Physiology of Hypertension - Cowley

Question 1

What is the formula for calculated Mean Arterial Pressure (MAP)?

Answer 1

MAP = CO _^x SVR (systemic vascular resistance)

N.B. Technically the foruma is based on R = ΔP/Q, where ΔP represents (MAP-CVP) (central venous pressure), so the full formula is:

MAP = (CO ^_x SVR) + CVP

But CVP is normally small enough to be ignored in the formula.

Question 2

Name four ways in which aterial pressure can be increased.

Answer 2

1) Contricting the body’s arterioles, which present the greatest resistance to flow in the system and thus increase total peripheral resistance.
2) Increased blood volume, which increases venous return and CO.
3) Constricting large vessels in the system, thereby increasing venous return and CO.
4) Directly increasing CO by increasing HR and contractility.

Question 3

Vascular resistance is regulated by many factors. Name one vasoconstrictor and one vasodilator of arterial smooth muscle that are under NEURAL control.

Answer 3

Constrictor:

1) Sympathetic nerves

Dilator:

1) Neurons releasing NO

Question 4

Vascular resistance is regulated by many factors. Name one vasoconstrictor and a few vasodilators of arterial smooth muscle that are under LOCAL control.

Answer 4

Constrictor:

1) Myogenic response

Dilators:

1) Po₂ Reduction
2) K⁺, CO₂, H⁺
3) Osmolarity
4) NO
5) Adenosine

Question 5

Vascular resistance is regulated by many factors. Name a few vasoconstrictors and a few vasodilators of arterial smooth muscle that are under HUMORAL control.

Answer 5

Constrictors:

1) NE
2) Angiotensin II
3) Vasopressin
4) Endothelin
5) Thromboxanes

Dilators:

1) Epi
2) ANP
3) Bradykinin
4) Histamine
5) Prostaglandins

Question 6

What type of transmembrane protein do NE, AII, and ET-1 signal through their receptor to?

What transduction pathway carries the signal?

Answer 6

Transmembrane: Gq

Pathway: Gq → PL-C → IP₃ + DAG → PKC + Ca²⁺ → enchancement of MLCK

Question 7

What type of transmembrane protein does Epi signal through its receptor to?

What transduction pathway carries the signal?

Answer 7

Transmembrane: Gs

Pathway: Gs → AC → cAMP → inhibition of MLCK

Question 8

What transduction pathway carries the signal from NO?

Answer 8

Pathway: GC → cGMP → inhibiton of contraction

Question 9

What is neural regulation of the circulation essential for?

Answer 9

Very rapid control of arterial pressure.

Question 10

Name 3 areas of the brain that are important in nervous regulation of circulation.

What parts of these areas cause excitement? Inhibition?

Answer 10

1) Reticular Substance

• Lateral & Superior: excitation
• Medial & Inferior: inhibition

2) Hypothalamus

• Posterior & Lateral: excitation
• Anterior: either

3)** Motor Cortex:**

• Either, depending on region

Question 11

1) What is this region of the brainstem called?
2) Identify A, B, and C.
3) Describe the locations and functions of A, B, and C.

Answer 11

1) The Vasomotor Cortex
2) See Image
3) A: Also called the A-1 area. In anterolateral lower medulla. Inhibits the C-1 area.

B: Increases vagal tone to decreased cardiac output as needed.

C: Also called the C-1 area. In anterolateral upper medulla. Sympathetic discharge.

Question 12

1) What is the other name for the “sensory area” in the vasomotor cortext?
2) Where is it located?
3) What is its function?

Answer 12

1) Name: Area A-2
2) Location: Found bilaterally in Nucleus Tractus Solitarii (nuclei within a tract in the medulla)
3) Function: Receive sensory signals from CNs IX and X. Controls C-1 and A-1 areas.

Question 13

What is the main function of sympathetic nerves on blood vessels?

What vessels do sympathetic fibers innervate?

