Cv 08: Hypertension Physiology

Front 1

What is the equation for determining Arterial Pressure?

Back 1

AP = CO x TPR
Arterial Pressure = Cardiac Output x Total Peripheral Resistance

Front 2

How can you increase arterial pressure?

Back 2

- Constricting almost all arterioles of body (increases TPR)
- Increasing blood volume (increases venous return and CO)
- Constricting large vessels of circulation (increases venous return and CO)
- Directly increasing CO (via increase in HR or contractility)

Front 3

Constriction of what can cause an increase in arterial pressure?

Back 3

- Almost all of the arterioles of body (increases total peripheral resistance)
- Large vessels (increases venous return and CO)

Front 4

How can you increase CO? How does this affect arterial pressure?

Back 4

- Increase in blood volume (increases venous return and CO)
- Constriction of large vessels (increases venous return and CO)
- Direct increase in CO via increase in HR or contractility

- Leads to an increase in arterial pressure

Front 5

What factors directly affect blood pressure?

Back 5

- Cardiac Output
- Total Peripheral Resistance

(remember BP = CO x TPR)

Front 6

What factors directly affect cardiac output?

Back 6

- Venous return
- Heart rate

(remember CO = VR x HR)

Front 7

What factors directly affect peripheral resistance?

Back 7

Vascular tone

Front 8

What factors directly affect venous return?

Back 8

- Vascular volume
- Venous tone

Front 9

What factors directly affect vascular volume?

Back 9

- ADH (anti-diuretic hormone)
- Aldosterone (which is increased by AngII binding to AT1 receptors)

Front 10

How is HR controlled directly?

Back 10

- PNS (decreases)
- SNS (increases via β1 receptors)

Front 11

How is venous tone controlled directly?

Back 11

SNS: α2 receptors (constricts)

Front 12

How is vascular tone controlled directly?

Back 12

- SNS: α1 receptors (constricts)
- Angiotensin II: AT1 receptors (constricts)

Front 13

How is renin controlled directly?

Back 13

SNS: β1 receptors (secrete renin)

Front 14

How does PNS control BP?

Back 14

- Inhibits HR (↓)
- Leads to a ↓CO
- Leads to ↓BP

Front 15

How does SNS control BP?

Back 15

- α1: vasoconstricts - ↑ vascular tone → ↑TPR → ↑BP

- α2: vasoconstricts - ↑ venous tone → ↑ venous return → ↑CO → ↑BP

- β1: secretes Renin → ↑ Ang II → vasoconstriction via AT1 receptors → ↑ vascular tone → ↑TPR → ↑BP

- β1: increases HR → ↑CO → ↑BP

Front 16

What are the neural controls of arterial smooth muscle? Impacts?

Back 16

- SNS nerves → vasoconstriction

- Neurons releasing Nitric Oxide → vasodilation

Front 17

What are the local controls of arterial smooth muscle? Impacts?

Back 17

- Myogenic response → vasoconstriction

- ↓ PO2 → vasodilation
- ↑ K+, CO2, H+ osmolality → vasodilation
- Nitric Oxide → vasodilation
- Adenosine → vasodilation

Front 18

What are the humoral controls of arterial smooth muscle? Impacts?

Back 18

- NE → vasoconstriction
- AngII → vasoconstriction
- Vasopressin → vasoconstriction
- Endothelin → vasoconstriction
- Thromboxanes → vasoconstriction

- Epinephrinine → vasodilation
- ANP → vasodilation
- Bradykinin → vasodilation
- Histamine → vasodilation
- Prostaglandins → vasodilation

Front 19

What humoral controls of arterial smooth muscle cause vasoconstriction?

Back 19

- NE
- AngII
- Vasopressin
- Endothelin
- Thromboxanes

Front 20

What humoral controls of arterial smooth muscle cause vasodilation?

Back 20

- Epinephrinine
- ANP
- Bradykinin
- Histamine
- Prostaglandins

Front 21

What is the mechanism by which NE, AngII, and Endothelin affect the vascular smooth muscle? Outcome?

