL
2 variations: LP (a) and SD-LDL (high cholesterol and high VD)
chylomicron structure
phospholipids on outside with TG and cholesterol ester (makes more soluble) inside with proteins in phospholipid layer
which lipoprotein is good and reduces CVD?
HDL (high) because picks up cholesterol and gets rid of it
exogenous lipid transport pathway (how fat in diet is metabolised)
bile emulsify dietary fat - broken to glycerol and fatty acids
1) enterocytes package TG to chylomicron
2) through lymphatics to vasculature
3) chylomicron pick up TGs, C-II (2) on chylomicron interacts with lipid protein lipase (LPL, given off by HDL to help chylomicron bind and endocytosis) in vasculature so breaks TG to free fatty acids (FFA) and glycerol
4) offload into tissues and use FFA for metabolism
5) remnant circulates to liver where ApoE protein bind receptor in liver so broken
enterocytes
intestinal absorptive cells in lining of gut
endogenous lipid transport pathway
stuff made in liver
1) liver can generate all the cholesterol it needs
2) cholesterol packaged into LDL (HDL helps transfer Apo C-II and ApoE to VLDL)
3) VLDL binds with ApoC-II to vasculature walls and LPL breaks TG to FFA and offloads TGs
4) now IDL which turns to HDL to LDL (or straight to LDL, low density) and can bind tissues to offload cholesterol/TG
5) bind to liver by rLDL (receptor) and offload cholesterol to cells
6) lots LDL means saturate tissues and liver, reduce receptors so leave high plasma LDL (in blood) and blood LDL conc increases
reverse cholesterol transport
by HDL - when it interacts with tissues it collects cholesterol (which is good) unlike LDL which offloads it
it takes it to adrenal/ovaries/testes for steroidogenesis
can go back to liver for breakdown - receptor mediated endocytosis
talks to LDL and VLDL to offload cholesterol/proteins
so can give proteins to help other lipoproteins do job
atherosclerosis pathogeneis
high plasma level of LDL so plaques - deposition of lipids in medium/large arteries
proliferation of extracellular matrix (ECM) beneath smooth muscle layer so protrusion of fibrous plaque to lumen of vessel and affects flow
can be asymptomatic until ischaemia, closure of vasculature by plaque closure, clot, aneurysm, embolism
ischaemia
reduced O2 to tissues
aneurysm
weak walls can split
embolism
clot travel to other parts of body
hypotheses for atherosclerosis
lipid hypothesis - excess lipids
response to injury hypothesis - damage to epithelium
inflammation hypothesis - combination of both
neoplasia
proliferation of smooth muscle cells
prostaglandins
prostacyclin and thromboxane imbalance - influence thrombus formation
thrombosis
main event forming atheromatous plaques
stages of atherosclerosis and how it’s caused
1) damage endothelial cells activates cascade so inflammation and attracts WBCs
2) macrophages try take things up but can’t do anything with it so now foam cell - cholesterol becomes oxidised and more reactive to cells so more inflammation and protrusion under endothelial - fatty streak,
more ECM and plaque, compression of smooth muscle cells and cells migrate to fatty streak
3) protrusion with hard lipid core - mitochondria dysfunction, necrosis and neoplasia, epithelial cells take up lipids and lots ECM produced and proteases produced so protrusion into vasculature and it affects blood flow,
increased cell adhesion expression so sticky and platelets stick to walls so clot
4) fibrous cap, lots fibrin, lipid core, destroy underlying layer, lots collagen, more MMPs which break ECM down and make unstable which is dangerous, develop thrombus and high stage atherosclerosis
what causes damage to endothelial cells?
smoking
high BP
high lipid
what determines if a plaque is vulnerable?
