HTN II: Cowley

Question 1

Blacks are 4.2 times more likely to develop:

Answer 1

ESRD (end stage renal disease)

Question 2

HTN is closely associated with

Answer 2

heart disease, stroke and renal disease

Question 3

For every 20 mmHg systolic or 10 mmHg diastolic increase in BP, there is____ mortality from both ischemic heart disease and stroke

Answer 3

2X

Question 4

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

Answer 4

2nd

3-fold

Question 5

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_____

Answer 5

women

of little relevance

Question 6

______ rises progressively with age and elderly people with hypertension are at greater risk for CV disease

Answer 6

Systolic BP

Question 7

Once diastolic pressures rises to _____ your increase your risk for mortality significantly

Answer 7

95-99

Question 8

Essential hypertension is:

Answer 8

polygenic and mutlifactorial

Question 9

Exogenous causes of HTN:

big ol’ list

Answer 9

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).

Question 10

90% of HTN is ESSENTIAL and the clinical clues are:

Answer 10

age of onset: 20-50
family hx
nromal serum K+, unialysis
unknown cause

Question 11

Rare mendelian forms
Essential HTN (genes +envir or complex polygenic disease are \_\_\_\_\_ genetic forms

Answer 11

PRIMARY

Question 12

Renovasulcar, renal parenchymal disease, pheochromocytoma, Cushings and coarctation of aorta are ______ forms of HTN

Answer 12

secondary

Question 13

Hypertnesion has lots of co-morbitities:

Answer 13

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

Question 14

Why is the kidney an important determinant of BP

Answer 14

Cardiovascular system is open to the environment

**Na/H20 in must = Na/H2O out to achieve mass balance

Question 15

How is mass balance of Na/H2O achieved?

Answer 15

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

Question 16

What is the pressure-natiruesis and role in regulation of BP

Answer 16

we have a negative feedback loop

as MAP increase (from 90 to 120) start to see large increase in Na/H20 excretion

Question 17

What are the three determinants of pressure-natriuesis relationship?

Answer 17

1. Vascular resistance (in the afferent areteriole)
2. GFR
3. Tubular reabsorption

Question 18

Relationship between pressure and sodium excretion

determined by a balance of

Answer 18

“intrinsic factors” and “extrinsic factors”

Question 19

Physical factors

• Angiotensin II
• Prostaglandins
• Kinins
• ROS (O2H2O2,NO)
• 20-Hete

Answer 19

All intrinsic factors in BP/ and Na excretion balance

Question 20

• Angiotensin II
• CNS Sympathetic
• Aldosterone
• Vasopressin
• Atrial Natriuretic Peptide
• Endothelin

Answer 20

all Extrinsic factors in BP/Na excretion balance

Question 21

Antiotensinogen is secreted by the ____

Angiotensinogen–> Ang I via renin secreated from ____

Answer 21

liver

kidney

Question 22

Ang II binds to AT1 and has what affects on these systems
Adrenal gland
Arterial smooth muscle
SNS
Kidney
Brain
heart

Answer 22

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

Question 23

As MAP increases, Ang II levles will____

resulting in _____of Na/H20 excreation

Answer 23

increase

increase

Question 24

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?

Answer 24

rise

reduces the slope of the pressure-natriuresis relationship

Question 25

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:

Answer 25

a rise of renal perfusion pressure was required | to achieve Na+ and H2O balance.

Question 26

When the Ang II infusion was done on dog with left kidney clamped, was there regulation of hypertension?

Answer 26

Yes, MAP was still maintained despite only one kidney reading the increase in Na and Ang II

Question 27

What happens to the juxtamedullary glomeruli in NE and Ang II uncontrolled situations?

Answer 27

see large increase of damage to the glomeruli

Question 28

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)

Answer 28

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

Question 29

Individuals with essential HTN: As they increase in age, _____ contributes less to blood pressure and ______ contributes more

Answer 29

CO | TPR

Question 30

Salt sensitivity is associated with ______ In both normotensive and hypertenisve humans aged 25 at beginning of study (30 year study)

Answer 30

mortality | people both H + S had worse outcomes

Question 31

In rat models that were designed to mimic salt sensitive HTN, what are some significant findings?

Answer 31

low renin form of HTN (seen in African Americans) proteinuria and glomerosclerosis (filtration decreases) medullary interstitial fibrosis early stage renal fail

Question 32

When they did the genetic linkage map of CV function from these salt sensitive and salt resistance rats did they see chromosomal relationships?

Answer 32

a little association of HTN links in 1,2,3, 7, 11 and 18 | not sure if this is important

Question 33

Dahls salt rats showed 2 phases of HTN development. | Phase I

Answer 33

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

Question 34

Dahls salt rats showed 2 phases of HTN development. | Phase II

Answer 34

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

Question 35

``` Consequences of prolonged high Na/Cl diet Heart: BV: Kidneys: arterial P: ```

Answer 35

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

Question 36

Exploitation of rare extreme outliers in families with | monogenic (Mendelian) mutations – all are

Answer 36

kidney related. | All mutations affect renal Na+reabsorption; 8 cause hypertension, 9 cause hypotension.

Question 37

Which chromosomes are the 'HTN' ones according to the human genome study?

Answer 37

1, 2, 3 | 17 and 18

Question 38

Results of the gene-centric meta analysis in Europe

Answer 38

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

Question 39

Now that genes associated with HTN have been identified, what is our next step(s)?

Answer 39

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.