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Panta RheiManta Ray =

Everything Flows

Heraklitus of Ephesus
c. 535-475 BC
Blood Pressure
- provides the driving force to move
blood through the vascular system
- regulated by integrated action of
several systems:
- cardiovascular
- renal
- neural
- endocrine
Hypertension-Prevalence
• Up to 30% of us population
• 80 million>140/90
• Leading cause for Internist office visit
• No 1 cause of prescription medication in
US
• Direct cost ( US-1995) – 24 billion $
Hypertension-Pathophysiology
• Genetic Predisposition
• Sodium Intake
• Renal Function
• Renin Angiotensin System
• Sympatetic Nervous System
• Vascular changes
• Insulin Resistance
Measurement of Systolic & Diastolic BP
Mean Blood Pressure

Mean BP = Pdiast + 1/3 pulse pressure

Pulse pressure = P syst. – P diast.


Mean Blood Pressure

CO
TPR
Art. Volume
compliance
Blood Pressure in Mammals
- All have aortic root mean BP ~ 100 mm Hg
- regardless of heart weight, rate, etc which are
scaled to body mass

- The only exception

- Giraffe →~ 180-300 mm Hg
~ 100 mm Hg (scull base)
baroreceptors
Arterial (High Pressure)
Baroreceptors

- AFF. to Vasomotor cnt. (Med. Oblun.)


- Eff. by Vagus
- important in acute situations (e.g.,
hemorrhage,acute HT)
- insignificant role in long-term BP
determination
Venous (Low Pressure) receptors

• Atria, Pul. Artery, Vent. Endocardium


• Respond to Volume changes in Rt side
• Example
Vol. Inc. (Transf., Pre-Exerc.)
Decr. Symp.+ Renin
Blood Pressure

Mean BP = CO X TPR
MAP = CO X TPR

SV x HR TPR

LV function SNS Angioten.II NO


Blood Volume α1R β2R
SNS Endothelin Prostaglandins
RAS Vasopressin Bradykinin
Stroke volme

SV

Cardiac Output
Arterioles and TPR
Regulation of peripheral arterioles

Opie, the Heart, p 430


Poiseuille’s Law (edited)

Q × L × Vis
P ~
r4
Arterioles and TPR
Pressure drop
Renin-Angiotensin System
)(RAS

- Salt and water homeostasis

- Maintenance of vascular tone


ACE

Angiotensin I
Sites of action of AII

Opie, the Heart, p 428


Role of angiotensin II in maintaining blood
pressure during hypotension
Site of action of AII Effect
Vascular smooth muscle Constriction; increase of PVR
Renal efferent arteriole Constriction; maintenance of GFR

Proximal renal tubule Na+ reabsorption ↑


Adrenal cortex Aldosterone secretion ↑
Central adrenergic activation Increased release of NE
Ganglionic facilitation Increased release of NE
Presynaptic receptors Increased release of NE;
decreased re-uptake
Baroreflexes Withdrawal of vagal tone
GFR, glomerular filtration rate; NE, norepinephrine
Opie, The Heart pp 427
Macula Densa
Mechanisms of Renin release

Opie, the Heart, p 426


Atherosclerotic R.A. Stenosis
Aldosterone Stimulates Myocardial
Fibrosis in Animal Model
Plas HB LV Fibros
ma P H is
Unilateral
Angiotensin
renal Ye Ye Ye
artery II
s s s
stenosis Aldosterone
Fibro
sis
Aldosterone
infusion in Angiotensin
Ye Ye Ye
uninephric II
s s s
rat Aldosterone Fibro
sis
Infrarenal
aortic Angiotensin
Ye Ye No
banding II
s s
Aldosterone
No
HBP = high blood pressure; LVH = left ventricular fibrosis
hypertrophy
Brilla et al, Circ Res 1990.
Nitric Oxide (NO)
Furchgott
- Fortuitous discovery of EDRF
(Endothelial-Derived-Relaxing-Factor)
- EDRF = NO
- In circulation →mostly bound to
proteins
- 4 different NO synthases (NOS)
Nitric Oxide
NOS
L-Arginine NO →↑cGMP
(guanidine
Nitrogen)
Citrulline

