THOMAS cardiovasc Flashcards
What is metabolic syndrome
Central obesity High BP high triglycerides low HDL cholestorol Insulin resistance
HOw to control Bp
3 Ways to increase blood pressure•↑ rate/strength of heart to ↑volume through vessels•↓ diameter of blood vessels to ↑ flow•↑ retenƟon of water/salt to ↑ blood volume
Early treatment of bp?
Low salt diet•Sympathectomy/adrenalectomy•Antimalerial(pentaquine
bp lower drugs
phenoxbenzamine SN blocker |->Dizziness tachycardia
guanethidine -> adrenergic inhibitor Hypotension sexual dysfunction diarrhoea
reserpine-> sedative |fatigue insomnia depression
hydralazine-> vasodilator |headaches tachycardia
propranololBeta blocker(s) Dizzinessinsomnia impotence
verapamilCalcium channelblockers
Diuretics
Kidney
‐filters ¼ of cardiac output/min‐Salt -rheostat and water follows salt
Antibiotic sulfanilamideleads to salt in urine
•1957 Chlorothiazide↑ salt in urine in dogs
•↓ BP in humans and ↓ risk by 1/3 of stroke/MI/HF/renal damage
Beta and calcium channel blockers
↓ load on/rate of heart ↓ angina
Adrenaline can ↑ rate/strength of heart
Therefore if you block adrenaline, can decrease load on heart
But how to do this specifically in heart?
1948 discovered alpha and beta adrenergic receptors
beta is in heart
→ propanolol
↓ angina and also ↓ BP
Research → verapamil (not beta blocker)
Verapamil block calcium entry in cells
Ca2+contracts cells
Relaxs blood vessels and ↓ BP
what did goldblatt work out
Patients with hypertension had narrowed blood vessels in kidney.
Would constriction of renal artery cause hypertension?
1934 one kidney clamp in dogs↑ BP
Model of hypertension
He suspected “renin”
if you clamp kidney bp increase by releasing renin
How does losartan work?
if you have normla blood pressure if you take losartan doesnt decrease, (at1 receptor blocker)
Relaxes blood vessel
Hypertensiec phenotype is renin agiotensin overactivity
mechanisms of hypertension
RAS is upregulated, create more angioteniss, constrict blood vessels
rat and human RAS relationship?
human angiotensinogen, isnt recognized by mouse and vice versa
Transgenic mice are humanized
LOCAL RAS
Local tissue system capable of generating AngII independent of the circulating RAS.
angiotensinogen is everywhere
Angiotensinogen in brain
Angiotensinogen •Mostly in astrocytes•Some neurons•In situ/IMC•Angiotensin generated in CNS •AT1R/AT2R behind BBB •ACE in brain •Renin where???
its in olfactory!
Angiotensinogen in brain
Angiotensinogen •Mostly in astrocytes•Some neurons•In situ/IMC•Angiotensin generated in CNS •AT1R/AT2R behind BBB •ACE in brain •Renin where???
its in olfactor
its in hypoth and medulla-> stress response!
RAs in adrenal?
RAS in volved in growth and developement
Animals which and hasnt AT2 receptor,
cortex exprss type 1
medulaa express type 2
Losartan blocks type 1 in cortex but stillshows medulla
Function – ↑ aldosterone; adrenal development and growth
RAS in kidney
Renin present outside JG cells (proximal tubule/collecting duct)AngIIgeneration in kidney higher than blood!
FunctionRenal development, glomerular blood flow, tubular sodium reabsorption, and renin secretionTransgenic/transplantation
How can we examine organ specific effects of RAS?
Local gene delivery/overexpression- delete or knockout orr add in places
Cross transplantation- kidney
Cell‐specific gene activation/deletion
RAS and Brain
Response to systemic
AngII seem to involve CNS•thirst•salt appetite
•Vasopressin release
•Sympathetic vasomotor activity
when injected mutant at1r in RVLM BP increased
when trangsenic mice which hus human angiotensigen expressing everywjere and put it in bloodstream you get raise in bloos pressure
renin is in nerve angGIN is everywhere
nerves have at2 so the whole cycle of anggin to ag2 has to happen, ACE expressed transmembrane
local RAS in kidney
ang 2 acts on kidney to increase sodium retention
cross transplantation of kidneys between at1r KO mice and wile type
loss of at1r in kiden alone can significantly reduce ang2 induced hypertension
when KO apart from kidney, sustained increase in hypertension are driven by kidney
when kidney knockout -> goes back to normal -> kidney crucial for long term BP regulation
ACE2
Homolog to ACE, not inhibited by captoprilHigh amounts in heart and kidney40% homology to ACE HPLC/ms‐carboxypeptidasefor AngIand AngII
converts into angI 1-9 and ang2 1-7
AngI/AngIIconversion to Ang1‐9/Ang1‐7 ↓BPACE2 overexpression ↓BP in hypertensionACE2 KO –CV actions/injury ‐controversial Recombinant soluble ACE2 as therapeutic
draw out model of cardiac RAS
hh
Functions prior to RAS/BP
ACE/ACE2 in bacteria; appears in tunicates –horizontal transferACE from insect to mouse ‐fertility and developmentpeptide processing in Drosophila seminal fluidMosquito –ACE activates embryogenesis after blood mealFreshfly–ACE activity in ovariesACE in germ cells in mice –KO → inferƟlity
RAAS survival advantageous
A highly active RAAS was of advantageous because salt and waterhomeostasis were important for survivalDramatic change to terrestrial life require efficient systemsTrue for H sapiens until we become domesticated and argiculturalSalt used for conservation of food → excess salt in dietRAAS in constant overdrive → hypertension → etcMismatch between evolution efficiency and availability is why ~50% of adults are hypertensive
polymorphisms in RAS genes
Pharmacogenomics –promise vs reality1000 genomes (http://www.1000genomes.org) 38M SNPs individuals have 76–190 raredeleterious non‐synonymous variants and up to 20 LOF and disease‐associated variants.Reasonable hypothesis = RAS SNPs → hypertensionRAS genesAo, renin, ACE, ACE2, renin receptor, AT1R, AT2R, MASenzymes/receptor related to aldosterone
Other actions RAS
huh
Cre/Lox RAS and the kidney
proximal tubule influence blood pressure, by local production of
What is Primary aldosteronism?
Autonomous and inappropriate secretion of aldosterone Activation of distal tubular sodium retention pathways • HYPERTENSION • SUPPRESSION OF RENIN • HYPOKALAEMIA Potassium loss Treatable by adrenalectomy in the case of aldosterone producing adenoma or mineralocorticoid receptor antagonists in bilateral disease
Primary aldosteronism is a common cause of hypertension
• Hypokalaemia is a red flag but only present in 20-40%
• Screen with an aldosterone/renin ratio but be careful of the
pitfalls
• There is a strong rationale for screening and specifically
treating PA, due to adverse effects on CVS disease and renal
effects
• Awareness among primary care doctors is low and current
rates of screening are poor