composition (not size)
large lipid core more likely to rupture and expose thrombogenic material
treatment of atherosclerosis
lifestyle change ACE inhibitors statins antiplatelets for thrombus surgery for coronary arteries and carotid arteries
statins
reduce cholesterol
stop cascade of production
Atorvastatin is common
risk of diabetes but worth the low 9% risk
60-70% CVD still not prevented
haemotology
study of blood
haematopoiesis
differentiation into all blood cells
expression of diff genes, controlled by env. of developing blood cell
cells in blood
leukocytes -white
erythrocytes -red
thrombocytes - platelets
rarely others like foetal and cancer
what is plasma made up of?
water electrolytes dissolved gases urea proteins lipids glucose
anti-coagulated - slow centrifugation of blood
shows main components
buffy coat layer with WBCs
haematocrit value is % volume (roughly 45%) of RBCs
blood cell lineages
all from single pluripotent stem cells called progenitor (stem cell but more specific)
which splits to myeloid from bone marrow - platelets , RBCs, myeloblast to granulocytes (eosinophil, basophil, neutrophil)
OR
lymphoid from lymph - lymphoblast to B lymphocyte/T/natural killer
leukocytes (WBCs) are which lineage?
all lymphoid and granulocytes from myeloid
properties of erythrocytes
membrane can deform to squeeze through 3um vessel,
shape maintained by cytoskeletal system and allows flexibility
anaemia
too few RBCs
breathlessness, fatigue
polycythaemia
too many RBCs
raised viscosity
strain on heart so need to work lots
where are leukocytes produced from?
primary lymphoid tissues - bone marrow or thymus
where do leukocytes function?
secondary lymphoid tissues - spleen, lymph nodes, mucosa-associated lymphoid tissues (MALT e.g. Peyer’s patches in gut)
which is the most abundant WBC in blood?
lymphocyte and neutrophils
lymphocyte structure
25% of blood
small, same size as RBC, 1 massive nucleus fills cell
neutrophil structure
65% of blood
1.5 x RBC
multilobed
monocyte
5% of blood
kidney shaped nuclei
largest cell - 2x RBC
eosinophil
5% of blood same size as neutrophil pink not blue bi-lobed nucleus lots granules
basophil
1% of blood
large granules
can barely see nucleus but bi-lobed
block clotting
which immunity corresponds to which blood cell lineage?
lymphocytes are for adaptive immunity - B/T/NK
myeloid lineage are for innate immunity - N/M/E/B
haematoxylin and eosin (H&E) stain
most common stain for blood
eosin is pink acidic dye which binds proteins and stains cytoplasm pink
haematoxylin is blue-purple basic dye which binds nucleic acids
what are platelets
fragments on cells NOT cells
histochemistry
stain enzymes on surface e.g. non-specific esterases turn brown
immunological detection
antibody binding of extra/intracellular AG on WBCs
immunocytochemistry - Ab linked to fluorescent chromophores, visualise on microscope
immunohistochemistry - Ab linked to enzymes to convert substrates
flow cytometry
diff coloured cells counted
intensity of fluorescence measured - dot plots (1 dot is 1 cell)
so add Ab coloured for each cell and use lasers and gate open depending on colour and counted as go through gate
lineage markers allow gate counting
monocyte markers
CD14+ marker
can be detected with Ab so tells us what they are
thrombocytes
platelets
formed from megakaryocyte in bone marrow,
cell attach where blood vessel is forming, project membrane through holes in vessel, bits come off to make platelets
satellistism
reduced platelets
plasma
fluid component of blood, with lots proteins
plasma proteins
albumin
alpha globulins 1/2
beta globulins
gamma globulins
where are plasma proteins synthesised?