What is the main function of parasympathetic nervous system on the heart?

Answer 13

Increasing vascular resistance via vasoconstriction of small arteries and arterioles.

All arteries except capillaries, precapilarry sphincters, and some meta arterioles. Also large veins (& the heart).

Control of heart rate via CNX.

Question 14

What controls vasomotor tone?

How can this be demonstrated?

Answer 14

Sympathetic fibers.

Total spinal anesthesia will produce a major decrease in arterial pressure; Injection of NE during this time causes a spike in blood pressure. NE is typically released by sympathetic fibers.

Question 15

Recall the major functions of activating the following adrenergic receptors:

α₁

α​₂

β₁

β₂

Answer 15

α₁: Vasoconstriction (smooth muscle contraction)

α​₂: Inhibition of NE release

β₁: Positive chronotropy & inotropy (Increased HR & contractility)

β₂: Bronchodilation

Question 16

Name the two locations where baroreceptors are found?

Answer 16

1) Carotid sinus (In the walls of the carotid bifurcation)
2) In the walls of the Aortic Arch

Question 17

What is the pathway that signals from the carotid sinus baroreceptors take back to the brain?

What is the pathway that signals from the aortic arch baroreceptors take back to the brain?

Answer 17

Carotid sinus: Hering’s nerve → CNIX → nucelus tractus solitarii (NTS) of the medulla

Aortic Arch: CNX → NTS of medulla

Question 18

Do arterial baroreceptors fire more or less frequently as aterial pressure increases?

Answer 18

More frequent firing with increasing pressure

Baroreceptors are excited by stretch, so firing likewise decreases as pressure decreases.

Question 19

What is the formula for Feedback Gain, “G”?

What does G reperesent?

Answer 19

G = (Correction of error) / (Error (abnormality still remaining))

Represents the strength of feedback in a negative feedback system / loop.

Question 20

What range of pressures do carotid sinus baroreceptors respond to?

At what pressure is the baroreceptor reflex more sensitive?

Do baroreceptors respond to changes in pressure or absolute pressure?

Answer 20

60-180 mmHg

100 mmHg (Impulses/sec vs. BP is sigmoidal, with inflection point around 100 mmHg)

Changes in pressure

Question 21

What two actions result from an increased number of impulses from the baroreceptors?

Answer 21

1) Inhibition of vasocontriction (decrease in sympathetic acitvity to vascular SMCs)
2) Activation of the vagal center (slows HR)

Question 22

What is the R-R interval of an EKG equivalent to?

Answer 22

The inverse of heart rate

Question 23

True or false:

Baroreceptors are used to slowly adjust BP and regulate it over long periods of time.

Answer 23

False.

Baroreceptors are required for rapid, moment-to-moment control of BP.

Question 24

What phenomenon does this graph represent?

(Hint: The y-axis is baroreceptor activity)

Answer 24

Resetting of baroreceptors.

Baroreceptors are thought to reset to new set points in response to changes in pressure that last greater than a day. This graph shows the differences in baroreceptor firing rates at various BP levels between a healthy person and a person with HTN. Note how the baroreceptors fire within similar ranges of activity despite those levels of activity being stimulated by vastly different BP levels between the two individuals. In the person with HTN, the baroreceptors have reset to accomadate the chronically high BP.

Question 25

What is the biochemical function of Renin?

Answer 25

Renin cleaves a Leu-Val peptide bond to convert Angiotensinogen to Angiotensin I.

Question 26

What is the biochemical function of ACE?

Answer 26

Angiotensin Converting Enzyme:

Splits a Phe-His peptide bond to convert Angiotensin I to Angiotensin II.

Question 27

What enzyme converts Angiotensin II to Angiotensin III?

What is the function of Angtiotensin III?

Answer 27

Enzyme: Aminopeptidase (cleaves Asp-Arg peptide bond)

**III’s Use: **From what I can find, it seems that III itself has some of the vasopressor and aldosterone activity of II. But it also seems that III binds the special AT₂ Receptor more often that II.