Back 21

- Bind receptor
- Stim. Gq (binds GTP)
- α subunit of Gq stimulates Phospholipase C (PLC) to convert PIP2 → IP3 + DAG
- DAG stimulates PKC → VASOCONSTRICTION
- IP3 causes release of Ca2+ from SR → stimulates MLCK (myosin light chain kinase) → VASOCONSTRICTION

Front 22

What is the mechanism by which Epinephrine affects the vascular smooth muscle? Outcome?

Back 22

- Binds β2 receptor
- Stim. Gs (binds GTP)
- α subunit of Gs stimulates Adenylate Cyclase (AC)
- Converts ATP → cAMP
- cAMP inhibits Myosin Light Chain Kinase → VASODILATION

Front 23

What is the mechanism by which Nitric Oxide affects the vascular smooth muscle? Outcome?

Back 23

- Diffuses into smooth muscle cell
- Stimulates Guanylate Cyclase (GC)
- Converts GTP → cGMP
- cGMP → VASODILATION directly and also inhibits Ca2+ influx to cell (which prevents activation of Myosin Light Chain Kinase)

Front 24

What is the mechanism by which activating Gi protein affects the vascular smooth muscle? Outcome?

Back 24

- Something binds receptor
- Stim. Gi (binds GTP)
- Inhibits Adenylate Cyclase (AC)
- Prevents conversion of ATP → cAMP
- Low cAMP allows Myosin Light Chain Kinase to stay active → VASOCONSTRICTION

Front 25

How do NE and Epi affect vascular smooth muscle?

Back 25

- NE → VASOCONSTRICTION
- EPI → VASODILATION

Front 26

What are the functions of nervous regulation of the circulation?

Back 26

- Ensures redistribution of blood flow to different areas
- Affects HR and pumping activity of heart
- Essential for very rapid control of arterial pressure

Front 27

What structure sends signals from the CNS to control circulation / BP?

Back 27

Vasomotor Center (bilateral in reticular substance)
- Portion of medulla and pons that regulates BP
- SNS: sends signals to sympathetic chain from "vasoconstrictor area C-1")
- PNS: sends signals via vagus nerve

Front 28

What are the components of the Vasomotor Center?

Back 28

- Vasoconstrictor area (C1)
- Vasodilator area (A1)
- Sensory area (A2)
- Cardiac Center

Front 29

What is the function of the "Vasoconstrictor Area" of the Vasomotor Center? What is the abbreviated name for this area? Location?

Back 29

- Sympathetic discharge
- C-1
- Anterolateral UPPER medulla

Front 30

What is the function of the "Vasodilator Area" of the Vasomotor Center? What is the abbreviated name for this area? Location?

Back 30

- Inhibits C-1 (vasoconstrictor area)
- A-1
- Anterolateral LOWER medulla

Front 31

What is the function of the "Sensory Area" of the Vasomotor Center? What is the abbreviated name for this area? Location?

Back 31

- Receives sensory signals from vagus and glossopharyngeal nerves from baroreceptors
- Controls C-1 (vasoconstrictor) and A-1 (vasodilator) areas
- Bilateral in nucleus tractus solitarii

Front 32

What is the function of the "Cardiac Center" of the Vasomotor Center?

Back 32

Controls heart rate and contractility

Front 33

Which blood vessels do sympathetic nerve fibers innervate?

Back 33

All vessels, except:
- Capillaries
- Pre-capillary sphincters
- Some meta-arterioles

Front 34

What is the function of sympathetic nerve innervation to the blood vessels?

Back 34

- Small arteries and arterioles: ↑ vascular resistance
- In general provides vasomotor tone

Front 35

What is the function of parasympathetic nerve innervation to the blood vessels?

Back 35

Control heart rate via vagus nerve

Front 36

What happens to vasomotor tone when spinal anesthesia is given? How can this be reversed?

Back 36

- Arterial pressure drops (lose sympathetic tone)
- Reverse with injection of NE

Front 37

How does NE affect α1 and α2 adrenergic receptors in the synapse between a sympathetic neuron and vascular smooth muscle?