all except gamma are synthesised by liver
serum
fluid left after blood has clotted, contains all proteins except for things involved in clotting (clotting factors, fibrinogens)
unusual results seen in gamma globulin in electrophoresis of plasma proteins
1 class of gamma globulin clear band instead of normal diffuse band - could be myeloma
no gamma could be leukaemia
normally diffuse band because lots diff Abs
polypeptide hormones in blood
e. g. anterior pituitary secretes prolactin which acts on mammary gland and regulates blood pressure
e. g. renin and angiotensins for BP
other enzymes
albumin
carrier for substances with low solubility in plasma like lipids, hormones, fatty acids
low affinity for lipophilic compounds
diminish binding of xenobiotics to hormone/receptor so protect endocrine disruption
binds calcium, helps maintain osmolarity of blood
function of complement in blood
opsonisation
chemotaxis
lysis
clumping of antigen bearing agents
gamma globulins
serum Abs
alpha-antitrypsin
inhibit trypsin
haptoglobulin
binds free Hb
coagulation factors
when activated they form an enzyme cascade - convert fibrinogen to fibrin which is insoluble so trap cellular components and clot
haemostasis
maintain blood fluid within circulatory system
by vasoconstriction platelet activation haemostatic plug coagulation clot clot dissolution
vWF
van Willebrand factor in endothelial
not visible normally until breakage
haemostasis and coagulation process (clotting)
1) extrinsic damage to endothelium
2) platelet membrane integrins mediate adherence to ECM (integrin a2b1 binds collagen, integrin alpha2b beta3 aka glycoprotein GPIIA/III binds other ECM proteins)
3) vWF becomes visible when bound to GP1b integrin - when breakage occurs
4) platelets activated so sticky so bind vWF and collagen and to site of injury
5) prothrombin to thrombin to fibrinogen to fibrin which binds more integrins and platelets
6) binding of integrins causes activation of platelets which release ADP - signals to more platelets to clot, and platelets also release thromboxin A2 (TXA2) which activates platelets and vasoconstriction
7) activated platelets bind and release protein factors (coagulation factors, growth factors for healing) and phosphollipids up-regulated on platelets
8) tissue factor (factor II/thromboplastin) activates plasma coagulation - in tissue not circulation so clots if contact tissue
how to prevent excessive clotting
thrombomodulin on endothelium binds thrombin to activate protein C so inactivate factors Va and VIIa
antithrombin in plasma
protease ADAMTS13 degrades vWF
how to remove clots
fibrinolytic mechanisms
depends on fibrin digestion by plasmin protease
inactive precursor plasminogen activated by tPA (tissue plasminogen activator) to plasmin - drugs can activate this
haematopoietic stem cell
blood cells constantly made in bone marrow (5 x 10^11 daily) because most blood cells short 1/2 life
accelerated when haematological stress (infection needs leukocytes, high altitude needs RBCs)
haematopoiesis process
1) early in embryonic development (3 weeks in humans), not in bone marrow, embryo separate into 2 (embryo proper & adult tissues AND yolk sac)
2) yolk sac - heart forms earliest, YS joined to embryo by stalk which forms capillary system (plexus)
3) heart and aorta form same time and join with capillary plexus, RBCs start to circulate, 3 niches of RBCs are YS/liver/bone marrow
4) primitive = early haematopoiesis in YS, nuclei blood cells,
definitive = switch to liver haematopoiesis at 5 wks then BM at birth
5) bone marrow is highly specialised tissue with lots cells
6) IS cells proliferate and differentiate in periphery (2nd lymphoid)
where are blood cells made before and after birth?
