HTN II: Cowley Flashcards
Blacks are 4.2 times more likely to develop:
ESRD (end stage renal disease)
HTN is closely associated with
heart disease, stroke and renal disease
For every 20 mmHg systolic or 10 mmHg diastolic increase in BP, there is____ mortality from both ischemic heart disease and stroke
2X
Hypertension is the____ leading cause of ESRD. “High normal” BP (130-139 / 85-89 mmHg) is associated with ~ _____greater risk of future development of ESRD
2nd
3-fold
Gender and risk: Age-specific associations of ischemic heart disease (IHD) with BP is slightly greater for_____; for vascular mortality as a whole, sex is_____
women
of little relevance
______ rises progressively with age and elderly people with hypertension are at greater risk for CV disease
Systolic BP
Once diastolic pressures rises to _____ your increase your risk for mortality significantly
95-99
Essential hypertension is:
polygenic and mutlifactorial
Exogenous causes of HTN:
big ol’ list
Oral contraceptives (hepatic synthesis of angiotensinogen resulting in increased to AngII and Aldosterone with Na retention).
• Nonsteroidal anti-inflammatory drugs (COX2 inhibitors).
• Cocaine, ethanol, amphetamines, decongestants (increase sympathetic activity).
• Glucocorticoids (central obesity; Na retention).
• Cyslosporin (anti-rejection drug; Na retention).
• Erythropoietin (hormone that stimulates RBC formation; blood viscosity increased).
90% of HTN is ESSENTIAL and the clinical clues are:
age of onset: 20-50
family hx
nromal serum K+, unialysis
unknown cause
Rare mendelian forms Essential HTN (genes +envir or complex polygenic disease are \_\_\_\_\_ genetic forms
PRIMARY
Renovasulcar, renal parenchymal disease, pheochromocytoma, Cushings and coarctation of aorta are ______ forms of HTN
secondary
Hypertnesion has lots of co-morbitities:
Atherosclerosis • Coronary artery disease • Myocardial infarction • Stroke • Congestive heart failure • Peripheral vascular disease • Chronic kidney disease • Obesity • Diabetes • Metabolic syndrome • Obstructive sleep apnea • Cognitive impairment
Why is the kidney an important determinant of BP
Cardiovascular system is open to the environment
**Na/H20 in must = Na/H2O out to achieve mass balance
How is mass balance of Na/H2O achieved?
increase of Na/H2O–> increase blood volume–> will decrease: SNS/ADH/Renin AngII/aldosterone and increase ANP and prostaglandin’s to increase excretion of Na/H20
What is the pressure-natiruesis and role in regulation of BP
we have a negative feedback loop
as MAP increase (from 90 to 120) start to see large increase in Na/H20 excretion
What are the three determinants of pressure-natriuesis relationship?
- Vascular resistance (in the afferent areteriole)
- GFR
- Tubular reabsorption
Relationship between pressure and sodium excretion
determined by a balance of
“intrinsic factors” and “extrinsic factors”
Physical factors
- Angiotensin II
- Prostaglandins
- Kinins
- ROS (O2H2O2,NO)
- 20-Hete
All intrinsic factors in BP/ and Na excretion balance
- Angiotensin II
- CNS Sympathetic
- Aldosterone
- Vasopressin
- Atrial Natriuretic Peptide
- Endothelin
all Extrinsic factors in BP/Na excretion balance
Antiotensinogen is secreted by the ____
Angiotensinogen–> Ang I via renin secreated from ____
liver
kidney
Ang II binds to AT1 and has what affects on these systems Adrenal gland Arterial smooth muscle SNS Kidney Brain heart
adrenal gland: increase aldosterone secreation
arterial smooth: vasocnx
SNS: release of Nepi
Kidney: increase renal tubular Na+ resorption
Brain: stims thirst and vasopressin secreation
Heart: enhances cnx adn ventricular hypertrophy
As MAP increases, Ang II levles will____
resulting in _____of Na/H20 excreation
increase
increase
need for renal perfusion pressure to_____ to achieve
sodium and water balance when angiotensin II
levels are increased
What affect does this have on the pressure-natriuresis slope?
rise
reduces the slope of the pressure-natriuresis relationship
Ang II was infused into dog, but renal perfusion was controlled at normal level; as a result the dog had severe HTN and retention of Na/H2O with pulmonary edema. Once the controller was stopped, the kidneys saw this huge increase in pressure, urine output increased significantly… This demonstrates that:
a rise of renal perfusion pressure was required
to achieve Na+ and H2O balance.