Back 37

- α1: leads to vasoconstriction in vascular smooth muscle
- α2: uptake in sympathetic neuron leads to inhibition of NE release

Front 38

How does NE affect β1 and α2 adrenergic receptors in the synapse between a sympathetic neuron and myocardium?

Back 38

- β1: ↑ HR contractility
- α2: uptake in sympathetic neuron leads to inhibition of NE release

Front 39

What areas of the brain play important roles in the nervous regulation of the circulation?

Back 39

- Reticular substance
- Hypothalamus
- Motor cortex

Front 40

What is the role of the different areas of the reticular substance on circulation?

Back 40

- Superior / Lateral: excites
- Inferior / Medial: inhibits
(referring to vasomotor cortex)

Front 41

What is the role of the different areas of the hypothalamus on circulation?

Back 41

- Posterior / Lateral: excites
- Anterior: mild excitation or inhibition (depending on specific area)
(referring to vasomotor cortex)

Front 42

What is the role of the motor cortex on circulation?

Back 42

Excitation

Front 43

What is the location of baroreceptors?

Back 43

- Carotid Sinus (at carotid bifurcation)
- Walls of Aortic Arch

Front 44

Where are the signals from the baroreceptors transmitted?

Back 44

- Signals from Carotid Sinus transmitted by Hering's Nerve → Glossopharyngeal Nerves → Nucleus Tract Solitarii (NTS) of medulla
- Signals from Arch of Aorta transmitted by Vagus Nerve → NTS

Front 45

What is the feedback mechanism for Baroreceptors?

Back 45

Negative feedback control system:
- ↑ BP reflexively causes ↓ HR and ↓ BP
- ↓ BP activates the baroreflex, causing ↑ HR and ↑ BP

- Feedback gain "G" represents the strength of the feedback
- G = (correction of error signal) / (error [abnormality still remaining])

Front 46

What happens if you constrict the common carotids?

Back 46

- Decreased pressure at carotid sinuses (carotid bifurcation)
- Increases arterial pressure via baroreceptor reflex

Front 47

At lower/higher pressures does the baroreceptor reflex fire more/less frequently?

Back 47

- Low pressure → fewer impulses
- High pressure → more impulses → inhibition of vasoconstrictor & activation of vagal center

Front 48

What pressures do Carotid Sinus Baroreceptors respond to? What are they responding to? When is the reflex most sensitive?

Back 48

- 60-180 mmHg
- Responding to changes in arterial pressure
- Most sensitive at pressure of 100 mmHg

Front 49

What is the relationship between carotid distending pressure and muscle sympathetic nerve activity?

Back 49

As pressure ↑, muscle sympathetic nerve activity ↓

Front 50

What is the relationship between carotid distending pressure and ΔR-R interval (inverse of ΔHR)?

Back 50

As pressure ↑, ΔR-R interval ↑ (HR ↓)

Front 51

How does the arterial pressure compare before and several weeks after baroreceptors have been denervated?

Back 51

- Before: the arterial pressure remains fairly constant
- After: without baroreceptor reflex, the arterial pressure is highly variable

Front 52

Case: 35-yo obese woman w/ mild HTN undergoes radiologic tx for neck tumor. Begins exhibiting orthostatic lightheadedness and syncope w/ palpitations and tachycardia. Supine resting plasma [NE] is normal and remains normal standing. BP measured in supine position remains mildly elevated.

What is most likely to be wrong with patient?

Back 52

Arterial baroreceptors are dysfunctional d/t radiologic therapy for neck tumor

Front 53

What does "resetting of the baroreceptor" do?

Back 53

Prevents reflex from functioning as a control system for changes in pressure that last more than a day

Front 54

How does the carotid sinus nerve activity compare in a normal individual to a hypertensive individual?

Back 54

- Same burst amplitude/rate and same change in burst amplitude per change in diastolic blood pressure (slope)
- Difference is that the hypertensive person bursts at a higher diastolic pressure than normal (new set-point)
- Inverse relationship between diastolic blood pressure and burst amplitude (more bursting at lower BP)

Front 55

What is the Cushing Reaction?