Question 28

What is the AT₁ Receptor, what activates it, and what does its activation cause?

What is the AT₂ Receptor, what activates it, and what does its activation cause?

Answer 28

AT₁R: Angiotensin Type 1 Receptor. Bound by Ang II (and sometimes Ang III?) Produces the actions associated with activation of RAAS: Vasoconstrictive, Fibrotic, Pro-Inflammatory, Antinatiuretic.

AT₂R: Angiotensin Type 2 Receptor. Can be bound by Ang II (Ang III binds it more often?) Produces the actions associated with inhibition of RAAS: Vasodilative, Anti-Fibrotic, Anti-Inflammatory, Natiuretic.

Question 29

What is ACE-2? What functions do its products have?

Answer 29

Angiotensin Converting Enzyme 2.

Produces the heptapeptide Angiotensin 1-7, which binds MasR and produces anti-RAAS effects (similar to AT₂R): Vasodilative, Anti-fibrotic, Anti-Inflammatory.

Question 30

What eznyme converts Prorenin into Renin?

Answer 30

Cathepsin B

Question 31

Aside from creating Ang II, ACE has another substrate. What is it, and how does its modification by ACE also aid the functions of the RAAS?

Answer 31

Bradykinin.

ACE **inactivates bradykinin. **Bradykinin normally contributes to vasodilation and Na+ excretion by stimulating NO release and prostaglandin synthesis, so its inactivation is conducive to RAAS activation.

Question 32

In what ways are ROS thought to contribute to the development of HTN via effects on the following organs?

Brain

Heart

Kidneys

Vessels

Answer 32

Brain: Increased production/release of vasoactive neurotransmitters, release of Aldosterone

Heart: Increased contractility. Cardiac remodeling, inflammation, and fibrosis.

Kidneys: Activation of RAAS

Vessels: Increase in peripheral resistance (vasoconstriction & endothelial dysfunction), vascular remodeling, inflammation, fibrosis

In summation, these changes lead to vasoconstriction, increased fluid and sodium retendion, and pathological inflammation, fibrosis, and remodeling that can all support the development of HTN.

Question 33

How prevalent is Essential Hypertension (EH) worldwide?

How many Americans are affected?

In what percentage of Americans is EH controlled?

Answer 33

26.4% of the world population

67 million

~50%

Question 34

What demographic characteristics are associated with an increased risk of HTN?

Answer 34

Age

Non-hispanic black ethnicity

Sex: About the same between F & M with a slight increase in F risk over M with age.

Question 35

What BP range is considered normal?

What BP range is considered prehypertension?

Stage 1 HTN?

Stage 2 HTN?

Answer 35

Normal: SBP <120 **AND **DBP <80

Pre: SBP 120-139 OR DBP 80-89

Stage 1: SBP 140-159 OR DBP 90-99

Stage 2: SBP >160 OR DBP >100

Question 36

What is the “opertational” definition of HTN?

What is the relationship between arterial pressure and mortality?

Answer 36

“The level [of blood pressure] at which the benefits of action exceed those of inaction.”

The relationship is quantitative: the higher the BP, the worse the prognosis.

Question 37

Who the hell were Platt and Pickering, and what role did they play in the history of HTN?

Answer 37

Platt hypothesized that Essential HTN was a genetic disease with clear Mendelian inheritence, and that people with high BP but who did not fit the genetic model did not have EH at all, but rather their elevated BP was always secondary to some other pathology (renal, tumor, etc.) Thus his hypothesis suggested a population distribution of BPs that would be clearly bimodal: one peak for the range of “normal” BPs, and one peak for the range of “genetic HTN” BPs

Pickering was pickier (haha). His data indicated that the population distribution of BPs was simply a normal curve with a positive skew. He argued with Platt’s assertion, agreeing that HTN had genetic components but that it was a complex issue with no clear method of genetic inheritance.

