CV Lecture 7

CV system regulation

Cardiovascular regulation

A. Local (intrinsic) regulation

B. Systemic (extrinsic) regulation

Heart activity

Vascular tone

CV Integration

LV

Cardiovascular ‘unit’

= R 8 π

. ηl r 4

= R ΔP F

A. Local/intrinsic regulation

Heart activity regulation

1. Ca2+ role

- Ca2+ homeostasis

- Ca2+ regulation factors

2. Frank-Starling low of the heart

3. Other +/- inotropic factors

Microcirculation regulation

1. Myogenic autoregulation

2. Metabolic factors, chemical messengers, endothelial factors

Atmospheric O2, angiogenesis...

B. Systemic regulation

Short-term regulation

- Nervous reflex regulation

Long-term regulation

Integrated regulation

- Humoral regulation

Short-term regulation

Long-term regulation

A. Local Regulation

Heart activity regulation 1. Ca2+ role

- Ca2+ homeostasis

- membrane transport systems for Ca2+

Calsequestrin

Sarcoplasmic reticulum

Ca2+ pump

Ca2+ channels Na+/Ca2+

exchanger

Na+/K+ pump Ca2+

pump

Phospholamban

(unphosphorilated)

(-)

Heart activity regulation

1. Ca2+ role Ca2+ regulation factors - sympathetic stimulation via β1 receptors cAMP PKA

phospholamban phosphorylation its inhibition on SERCA is

relieved upon phosphorylation ↓ [Ca2+]i lusitropic effect

& more Ca stored in SR +inotropic effect

L-type Ca Channels

- “garden-hose” effect: regulation by changes in coronary perfusion pressure

↑ [Ca2+]i

- ↑ heart rate – positive (Bowditch) staircase:

cumulative increase in [Ca2+]i ↑ contractility

- cardiac glycosides (digitalis):

inhibit Na/K pump, Na/Ca exchanger ↑ [Ca2+]i

- pH: intracell H+ competes with Ca2+ for binding on troponine complex

A. Local Regulation

T-tubule

Sarcoplasmic

reticulum

Sarcoplasmic

reticulum

Heart activity regulation

2. Frank-Starling low of the heart: within physiological limits, the heart pumps all the blood that returns to it

- Preload: the wall tension that corresponds to ED pressure venous return - skeletal mm pump & respiratory pump

- sympathetic constriction of veins

EDV - length of sarcomere at beginning of contraction - Afterload – blood pressure - total peripheral resistance

- Inotropic state of the heart

A. Local Regulation

2,2 µm 1,8 µm 2,8 µm

Frank-Starling law of the heart

The more blood there is in the ventricle at the beginning of contraction

(EDV), the greater the stroke volume will be. Stroke volume is

proportional to force.

A A’ A” B B’ B”

D” D’

E”

E’ E

D

Left Ventricular Volume

Left

Ven

tric

ula

r P

ressu

re

Frank-Starling law of the heart

normal

↑ EDV

↓ EDV

End-systolic pressure-volume relation

3. Inotropic factors:

- Extracellular Ca2+

- Adrenergic agonists activate through β1-receptors

G proteins AMPc PKA protein phosphorylation - Cardiac glycosides (digitalis) – Na/K-pump

- Increase in heart rate

- Ca channels blockers

- Extracellular Na+

Intracellular Ca2+

Negative

- Intracellular H+

- Extracellular Ca2+

- Extracellular Na+ Positive

Hormones effects on cardiac contractility

Circulating catecholamines from adrenal medulla, but rarely rise

sufficiently high to affect cardiac function appreciably.

Thyroid hormones enhance myocardial contractility (increase the rates

of calcium uptake and of ATP hydrolysis by the SR; increase protein

synthesis cardiac hypertrophy; increase myosin isoenzymes with

the greatest ATPase activity enhance myocardial contractility

substantially. In hyperthyroidism: tachycardia, high cardiac output,

palpitations, and arrhythmias.

Insulin enhances myocardial contractility, partially explained by the

concomitant increase of glucose transport into the myocardial cells.

Glucagon has potent positive inotropic and chronotropic effects on the

heart, mediated by activation of the adenylyl cyclase-cAMP system.

Blood gases affect the heart directly and indirectly

• Indirect effects - changes in PaO2 and PaCO2 of the blood perfusing the

brain and the peripheral chemoreceptors affect the heart through nervous

mechanisms.

Moderate degrees of hypoxia characteristically increase heart rate, cardiac

output, and myocardial contractility by increasing sympathetic nervous

activity (changes largely abolished by blocking β-adrenergic receptor)

Also, systemic increases in PaCO2 activate the sympatho-adrenal system.

• Direct effects - PaO2 of the blood perfusing the myocardium also

influences myocardial performance directly. The effect of hypoxia is

biphasic: moderate degrees are stimulatory and more severe degrees

are depressant.

Direct depressant effect of the increased PaCO2 on the heart: act

through reduced intracellular pH diminishes the influx of Ca2+ into the

cell via Ca channels, Na/Ca antiporter, decreases Ca2+ released from SR,

and affects myofilament sensitivity to Ca2+ directly.

Effect of ischemia on left ventricular pressure and intracellular pH in an isolated

perfused rabbit heart.

LV

Cardiovascular ‘unit’

= R 8 π

. ηl r 4

= R ΔP F

A. Local/intrinsic regulation

Heart activity regulation

1. Ca2+ role

- Ca2+ homeostasis

- Ca2+ regulation factors

2. Frank-Starling low of the heart

3. Other +/- inotropic factors

Microcirculation regulation

1. Myogenic autoregulation

2. Metabolic factors, chemical messengers, endothelial factors

Atmospheric O2, angiogenesis...