in development, in yolk sac and liver then switch to bone marrow at birth
stalk that joins yolk sac to embryo
contains mesoderm derived stem cells - haemangioblasts which differentiate to RBCs with nuclei and endothelial cells to generate capillary system (plexus) in yolk sac
cells other than blood cells in bone marrow
stromal cells for support
growth factors
osteoblasts
bone structure
specialised connective tissue with rigid ECM, rigid outer layer of dense compact bone, inner core less dense spongy bone
units of bone
osteon
Haversian canal
Volkmann’s canal
vessels and nerves go up and down
sideways join Habersians
bone marrow structure
within medullary cavity and spongy bone
2 kinds: red and yellow
red in flat bones and epiphyses of long bones, contained granulocytes, erythroid islands, megakaryocytes,
yellow in shafts of long bones (lots fat)
Hayflick limit
stem cells divide certain number of times because of telomere shortening
model explaining telomere reduction in serial transplantation
HSC in adult mice non stressed resting state - not much shortening
transplant to primary recipient - cycling activity increased for reconstruction of lineages
primary to 2nd recipient - considerable increase in HSC turnover so cycling time speeds, cell cycle time decreases so telomere shorten
experiment showing HSC are multipotent
so parental cell for all blood cells
x-rays cause double stranded breaks in BM cells’ DNA, try repair and cause chromosome markers - each unique, so all descendents of marked cell have same marker so can map DNA mutation
found that all leukocytes had same marker, then all myeloid had same and all lymphoid has a different same marker
so stem cells more restricted potency - myeloid/lymphoid from progenitor - CLP/CMP make lymphoid/myeloid
HSC marker (Hematopoietic Stem Cell)
rare cell in bone marrow (<0.1%) with CD34+ marker
but endothelial express CD34 as well so not unique to HSC
stem cell niche for HSC
2 speeds of cell division
1) endosteum - long term, maintain vascular niche, between solid bone and marrow, associated with osteoblasts, SLOW cycling
2) perivascular - progenitor cells produced, region around vascular sinusoids with large vessels thin walls and fenestrated endothelium, FASTER cycling
receptors on niche and HSC so bind and signal to each other
stem cell niche (definition + 3 types)
microenvironment around stem cells provide support and signals regulating self-renewal and differentiation
1) direct contact: physical, juxtacrine, stem cell with niche cell
2) soluble factor: move, Hedgehog (maybe), Wnt
3) intermediate cell: stromal cells receive and send signal
growth and differentiation of HSC
HSC divides and 1 cell leaves niche to become progenitor cell so asymmetric division
control fate by moving things around inside like proteins and growth factors - drive growth then differentiation
growth factors and cytokines act in paracrine fashion within tissue so diffuse and juxtacrine
so when move to diff niche get diff signal and send out diff signal
specificity of differentiation of HSC examples
GM-CSF from lymphocytes (monocytes, macrophageS)
EPO from kidney, in RBC development
IL-3 to make basophils
development of erythrocytes and platelets
early stage pass pathway generating MEP (megakaryocyte/erythrocyte precursor) then split
erythropoiesis
generation of RBCs with EPO (erythropoietin) signal
MEP to proerythroblast to erythroblast (dividing) to reticulocyte (with nucleus, non-dividing) to RBC (non-dividing)
thrombopoiesis
generation of platelets
TPO (thrombopoietin) initiates for megakaryocytes produced by liver
IL-6 doubles production by liver (stimulates thrombopoiesis)
in thrombocytopenia - decreased platelets, BM stromal cells produce TPO
platelets have TPO receptors so remove from circulation (-ve feedback)
blood groups genotypes, phenotypes, alleles?
3 alternative alleles for 1 gene
6 genotypes
but 4 phenotype: A, B, AB, O
why is it an AB group and not one or the other?
A and B are co-dominant
ABO alleles
A/B dominant and O recessive so..
I^A
I^B
i^O
what does I stand for in blood group alleles?
isoagglutinogen
what do the enzymes encoded by blood group alleles do?