The back-and-forth arguments and findings between the two through the 1940s to the 1960s majorly contributed to our understanding and treatment of HTN today.

Question 38

What is the criteria for a diagnosis of HTN?

Answer 38

The running average is more important than individual readings.

Criteria: HTN is diagnosed if the average of at least 2 readings** per visit** obtained at three seperate visits, each visit 2 to 4 weeks apart, is 140mmHg or greater systolic or 90mmHg or greater diastolic.

Question 39

What is most common at young ages: elevated SBP, DBP, or both? How does this change with age?

Answer 39

In younger pts (<40), elevated DBP is most common.

At age 40-50, there is a balance with elevation of both slightly predominating.

**Older **than this, elevated SBP becomes increasingly predominant.

Question 40

Fill in the blank:

Age and degree of BP elevation in HTN are both predictive of _ _

Answer 40

Mortality

Question 41

Name 3 racial disparities in the prevalence and outcomes of HTN between non-hispanic blacks and other groups?

Answer 41

Non-Hispanic Blacks have:

1) The highest prevalence of HTN (44%),
2) an Elevated risk of ESRD (End-Stage Renal Disease) due to HTN, and
3) the highest risk of death from HTN-related complications.

Question 42

HTN is closely associated with heart disease, stroke, and renal disease.

How do the risks of ischemic heart disease and stroke increase with blood pressure?

How does the risk of ESRD increase with blood pressure?

Answer 42

**x2 Mortality **from both ischemic heart disease and stroke **for every 20mmHg increase systolic or 10mmHg increase diastolic **in BP.

HTN: 2nd leading cause of ESRD. Even “high-normal” prehypertension values are associated with a 3-fold greater risk of ESRD.

Question 43

Name 6 groups of drugs associated with increased risk of HTN.

Answer 43

1) Oral contraceptives (increased angiotensinogen)
2) NSAIDs (COX2 inhibitors)
3) Recreational or OTC drugs: Cocaine, EtOH, amphetamines, decongestants (increased sympathic activity)
4) Glucocorticoids (obesity, Na⁺ retention)
5) Cyclosporin (Na⁺ retention)
6) Erythropoietin (increased blood viscosity via RBC formation)

Question 44

What is the most common type of HTN?

What are some other causes of HTN?

Answer 44

Most common: Essential Hypertension (EH) (~90%)

Others: Chronic Renal Disease (2-4%) , Primary Aldosteronism (2-15%), Renovascular (1%), Pheochromocytoma, Coarctation of Aorta, Cushing’s Syndrome

(last three are all rare, ~0.1-0.2%)

Question 45

What differences in metabolite balance and/or urinalysis are often found in:

1) EH?
2) HTN from chronic renal disease?
3) HTN from primary aldosteronism?
4) HTN from a renovascular cause?

Answer 45

1) Normal serum K⁺, normal urinalysis
2) Increased creatinine in urinalysis
3) Decreased serum K⁺
4) Decreased serum K

Question 46

What cause of HTN is indicated by episodic hypertension in about 1/3 of patients with it?

Answer 46

Pheochromocytoma

(A catecholamine-secreting adrenal tumor)

Question 47

In HTN from coarctation of the aorta:

What BP findings are seen?

Where can a midsystolic murmor be heard?

What is seen on xray?

Answer 47

BP in arms > legs, or R arm > L arm

Murmur can be heard between scapulae

Xray: Aortic indentation. Ribnotching (notched deformities in ribs due to enlarged arterial collaterials passing by)

Question 48

Name two rare forms of primary HTN with Mendelian inheritance.

In all types of both of these diseases, what kind of protein is dysfunctional?

Answer 48

1) Bartter’s Syndrome (3 types)
2) Liddle’s Syndrome

Dysfunctional protein is always a renal ion transporter.

Question 49

Name whether each of the following reflex or hormonal responses act to increase or decrease water excretion.