Back 55

* Helps protect vital centers of brain from loss of nutrition if CSF pressure rises high enough to compress cerebral arteries *

- Increased pressure of CSF around brain / in cranial vault, equal or above arterial pressure, compresses brain as well as arteries in brain and cuts off blood supply
- Initiates a CNS ischemic response that causes arterial blood pressure to rise
- Once arterial BP is higher than CSF pressure blood flow resumes
- Usually comes to a new equilibrium

Front 56

What are Respiratory Waves?

Back 56

4-6 mmHg changes in pressure amplitude, due to spillover from respiratory center to vasomotor center, chest expansion, and baroreceptors

Front 57

What are Vasomotor Waves / Mayer Waves? How do they compare to respiratory waves?

Back 57

10-40 mmHg changes in pressure amplitude, triggered every 7-10 seconds (these are greater changes in amplitude than would be expected from respiratory waves: 4-6 mmHg, and also at a slower rate)

Front 58

What causes Vasomotor Waves / Mayer Waves (10-40 mmHg changes in pressure amplitude every 7-10 seconds)?

Back 58

"Reflex Oscillation" of one or more nervous pressure control mechanisms:
- Baroreceptor Reflex oscillation (↑ BP excites → inhibits SNS → ↓ BP → excites SNS → etc.)
- CNS Ischemic Response oscillation (↑ CSF P → brain ischemia → ↑ BP → blood flow resumes → no longer need excited SNS → ↓ BP → CSF P > BP → brain ischemia → etc.)

- Any reflex pressure control mechanism can oscillate if feedback is strong enough and there is a delay between excitation and subsequent response

Front 59

What is the mechanism of activating the Renin-Angiotensin System?

Back 59

- Renin splits bond in Angiotensinogen → Angiotensin I
- Angiotensin Converting Enzyme (ACE) splits bond in Ang I → **Ang II**
- Aminopeptidase splits bond in Ang II → Ang III

Front 60

What is the action of Angiotensin II?

Back 60

- Vasoconstriction
- Releases aldosterone (zona glomerulosa in adrenal) → Na+ retention → H2O retention
- Increases thirst
- Decreases baroreceptor reflex
- Increases Na+ reabsorption from kidneys

* ↑ BP *

Front 61

What is the action of Angiotensin Converting Enzyme (ACE)?

Back 61

- Splits bond in Ang I → Ang II (↑BP via vasoconstriction and ↑aldosterone)
- Splits bond in Bradykinin to inactivate it (less available to stimulate NO release and PG synthesis → less vasodilation and Na+ excretion)

* Ultimate effect is activate AngII and inactive Bradykinin → VASOCONSTRICTION → ↑ BP

Front 62

What are the actions of Angiotensin Converting Enzyme Inhibitors (ACE-I)?

Back 62

- Prevents conversion of AngI → AngII (no vasoconstriction or aldosterone release)
- Prevents inactivation of Bradykinin → stimulates NO release and PG synthesis → Vasodilation and Na+ excretion
- Some side effects d/t ↑Bradykinin (eg, coughing)

* Ultimate effect is VASODILATION → ↓ BP

Front 63

How does Nitric Oxide (NO) and Reactive Oxygen Species (ROS) affect vasculature?

Back 63

- Endothelial dysfunction (ONOO-)
- Medial wall hypertrophy (H2O2)

Front 64

How is Nitric Oxide synthesized?

Back 64

- From L-arginine, oxygen, and NADPH by various coupled nitric oxide synthase (NOS) enzymes, requires high BH4
- In endothelium, it is called eNOS

Front 65

What happens to Nitric Oxide in the vasculature when combined with reactive oxygen species?

Back 65

- Combines w/ O2- (superoxide)
- Forms ONOO-
- Leads to endothelial dysfunction

Front 66

What forms the O2- (superoxide) that Nitric Oxide (NO) can combine w/ to damage the endothelium?

Back 66

O2- (superoxide) is produced in large quantities by the enzyme NADPH oxidase from free O2

Front 67

What can happen to superoxide (O2-) in the vasculature?