‘decorate’ carbohydrates on lipids (glycolipids) on RBCs (H-antigen attached to sphingosine to form glycolipid in group O, then more attached to this to form A and B)
O with Gal and Fuc
A with Gal, Fuc and Gal-NAc
B with Gal, Gal and Fuc
glycosphingolipids
glycolipids with sphingosine
types:
cerebroside (ceramide with sugar residue) - stick in membrane, sphingosine group in membrane,
ganglioside (ceramide with chain of sugar residues)
why does agglutination between blood groups occur?
diff blood groups express diff enzymes on surface of RBC
so A agglutinate B, AB no agglutinin Abs and O has both A/B Abs
so can mix AB with all blood types
paternity of blood groups
same group as parents
but sometimes AB allele but phenotype O from epistasis - mutation means H-antigen can’t be made and H encodes FUT1 (Fucase transferase)
secretor phenotype
non-secretors
77% Caucasians
water soluble A/B AGs in secretions (Se/Se or Se/se),
independent of blood type, encoded by FUT2
non: se/se with increased risk of oral disease, asthma, snoring, diabetes, alcoholism, infections, autoimmune
MN blood groups
separate from ABO and don’t matter much because no natural Abs, so not affect transfusion
L^M and L^N are co-dominant
attachment site for plasmodium sp so malaria, encodes protein on RBC membrane
Rh blood groups (Rhesus)
85% white Caucasians are Rh+
15% Rh-
many alleles, no natural Abs
3 genes on chromosome 1, 1 on chromosome 6
genotypes CDE, only cde/cde is rr and Rh- so triple mutant so rare
haplotype
if carry 1 mutation, carry another because on same chromosome so inherit together, tightly linked so recombination can’t separate
Rh incompatibility in pregnancy
Rh- female with Rh+ male first child is Rh+ so fine
but immunised in pregnancy so produce anti-Rh IgG so 2nd/3rd pregnancy causes haemolytic disease of foetus so still birth/neonatal death
can treat with anti-Rh Ab to prevent immunisation, or child blood transfusions
ABO compatibility
anti-A/B IgM important in early pregnancy
female O male A (B,AB) more miscarriage than female A (B,AB) male O
transfusions improvements
storage split products from RBCs testing anticoagulants preservatives refrigerate blood bands venous access safety - contamination, allergic
types of vessel formation
vasculogenesis
angiogenesis
lymphangiogenesis
arteriogenesis
what usually causes angiogenesis
pathological process like trauma, embolism, neoplasia, diabetes, or regeneration of endometrium after menstruation, or just growth
what are the 2 ways in which endothelial cells (ECs) grow in angiogenesis?
sprout
intussusceptive
sprouting (angiogenesis)
something makes endothelium grow out
form lumen
another tube
pseudopodial processes guide sprout by migrating endothelial cells
intussusceptive (angiogenesis)
endothelial cells grow down middle of tube to form 2 tubes,
requires cells to move away from ECM,
MMP enzymes break connections to form 2 capillaires with lumen in middle
what is the process of triggering angiogenesis?
hypoxia - VHLp not oxidised so prevent binding to HIF-alpha so alpha binds beta and conformational change releases NLS so find target in nucleus
switch VEGF on - bind receptor on endothelial cells and drive proliferation and mitosis of cells,
express receptor for growth hormone so new capillaires
(and EPO synthesis for RBC formation)
HIF-alpha/-beta
hypoxia-induced factor
destroyed in O2
VEGF
vascular endothelial growth factor
a pro-angiogenic factor
what happens in high O2 (angiogenesis)
no VEGF so VHL protein phosphorylated and hydroxylated to VHL-p-OH and binds to HIF-alpha so target to proteasome for destruction
arteriogenesis
formation of arteries after blood flow obstruction (e.g. embolism clot or stenosis narrowing)
develop from pre-existing anastomosing (collateral) arterioles - anastomosis are small channels joining 2 large channels
process of arteriogenesis
blood flow transfers from main arteries to anastomosing arterioles which response by enlarging (not just force more blood but growth driven by force and flow, NOT driven by O2)
shear stress and stretch detected by plasma membrane and cytoskeleton regulates cell shape change
SSRE (shear stress response element) indirectly activates genes like growth factors, adhesion molecules, proliferation of ECs so arterioles larger
cytopenia and anaemia
cytopenia lack of cells so changed blood cell count
anaemia is fewer RBCs/ lack Hb in them
types of anaemia
aplastic - few cells
iron deficiency - lack Hb
pernicious - vitamin B12 deficiency
causes of anaemia
bleeding Hb synthesis defect destroy RBCs by spleen haematopoiesis defect myelodysplasia - defect in lineage production leukaemia