1) Sympathetic activity
2) ADH
3) Renin, Ang II, Aldosterone
4) ANP
5) Prostaglandins

Answer 49

1) Sympathetic activity - decrease
2) ADH - decrease
3) Renin, Ang II, Aldosterone - decrease
4) ANP - increase
5) Prostaglandins - increase

Question 50

What is the relationship between blood pressure and natriuresis?

How can this relationship be altered?

Answer 50

Direct linear (As pressure increases, natriuresis increases linerally with it - acts as a negative feedback system to control BP.)

The slope and intercepts of said line are altered by intrinsic (Ang II, protaglandins, kinins, ROS, etc.) and extrinsic factors (Ang II, Sympathetic stimulation, aldosterone, vasopressin, ANP, endothelin, etc.)

Question 51

What effect would Ang II have on a graph of H₂O/Na⁺ excretion (y) vs. MAP (x)?

Answer 51

Decreased slope. A given MAP would stimulate less excretion when the body was under the effects of Ang II.

Question 52

Which plays a greater role in the progression of EH at young ages, CO or TPR?

At older ages?

Answer 52

Young: CO

Old: TPR

Excluding other CV pathology, rise of TPR occurs after initial hypertension has already occurred and thus is secondary to it, not its cause.

Question 53

• Dr. Hall did an experiment on dogs wherein he placed an electronic servo-controller over the abdominal aorta just proximal to the branching off the of renal arteries. The servo could be used to set a maximum blood pressure in this section of aorta and, thus, the renal arteries as well. He then infused the dogs with AngII over a multi-day period and used the servo to set the maxmimum renal artery perfusion pressure to a normal limit (120mmHg).*
  1) What happened in these dogs?
  2) What happened after the servo was turned off?
  3) What important principle does this demonstrate?
  4) Why is the answer to #3 a problem in the treatment of AngII (and likely other) HTN?

Answer 53

1) The dogs BP rose continuously to dangerous levels. Their Na⁺ levels became unbalanced. Urinary Na⁺excretion dropped to a level even below baseline.
2) With the servo off, BP and Na⁺ balance were finally able to somewhat recover and stabilize over a period of several days.
3) Increased renal perfusion pressure is required to achieve Na⁺ and H₂O balance in response to Ang II HTN.
4) Increasing renal perfusion pressure eventually damages the kidneys and lowers their maximum output. The kidneys cannot keep up!

**N.B. **In later expts, Hall demonstrated these same principles with NE-induced HTN.

Question 54

1) What does it mean to be “salt sensitive”?
2) In the US, what demographic group most often have salt sensitivity?

Answer 54

1) Sensitivity: In general, a greater increase in MAP for a given amount of salt consumed as compared to a “non-sensitive” person.
2) African Americans

Question 55

Salt-sensitive HTN occurs in two phases.

What happens in Phase 1?

What happens in Phase 2?

Answer 55

Phase 1: The kidney increases the filtered load of Na⁺ to offset increased intake. Eventually, ROS and RNS can be formed and damage the renal medulla, reducing its blood flow and thus function. With the kidneys unable to meet the Na⁺ excretion demand, NaCl retention and increased BP occur.

Phase 2: Increased renal perfusion pressure leads to further damage in the form of ROS & RNS, Cytokines, Ang II, Inflammation, Fibrosis, Glomerular Sclerosis, and Proteinuria. Kidney function declines.

Question 56

HTN-related genes appear to be located throughout the human genome, but what 5 human chromosomes seem to contain the most major QTLs (Quantitative Trait Loci) for HTN?

Answer 56

Chrs 1, 2, 3, 17, 18.

Question 57

Name six major consequences of arterial HTN.

Answer 57

1) HF
2) Myocardial Ischemia & MI
3) Aortic Aneurysm & Dissection
4) Stroke
5) Nephrosclerosis & Renal Failure
6) Retinopathy