Back 67

- Combine w/ NO to form ONOO- → Endothelial Dysfunction
- Converted by Superoxide Dismutase (SOD) to H2O2 → Medial Wall Hypertrophy

Front 68

How do Reactive Oxygen Species (ROS) play a part in the development of HTN?

Back 68

- Brain: ↑ production and release of vasoactive NTs
- Kidney: activation of Renin-Ang system → ↑ release of Aldosterone
- Vessels: ↑ PVR, vascular remodeling, inflammation, fibrosis
- Heart: ↑ contractility, cardiac remodeling, inflammation, fibrosis

Outcome → Vasoconstriction, ↑Na+ reabsorption, ↑BP inflammation, fibrosis

Front 69

What is the prevalence of HTN amongst different groups in the US? Overall?

Back 69

- 60 and over: 67%
- Men (29%) slightly more than females (28%)
- Black (40%) > White (27%) > Hispanic (26%)

- Overall: 28.6%

Front 70

What is the operational definition of hypertension determined based on?

Back 70

BP level at which benefits of action exceed those of inaction

Front 71

For adults (18+), what is normal BP defined as?

Back 71

- Systolic <120 mmHg
- Diastolic <80 mmHg

Front 72

For adults (18+), what is pre-hypertension defined as?

Back 72

- Systolic 120-139 mmHg
- Diastolic 80-89 mmHg

Front 73

For adults (18+), what is hypertension stage 1 defined as?

Back 73

- Systolic 140-159 mmHg
- Diastolic 90-99 mmHg

Front 74

For adults (18+), what is hypertension stage 2 defined as?

Back 74

- Systolic >160 mmHg
- Diastolic >100 mmHg

Front 75

What change in BP increases your risk of mortality by 2x?

Back 75

For every 20 mmHg systolic or 10 mmHg diastolic increase in BP, there is a 2x higher risk of mortality from both ischemic heart disease and stroke

Front 76

What BP increases your risk of end-stage renal disease (ESRD)? By how much?

Back 76

High normal (130-139 / 85-89) is associated w/ 3x greater risk of future development of ESRD

Front 77

How does BP change with age?

Back 77

Systolic BP rises progressively with age (arteries less flexible) and elderly w/ HTN are at greater irks for CV disease

Front 78

How does race affect the risk for HTN and mortality?

Back 78

Blacks tend to have higher levels of BP (compared to non-Blacks) and higher overall HTN-related mortality rates

Front 79

How does stroke mortality vary with BP and age?

Back 79

- Increased stroke mortality w/ increased systolic and diastolic BP
- Increased stroke mortality w/ increased age at same level of BP

Front 80

What is the relationship between Diastolic BP and Cardiovascular Mortality?

Back 80

Diastolic above 95 greatly increases mortality risk (although increases for anything >70-74

Front 81

How does race affect likelihood to develop end-stage renal disease in patients w/ HTN?

Back 81

Blacks are 4.2x more likely to develop ESRD

Front 82

What are the identifiable causes of HTN?

Back 82

- Chronic kidney dz
- Coarctation of aorta
- Cushing syndrome (other glucocorticoid excess states)
- Drug induced / related (NSAIDs, cocaine, amphetamines, decongestants, oral contraceptives, cyclosporine, etc)
- Obstructive uropathy
- Pheochromocytoma
- Primary aldosteronism (other mineralocorticoid excess states)
- Renovascular HTN (stenosis, reduced mass)
- Sleep apnea
- Thyroid or parathyroid dz

Front 83

What are some primary genetic forms that predispose to HTN?

Back 83

Rare Mendelian forms:
- Bartter's Syndrome
- Liddle's Syndrome

Essential HTN: genes + environment; complex polygenic dz

Front 84

What are some secondary causes that predispose to HTN?

Back 84

- Renal artery stenosis
- Reduced renal mass
- Renin secreting renal tumor
- Cushing's syndrome
- Pheochromocytomia

Front 85

What are some comorbidities associated w/ HTN?