symptoms of anaemia
enlarged spleen, yellow eyes (icterus)
blood tests for anaemia
RBC/Hb low,
size smaller - MCV (mean corpuscular volume - RBC size), microcytic smaller when iron deficiency, macrocytic bigger when B12 deficiency
how to treat anaemia
blood transfusions
cell transplant
pacytopenia
leukopenia
neutropenia
thrombocytopenia
all cells reduced
WBCs reduced
neutrophils reduced
platelets reduced so not clot
neutropenia
susceptible to infection
take FBC (full blood cell count) with differential (diff types of each cell counted)
can occur from chemo
haematological neoplasia (+ 3 types)
new growth in blood
leukaemia, lymphoma, myeloma - depends on what overgrowth
leukaemia
abnormal cells in BM so normal cell production pushed out, abnormal cells spill to circulation where don’t divide
lymphoma
abnormal cells in lymph node and proliferate and spread to other nodes and destroy function, to other tissues and bone marrow, in secondary lymphoid tissues so from mature cells
e.g. B-cell neoplasms, T-cell and NK-cell neoplasms, Hodgkin lymphoma
Hodgkin’s lymphoma
germinal B cells are owl like - swellings of overgrowth cause Reed Sternberg cells
blood counts are normal
enlarged nodes
high grade so need immediate chemo, quite treatable if early enough
hypertension
high BP
persistent
>140/90
high even at rest
where is arterial blood pressure measured in?
branchial artery
white coat hypertension
anxious with doctor so increase BP
overcoming white coat hypertension
at home measurements - ABPM (ambulatory blood pressure monitoring)
inflate every 1/2 hour and measure BP in clinic,
have all day during normal activity and when sleep, so 14 measurements
in clinic 2 per hour during waking hours and 14 total
at home: 3 measurements 1 min apart so take average, twice daily for 4-7 days and check both arms
ausculation and korotkoff sounds and how to measure BP
body sounds when measuring blood pressure
1) inflate cuff and measure pressure in cuff, turn valve to turn pressure off so deflates,
pressure in cuff is line under red sound waves
2) pump cuff high to stop blood flow and hear no sound in arm
3) turn pressure off so blood flow again and 1st sound you hear is systolic pressure - 1st measurement, becomes louder as pressure decreases, sound stops means diastolic pressure - when flow normal
auscultatory gap
sound suddenly stops during BP measurement
rare
if not pump cuff enough
mean arterial pressure
60% diastolic and 40% systolic
(systolic + 2xdiastolic) divided by 3
primary/essential hypertension (EH)
90-95% of all hypertension
probs complex genetics
secondary hypertension
result of complications
symptoms of hypertension
mostly none
headaches, dizzy, flushing, aware of heart beat, epistaxis (nose bleeds)
clinical signs of hypertension
BP,
cardiomegaly/left ventricle hypertrophy (enlarges from high BP),
abnormal renal function
hypertension complications
risk of stroke aortic aneurysm - swelling heart failure renal failure end organ damage
hypertension management
1) education/lifestyle changes
2) mostly drug treatment
3) surgery if 2ndary causes, underlying primary cause
filling pressure
how much blood comes back to heart
contractility
determined by adrenaline and noradrenaline on beta receptors
more blood the pump pushes out, the bigger the pressure and more muscle fibres stretched so pumps more
determines stroke volume
stroke volume
how much blood per stroke
cardiac output
determined by stroke volume + heart rate
total peripheral resistance R
affected by diameter of arterioles
blood pressure
cardiac output x total peripheral resistance
controlling blood pressure (2, short term vs long)
short term: baroreceptor/sympathetic NS
long term: ECF volume/plasma renin activity
baroreceptor reflex (if fall in blood pressure)
fall in blood pressure in detected by baroreceptors (pressure receptors) in carotid sinus which cause a decrease in nerve impulses to vasomotor centre in medulla so stimulate sympathetic and inhibit parasympathetic so increase heart rate and contractility and vasomotor tone and decrease diameter of blood vessels so increase resistance and increase venous return so more blood to venous system so increase BP
treatment for hypertension: 2 ways to reduce it
reduce CO (stroke volume x heart rate): diuretics decrease BP, ACE inhibitors, Angiotensin II R antagonists, B-blockers
reduce TPR (total peripheral resistance): vasodilators to increase diameter, Ca channel antagonists, ACE inhibitors, Angiotensin II receptor antagonists, alpha-adrenoreceptor blockers
what happens if hypertension drugs don’t work?