When the Ang II infusion was done on dog with left kidney clamped, was there regulation of hypertension?
Yes, MAP was still maintained despite only one kidney reading the increase in Na and Ang II
What happens to the juxtamedullary glomeruli in NE and Ang II uncontrolled situations?
see large increase of damage to the glomeruli
An individual gets HTN; their Extracellular fluid volume rises, blood volume rises, arterial pressure rises at day zero, what happens to Total peripheral resistance?
(model based on reduced renal mass)
day 0 we get a decrease of TPR… then we get slow rise up to 33% increase of TPR by day 14 from HTN
*in this situation; rise of TPR occurs after the hypertension hasdeveloped and, therefore is secondary to the
hypertension and not the cause of the hypertension
Individuals with essential HTN: As they increase in age, _____ contributes less to blood pressure and ______ contributes more
CO
TPR
Salt sensitivity is associated with ______ In both normotensive and hypertenisve humans aged 25 at beginning of study (30 year study)
mortality
people both H + S had worse outcomes
In rat models that were designed to mimic salt sensitive HTN, what are some significant findings?
low renin form of HTN (seen in African Americans)
proteinuria and glomerosclerosis (filtration decreases)
medullary interstitial fibrosis
early stage renal fail
When they did the genetic linkage map of CV function from these salt sensitive and salt resistance rats did they see chromosomal relationships?
a little association of HTN links in 1,2,3, 7, 11 and 18
not sure if this is important
Dahls salt rats showed 2 phases of HTN development.
Phase I
increased Na/l intake in thick ascending limb, we get more generation of free radicals and decreased medullary blood flow
See Na/Cl retention that will act to increase BP with increase SNS and AVP activity
this phase is slow and still reversible
Dahls salt rats showed 2 phases of HTN development.
Phase II
we start to see a destructive positive feedback loop. renal perfusion pressure is high dt increased BP… this causes T cell infiltration and release of cytokines/ang II/inflammation/ fibrosis/proteinuria/glom sclerosis–> further contributes to low medullary blood flow
this phase is hard to reverse and causes destruction
Consequences of prolonged high Na/Cl diet Heart: BV: Kidneys: arterial P:
Heart:cardia hypertrophy/Diastolic + systolic dsyfnx
Blood vessels: oxidative stress/ endothelial dysnfnx/ fibrosis/ decreased vascular elastiticy
Kidneys: glomerular injury and renal fail
Increased arterial pressure
Exploitation of rare extreme outliers in families with
monogenic (Mendelian) mutations – all are
kidney related.
All mutations affect renal Na+reabsorption; 8 cause hypertension, 9 cause hypotension.
Which chromosomes are the ‘HTN’ ones according to the human genome study?
1, 2, 3
17 and 18
Results of the gene-centric meta analysis in Europe
Analyses confirmed 27 previously reported associations and an 11 additional previously described associations.
• Ten of the genes are predicted to be a target for small molecules and therapeutic intervention or drug response stratification.
***genes are involved.. may be therapeutic targets
Now that genes associated with HTN have been identified, what is our next step(s)?
Identification of sequence variants does not yield
mechanistic insights or targets for drug development.
• Gene variants discovered in human GWAS studies must
now be understood in the context of molecular networks
and pathways that define this complex disease.
• Mechanisms and pathways whereby GWAS nominated
genes must be illuminated in carefully controlled
experimental animal studies.
