= Manta Ray Panta Rhei: Everything Flows

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 LV function Blood Volume SNS RAS

SNS

TPR

Angioten.II α1R Endothelin Vasopressin

NO β2R Prostaglandins Bradykinin

Stroke volme

Cardiac Output

SV

Arterioles and TPR

Regulation of peripheral arterioles

Opie, the Heart, p 430

Poiseuille’s Law (edited)

P ~

Q × L × Vis 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 ma

HB LV P H

Fibros is

Unilateral renal artery stenosis

Angiotensin II Aldosterone

Ye s

Ye s

Ye s

Aldosterone infusion in uninephric rat

Angiotensin II Aldosterone

Ye s

Ye s

Ye s

Angiotensin II Aldosterone

Ye s

Infrarenal aortic banding

Fibro sis Ye s

HBP = high blood pressure; LVH = left ventricular hypertrophy

Brilla et al, Circ Res 1990.

Fibro sis

No

No fibrosis

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 NO →↑cGMP

L-Arginine (guanidine Nitrogen)

Citrulline L-NMMA L-NAME

Nitric Oxide cGMP kinase

NO → ↑ cGMP

SMC

↑Ik+

↑Ca ATPase

PLC

SMC relaxation

↓P+ of MLC

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

Sodium intake And output

Renal function curve

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 rol

ESRD

Diabetes HTN

Neurohormo nal System

Stroke MI

Sudden Death

LVH

HF

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 LV Function Blood Volume SNS RAS

SNS

* TPR RAS ET

SNS Vasopressin

NO ANP PG

BK

Adrenomedullin

Renin Release (mechanisms) Experimental evidence Vascular Receptor Model Conscious dog with: - renal tubules & macula densa-destroyed - renal denervation & adrenalectomy Hypotensive hemorrhage  ↑PRA

Or 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) ↑PRA

AT ogen (liver) ↓PRA ←

↑ATII ↑ 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 synthase

Hypertension

Large conductance K+ channel

Hypertension

Atrial natriuretic peptide

Hypertension, salt-sensitive

Brain natriuretic peptide

Normotensive, cardiac fibrosis

β -Adducin

Hypertension

Glomerular epithelial protein phosphatase

Hypertension, abnormal glomerulus, decreased renal ultrafiltration

The pressure-natriuresis response

intrinsic kidney property (isolated kidney) Perturbations in the P-N response may predispose to chronic hypertension