add another in combination instead of increasing dose
ACE inhibitors
inhibit angiotensin converting enzyme so decrease arterial resistance and decrease blood volume and BP
side effects - rapid BP fall, persistent dry cough, no symptoms of hypertension so just makes you feel worse
angiotensin II receptor antagonist (ARBs)
reduce BP by stopping affects of angiotensin II
well tolerated side effects, 1 daily dose, no dry cough, cost effective,
calcium channel antagonists
block channels so vessels dilate and decrease TPR
cause headaches, flushing, ankle swelling
thiazide diuretics
weak/mild and low dose
works on DCT to increase water and sodium LOSS so decrease blood volume and decrease cardiac output and mean arterial pressure
use in morning to avoid needed the toilet
can cause hypokalaemia - potassium supplements needed
most effective in elderly/African origin
beta adrenoreceptor blockers (beta blockers)
no longer 1st line therapy
reduce contractility and decrease renin from kidney so decrease BP
non-specific so if block all beta receptors including bronchioles can induce asthma
can cause peripheral vasoconstriction so cold hands/feet
not effective in decreasing mortality, not sure why if reduces cardiac output
study of angiotensin II receptor antagonist vs beta blocker
Lorsatan vs Atenolol (b blocker)
double blind
Lorsatan similar decrease in BP but better mortality and better tolerates
alpha receptor blockers
vasodilation, fall in arterial pressure,
only used if resistant to other treatment
can cause postural hypotension
older drugs can cause reflex tachycardia because non-specific so block alpha2 as well
malignant hypertension
accelerated and very high BP so emergency and need hospital
IV vasodilation, oral beta blockers, calcium antagonists
don’t use ACE inhibitors because rapid decrease in BP could cause cerebral infarction and blindness so need slow decrease
myocardial infarction
heart attack
lack of blood flow to the heart
angina
chest pain from lack of blood flow to the heart
where is all the nutrients in the blood?
coronary arteries
little comes from the blood in chambers
coronary circulation pathway (coronary venous drainage)
aorta to coronary arteries to smaller arterioles to veins to coronary sinus and back to right atrium
phasic blood flow
heart contracts and blood flow reduces so relates the 2 and they are in phase
how is coronary blood flow reduced?
decreased diastolic interval - more time in systole and flow reduced when contract
increased ventricular end-diastolic pressure - so pump blood against pressure gradient so reduce flow - if problems with heart congesting
fall in arterial pressure
ventricular end-diastolic pressure
pressure at end of diastole measured in ventricle after filled with blood from left atrium
how is coronary blood flow controlled
high O2 extraction occurs (70% of blood O2 removed as flows in heart) so can’t increase this to when need more O2, but increase blood flow instead
coronary artery dilation
when more oxygen required
released vasodilator substances from cardiac muscle like adenosine potent dilator from ATP and K/bradykinin/H/CO2
causes of atherosclerosis
genetic predisposition
excessive cholesterol in arteries
invade by fibrous tissue
plaques
coronary syndromes
can predict because pain during exercise from not enough O2
stable angina, unstable angina, myocardial infarction
stable angina
reduced blood flow but not block
unstable angina
partially occlusive thrombus
occasionally bind and pain
unpredictable
myocardial infarction
occlusive thrombus
ruptures so complete block
what is the most common cause of morbidity and mortality?
