Hypertension:

Mechanism & Treatment

Yan Chun Li
cyan@medicine.bsd.uchicago.edu
Office: KCBD 9-9110
 Outline

Overview (Review) of blood pressure

regulation
Major neural and hormonal factors
Case study
Mechanism of Hypertension
Animal models
Inheritable/genetic diseases
Essential hypertension
Treatment of Hypertension
Anti-hypertensive drugs and mechanisms
 Hypertension Facts

Cardiovascular disease remains the #1 killer in U.S,

accounting for 26% (>50,000) of all death each year.

One in four American adults has hypertension.

Health care cost, medications and lost productivity:

$316 billion/year.

Of ~50 million Americans with hypertension, about 1/3

are not aware of their condition. Hypertension is often
referred to as a silent killer.
 Blood Pressure Facts

Human heart beats 100,000 times each day, sending 2,000

gallons of blood through blood vessels.

Normal blood pressure: 120/80 mmHg (systolic/diastolic,

measured in millimeters of mercury).

Hypertension (high blood pressure): >140/90 mmHg.

Adverse effects of hypertension: stroke, myocardial

infarction, congestive heart failure, progressive
atherosclerosis and renal failure.
 Regulation of Blood Pressure

The body has three major ways to raise blood pressure:

1. Increase the frequency of heart contraction or

cardiac output (volume of blood being pumped out),
so that a greater volume of blood is propelled through
the blood vessels;

2. Constrict the blood vessels or increase the peripheral

resistance so that the blood flow is restricted and faster;

3. Retain more salts and water in the blood to increase

the intravascular/extracellular volume.
 Regulation of Blood Pressure Homeostasis

Cardiac Total Systemic

Mean BP = Output X Vascular Resistance

Increased Decreased
Increased Cardiac Output Vasodilation
Vasoconstriction
Intravascular Volume Adrenergic Stimuli Prostacyclin
Glomerular filtration Angiotensin II Nitric oxide
Sodium excretion Endothelin EDHF*
Extracellular Fluid Vassopressin
Renal Nerve Activity Endothelium-derived
Myocardial Performance Contracting Factors
Adrenergic Activity Thromboxane

*Endothelium-derived
Hyperpolarizing Factors

Textor SC. Atlas of Diseases of the Kidney, 2001.

 Principles in Blood Pressure Regulation

Hormones (including neurotransmitters)

regulate cardiac performance,
vascular tones, and salt and water
balance (volume homeostasis)

Perturbations in salt/water balance initiate

hormonal responses - restore homeostasis

Malfunctions in hormonal actions can lead

to hypertension
Baroreceptor reflex Sympathetic System
response

Carotid and aortic Sympathetic stimulation

Baroreceptors: to heart and blood vessels
In response to (release E/NE)
blood pressure

Heart:
Rate and
Contractility
( adrenergic R)

Blood vessels ( R):

Arterioles constrict
peripheral resistance
Veins constrict
central veneous pressure
Adrenal medulla: chromaffin cells
Release of Epinephrine/NE
Nephron Structure Distal convoluted tubule

Collecting duct
 Arginine Vasopressin (AVP)/Anti-diuretic
Hormone (ADH)

Synthesized as preprohormone in pituitary;

active hormone is 9-amino acid peptide, stored in
granules in cytoplasm
Secretion stimulated by Angiotensin II
Secretion increased in response to
Osmolality
Extracellular volume
Blood pressure
Promotes water retention in the kidney (V2 receptor)
Increases vasoconstriction through V1 receptor
(antagonizes vasodilatory effect of NO, ANP)
Arginine vasopressin (AVP)/Anti-diuretic hormone (ADH)
Maintains plasma osmolality
Regulates extracellular volume and blood pressure
Plasma [ADH]

280-290 mOsm Plasma [ADH]

Plasma osmolality (mOsm/kg H2O) % Change in blood volume or pressure

ADH increases water permeability in the collecting duct

Urine Blood

Water
Aquaporin 2
Vasopressin increases vasoconstriction by activating
V1 receptor on vascular smooth muscle cells
VP/ADH actions
Adrenal gland Aldosterone

(aldosterone)

Synthesized in adrenal cortex

from cholesterol precursor
(mineralocoticoid, steroid)

Secretion highly stimulated by

Angiotensin II

Regulates Na+/K+ homeostasis.