Back 85

- Atherosclerosis
- Coronary Artery Dz
- MI
- Stroke
- CHF
- Peripheral Vascular Dz
- Chronic Kidney Dz
- Obesity
- Diabetes
- Metabolic Syndrome
- Obstructive Sleep Apnea
- Cognitive Impairment

Front 86

How do you diagnose HTN?

Back 86

Average of 2 readings / visit obtained at 3 separate visits each 2-4 weeks apart is:
- >140 mmHg systolic and
- >90 mmHg diastolic

Front 87

What do monogenic (Mendelian) mutations that cause HTN affect?

Back 87

Kidney: all mutations affect renal Na+ reabsorption
- 8 cause HyperTN
- 9 cause HypoTN

Front 88

Why is the kidney an important determinant of BP?

Back 88

Controls amount of Na+ and H2O excreted (needs to balance that which is coming in)

Front 89

How is mass balance of Na+/H2O achieved by kidney?

Back 89

- Sympathetic activity ↓
- ADH ↓
- Renin-Angiotensin II ↓
- Aldosterone ↓
- ANP ↑
- Prostaglandins ↑

- All lead to ↑ Na+ / H2O excretion

Front 90

What intrinsic factors contribute to controlling relationship between pressure and Na+ excretion?

Back 90

- Physical factors
- Ang II
- Prostaglandins
- Kinins
- ROS (O2-, H2O2, NO)
- 20-Hete

Front 91

What extrinsic factors contribute to controlling relationship between pressure and Na+ excretion?

Back 91

- Ang II
- CNS sympathetic
- Aldosterone
- Vasopressin
- ANP
- Endothelin

Front 92

What is necessary to achieve Na+ and H2O balance when AngII levels are increased?

Back 92

Need for increased renal perfusion rise to maintain excretion rate

Front 93

What happens if AngII is infused in a dog with renal perfusion pressure controlled at normal level (with inflatable occluder around aorta above renal arteries)? Why?

Back 93

- Severe HTN and retention of Na+ and H2O → pulmonary edema
- The renal perfusion pressure needed to be able to increase in order to maintain Na+ and H2O balance

Front 94

What happens if AngII is infused in a dog with renal perfusion pressure controlled for one kidney at normal level (with inflatable occluder around aorta above renal arteries) and one left even with the higher pressure? Why?

Back 94

- Kidney that is protected by inflatable occluder cuff was protected from high pressure
- Kidney that had higher pressure was uncontrolled and was not protected → renal injury (juxtamedullary glomeruli)

Front 95

What are the impacts of uncontrolled HTN on kidneys?

Back 95

Leads to end-stage renal disease

Front 96

What is a new treatment for protecting kidneys from HTN (when other, more traditional treatments don't work)?

Back 96

Renal Nerve Ablation (T10-L2)
- Renal nerves lie within adventitia of renal arteries
- Electrodes powered by battery, emit radio-frequency, destroy renal nerves

Front 97

What are the implications of bilateral renal denervation in patients with uncontrolled BP > 140/90 mmHg, despite treatment w/ 3+ HTN drugs?

Back 97

Successful decrease in BP (24 months later)

Front 98

How does a reduced renal mass affect BP?

Back 98

- With reduced renal mass the mean arterial pressure needs to be higher to maintain the same level of Na+/H2O excretion rate as normal
- ↑ Cardiac Output, ↑TPR (after HTN develops, not a cause of ↑BP)

Front 99

What symptoms do the Dahl S (SS) rats have?

Back 99

Mirror human forms of salt-senstive HTN (eg African Americans):
- Salt-sensitive (↑↑BP), insulin resistant, hyperlipidemic
- Low renin form of HTN
- Proteinuria and glomerosclerosis
- Medullary interstitial fibrosis
- Early-stage renal failure

Front 100

What are the impacts of prolonged high NaCl intake?

Back 100

- ↑ Arterial pressure
- Kidney: Glomerular injury; renal failure
- Heart: Cardiac hypertrophy; diastolic and systolic dysfunction
- Blood vessels: Oxidative stress; endothelial dysfunction; fibrosis; ↓vascular elasticity