heart attack (myocardial infarction)
ischemia
loss blood supply so necrosis
complete occlusion
dysfunctional endothelium so atherosclerosis and plaque rupture so occlusion
plaque causes turbulent flow so not straight through centre so build up on platelets when activated - causing thrombus occlusion
infarction
blood flow ceases so only cholateral - blood flows around not in blood vessel so overfills with stagnant (still) blood and use up O2 so deoxygenated Hb,
vessel walls now highly permeable so fluid leaks and muscle cells swell and cardiac muscle cells die
myocardial cell death
from ischemia (no O2) so less ATP and less metabolism and impaired Na K ATPase, increased H so increased Ca and increased membrane potential depolarisation so arrhythmias (messed up firing)
collateral circulation
long time blockage causes vessels to bypass plaque and join around block but slow vessels but increases heart attack survival, takes years to develop
causes of heart death
decreased cardiac output so cardiac shock
pulmonary oedema (fluid in lungs)
ventricular fibrillation (random beats)
heart rupture from thin/stretched walls
cardiac shock (+systolic stretch)
insufficient force to pump blood so not enough supply round body
systolic stretch - bulging instead of pushing blood out so can rupture
death of peripheral tissues
decreased cardiac perfusion
pulmonary oedema (excess fluid in lungs)
reduced systemic blood circulation pools in atria and vessels of lungs increased capillary pressure in lungs fluid in lungs so less urine and increased total blood volume
ventricular fibrillation
rapid disorganised electrical activity
dangerous in first 10 mins and 1 hr later
from K depletion, loss ATP, depolarise cells so fire, injury current (fire when die)
decreased BP causes sympathetic NS to activate and makes it worse
diagnosis of heart problems
history - chest pain down to left arm
unrelated to excercise
ECG and biochemical markers
ischemia can cause severe pain
ECG changes in heart
normally flat between QRS and T but now ST elevated
develop abnormal Q wave which may stay for life - injury current
diagnosing full occlusive thrombus
heart attack and prolonged ischaemia
detect biomarkers in serum and ST elevation (STEMI)
diagnosing transient ischaemia
no ST elevation, sometimes still biomarkers
diagnosing partially occlusive thrombus
no ST elevation
sometimes serum biomarkers
biochemical markers of myocardial infarction
troponins regulate muscle contraction
2 isoforms T and I
T structural skeletal muscle in utero
I catalytic only ever in myocardium
treatment of heart attack
confirm diagnosis
relieve ischemic pain
stabilise haemodynamic abnormalities
save myocardial tissue
give O2 if hypoxic, restore flow by breaking thrombus
recovery from myocardial infarction
dead fibres enlarge
non-function muscle recovers
dead absorbed by macrophages
fibrous tissue develops
gradual progressive contraction of fibrous tissue over the years,
hypertrophy of normal areas to compensate
cardiac function after recovery
may be fine resting but bad when demand, decreased pumping capacity
normally 300-400% more blood per min than at rest, while now reduced to 100%
angina pectoris (stable angina)
insufficient blood to heart, pain beneath upper sternum over heart
relieved with vasodilator and GTN
treatment of stable angina
balance supply and demand but most work by decreasing demand
vasodilators reduce preload (blood coming back to heart) and decreased filling pressure so decreased demand for O2 and increase blood flow
surgery - aortic-coronary bypass surgery, coronary angioplasty to open vessel
angioplasty
open vessel with balloon but plaque again so stent keeps plaque from reforming and drugs stop cells overgrowing around stent