Increase sodium retention in the
kidney; excrete potassium
Chromaffin cells
-Norepinephrine/Epinephrine
 Nuclear receptor action

NUCLEUS
Hormone

GENE TRANSCRIPTION
R
R R
DNA
HRE RNA Polymerase
Action of Aldosterone: Increase sodium retention

ATP
Na-K-ATPase
Potassium
channel

ADP

Nucleus

ENaC

K+ Na+

Kidney--Distal tubules/Cortical collecting duct

Aldosterone-SGK-1-Nedd4-2-ENaC cascade

Nedd4-2 is an
Ubiquitin ligase
P

degradation
 Ca2+
Reabs.
H+ Aldo
HCO3-
Glomerulus K+ Na+ PO43-
4-6 L/day
Na+ 300 mOsm
H2O K+
Cl-

urea

Na+ ADH
H2 O
H2O

1.5 L/day
1200 mOsm
The Renin-Angiotensin System
 The Renin-Angiotensin Cascade
Angiotensinogen (400 aa)
Renin (Rate-limiting step)

Angiotensin I (10 aa)

ACE (angiotensin-converting enzyme)
Angiotensin II (8 aa)

Angiotensin II Receptors (G protein-coupled membrane

receptor)

Thirst ADH Aldosterone

Vasocontriction
H2O Intake H2O Retention Na Retention

Extracellular Volume Blood Pressure

 Effects of Angiotensin II
Stimulation of aldosterone release from
adrenal gland
Na+ retention from the kidney
Vasoconstriction. Most potent vasoconstrictor
Acts on vascular smooth muscle cells
Peripheral vasculature resistance
Stimulation of thirst (brain) and ADH/VP
secretion
water reabsorption to complement Na+ retention
 1

2
Juxtaglomerular
apparatus (JGA)
3
JG cells

Renin secretion regulated by

Renal perfusion pressure
Tubular sodium chloride load
Sympathetic nerve activity
 Liver Regulatory Loop
Angiotensinogen Angiotensin I Angiotensin II

Renin ECF Vol

BP Brain
Na+ JGA-
SNS JG cells ADH
(+)
(+) ACTH
ECF Volume Plasma [K+]
Stimuli Plasma [Na+] Adrenal
Responses Gland
Turn off ECF Volume Plasma [K+]
Renin & Plasma [Na+]
Excrete K+
Restore
Balance Retain H2O Aldosterone
Retain
Na+,H20
Kidney
 Atrial Natriuretic Peptide:ANP
Cardiac atria contain
abundant electron-dense
granules:
ANP storage sites

Right Atria

Regulation of ANP release

Atrial stretch - Baroreceptor response due to
Blood volume or
Central venous pressure
Atrial Natriuretic Peptide: ANP
Different names: ANF, ANP, Atriopeptin
Produced in atrial cardiac myocytes
Synthesized as preprohormone
Active hormone: 28 amino acids
Anti-aldosterone
Anti-hypertensive
Acts via NPR-A and NPR-B
NPR activation by ANP stimulates intracellular
GTP conversion to cGMP
cGMP activates cGMP-dependent kinase to
regulate cellular functions
 Atrial Natriuretic Peptide
Kidney
Glomerular filtration
Diuresis (water excretion)
Na+ excretion (Na+ in blood)
Renin release
Adrenal Cortex
Aldosterone secretionZ. glomerulosa
Vascular smooth muscle
Potent vasodilation
Opposes AngII vasoconstrictive effect
Regulation of BP

ANS

ANP