L-NMMA
L-NAME
Nitric Oxide

NO → ↑ cGMP cGMP kinase

SMC ↑Ik+ ↑Ca ATPase PLC ↓P+ of MLC

SMC relaxation
NO in the kidney
Macula Densa NOS, activated by
↑ Na+ diet

Antihypertensive effects
- ↓PRA
- ↑ RBF (↑ Na+ excretion)
Kidney in B.P. Control

The normal kidney functions to

maintain normal blood pressure


The pressure-natriuresis response

intrinsic kidney property (isolated kidney)


Perturbations in the P-N response may predispose
to chronic hypertension
)Renal function curve (P-N Response

Guyton AC, Hypertension 1987;10;1-6


Renal Function Curves - Shift

Primary Alsosteronsm
RenoVascular Hypertension

Kimura G, Hypertension 1987; 10: 11-15,


Pressure-Natriuresis / Renal
Function Curve
Hypothesis
- Renal characteristics &
- Systemic effects

- Renal function curve

- long term effect on B.P.
BP / Volume homeostasis
BP Regulation- Summary
• Integrated action of many systems:
Cardiac
Vascular
CNS
Renal
Hormonal
Mechanisms of Hypertension
Volume (extra->intravascular)

Cardiac output
?
TPR
Whole Body Autoregulation
Phenomenon
- intrinsic mechanisms that adjust
local tissue blood flow to a set point
volume

Local O2 / nutrients

Arteriolar tension

TPR
Renal function
curve

Sodium intake
And output

100 200
Mean Arterial Pressure

-Vasoconstriction
↑ renal nerve activity
↑ ATII
↓ NO
- Genetics
AC Guyton, Hypertension 1987;10;1-6
AC Guyton, Hypertension 1987;10;1-6
Renal function curve
salt and water

- regulation of tubular Na+ reabsorption


- in channels /pumps
- aldosterone
- Genetics
- No of nephrons
Blood Pressure Determinators
Center of Cardiovascular Risk?

Choleste Diabetes
rol
ESRD HTN

Neurohormo
nal
Stroke
System LVH

MI HF
Sudden
Death

ESRD = end-stage renal disease, HF = heart failure, HTN = hypertension


LVH = left ventricular hypertrophy, MI = myocardial infarction
Compliance
∆V
C =
∆P
MAP = CO * TPR

SV * HR * TPR

LV Function SNS RAS NO


Blood Volume ET ANP
PG
SNS SNS
Vasopressin
BK
RAS Adrenomedullin
Renin Release (mechanisms)
Experimental evidence
Vascular Receptor Model
Conscious dog with:
- renal tubules & macula densa-destroyed
- renal denervation & adrenalectomy

Hypotensive hemorrhage
Or  ↑PRA
High aortic constriction
Renin Release (mechanisms)
Experimental evidence
Macular Densa
Conscious dog with:
-denervated kidney
-Inactive vascular receptor (papaverine)

hypotensive hemorrhage  ↑PRA


Pulse Pressure and Mean BP
Renin Release
Mechanisms
1. Intrarenal
- macula densa (sensitive to Na+, Cl- )
- renal vascular receptor

2. Sympathetic
- renal nerves
- circulating catecholamines

3. Humoral agents
- ADH - PG
- ATII - Electrolytes
Renin Release
- ↓ (Na+) (sensed by macula densa)
- ↓ perfusion pressure (afferent arteriole)

AT ogen ↑PRA
(liver)
↑ATII
↓PRA ← ↑ BP ← vasoconstriction
Fibromuscular R.A. Stenosis
The Sympathetic System

Opie, the Heart, p 19


The Parasympathetic System

Opie, the Heart, p 20


Role of Autonomic Nervous System

Opie, the Heart, p 18


Genetic engineering of blood pressure
Gene knockout Phenotype
Angiotensinogen Hypotension, abnormal kidney
Angiotensin-converting enzyme Hypotension, abnormal kidney
Angiotensin type I receptor Hypotension
Angiotensin type II receptor Normotensive
Endothelin-1 Normotensive, craniofacial
abnormalities
Endothelial cell-type nitric oxide Hypertension
synthase
Large conductance K+ channel Hypertension
Atrial natriuretic peptide Hypertension, salt-sensitive
Brain natriuretic peptide Normotensive, cardiac fibrosis
β -Adducin Hypertension
Glomerular epithelial protein Hypertension, abnormal glomerulus,
phosphatase decreased renal ultrafiltration
The pressure-natriuresis response

intrinsic kidney property (isolated kidney)


Perturbations in the P-N response may predispose
to chronic hypertension