B. Systemic regulation

Short-term regulation

- Nervous reflex regulation

Long-term regulation

Integrated regulation

- Humoral regulation

Short-term regulation

Long-term regulation

Φ = 1; F= 1ml/min

Φ = 2; F= 16ml/min

Φ = 4; F= 256ml/min

P=

100 m

mH

g

Microcirculation regulation

A. Local Regulation

l F

h

p

8

P r 4

D = Flow dependence on radius

100

75

50

25

0

Pre

ssu

re (

mm

Hg

)

art

eri

es

art

eri

ols

cap

ilari

es

vein

s

Effect of arteriolar vascular tone on arterial pressure

arteriolar dilation

normal

arteriolar constriction

A. Local regulation of microcirculation

Myogenic factors

Metabolic factors

Microcirculation regulation

A. Local Regulation - Short-term regulation

Chemical messengers, paracrines, endothelial

vasoactive factors

Myogenic factors

- stretch-activated nonselective cation channels…

Microcirculation regulation

A. Local Regulation - Short-term regulation

- myogenic autoregulation: vasoconstriction due to ↑ stretch

of wall when pressure ↑

- endothelins (ET): vasoconstrictor paracrines released

from endothelial cells as a response to stretch

Basal tone / tonic activity of vascular smooth mm,

independent on nervous system, related with intrinsic activity

-CO2, O2, H+/lactic ac, K+, ADP, adenosine (A rec–KATP channels

hyperpolarization), PGI2, NO…

-ATP (P2x rec = ligand-gated Ca channel), TxA2

Metabolic factors

Microcirculation regulation

A. Local Regulation - Short-term regulation

Chemical messengers, paracrines, endothelial

vasoactive factors

-Ach/bradykinine (NO), VIP, NE/E, histamine, serotonin

-ET (IP3&DAG, Ca2+)

-NO released by endothelial cells in response to shear stress

during rapid flow

Function of cellular metabolism

0 1 2 3 4 5 6 7

Metabolic rate (x normal)

B

loo

d F

low

x n

orm

al

0 1

2 3 4

A. Local Regulation - Short-term regulation

Metabolic rate ↑

Production of CO2 ↑

CO2 tissue conc. ↑

Arteriolar smooth mm.

↑ Vasodilation

↓ Resistance

↑ Blood flow

↓ CO2 tissue conc.

Negative feed-back

Metabolic regulation: CO2 concentration effect

A. Local Regulation - Short-term regulation

Blood flow

Vasodilators: Vasoconstrictors:

Nitric Oxide (NO) - EDRF

- ↑[Ca2+]i

Ach, bradykinine

shear stress

- Free radical & Lipophilic gas with short half-life (5-10 sec)

- NO origin: endothelial, muscular, neuronal…

- Potent vasodilator, inhibit platelet adhesion & aggregation

- NO NO rec = soluble GC cGMP vasodil.

activation of Ca pump in the SR ↓ [Ca2+]i vasodil.

(+) eNOS L-arginine NO + L-citruline

Metabolic regulation of blood flow:

Hyperemia

1. Active Hyperemia 2. Reactive Hyperemia

.

A. Long-term regulation of microcirculation

Oxygen role

- altitudine: decreased atm. O2 , erythropoietin

- decreased conc. O2 in the incubator for

premature babies influence on angiogenesis

Angiogenesis stimulating growth factors – endothelial

derived growth factor (VEGF), fibroblastic GF…

Intrinsic versus extrinsic control of

vascular tone

Intrinsic Control

-Auto-regulation (capacity

to resist changes in flow

with pressure changes)

-Endothelium-mediated

regulation (act as a barrier

for vasoactive substances)

-Metabolic regulation

(generation of substances

with vasodilating activity

that are involved in

hyperemic responses)

Extrinsic control

- Sympathetic (Norepi.) –

Most important, fast reg.

-Parasympathetic (Causes

vasodilation) - Less important

-Humoral circulating factors

(catecholamines and non-

catecholamines) – long-term

regulation

B. Systemic Regulation

- Short-term regulation

Nervous reflex regulation

- Intermediate/Long-term regulation

- Integrated regulation

Humoral regulation

Renal-body fluid control system

B. Systemic Regulation

Nervous Regulation through ANS

= Cardiovascular reflexes – with fast response

- Regulation factors: arterial pressure, volume

changes, H+, O2, CO2 conc.

-Types of receptors:

1. arterial & cardiopulmonary mechanoreceptors:

baroreceptors & volum-receptors

2. chemoreceptors

- Correlations with humoral regulation: ADH,

ANP, suprarenal hormones

Cardiovascular Reflexes:

baro- & chemoreceptors reflexes

(-)

Vagal n.

Cardiovascular Nervous Regulation

Vasomotor center: 1. Vasoconstrictor area

2. Vasodilator area: inhibits 1.

3. Sensory area: bilaterally in the

tractus solitarus (NTS), receives

sensory nerves signals from the

circulatory system throught n. X

& IX; controls 1. & 2. reflex

control

4. Cardioinhibitor center dorsal

motor nc. vagal nerve

Autonomic Nervous Regulation

S and PS branches of the ANS influence HR and AV node conduction through antagonistic control

PS: 70/min -- SAN: intrinsic rate of 90-100/min -- S: >100/min (Ach, muscarinic rec) (NE, b1 rec)

S tone - increase HR, AV conduction and contractility (b1rec) - determine vc by a1rec (NE) and vd by b2 rec (E in heart, liver, skeletal mm – fight or flight response)

PS tone - decrease HR and AV conduction

- M rec (Ach) AC(-), Ach-regulated K channels…

- Ach NO vd

ANS fast responses: within 3 -5 sec. HR can increase 2x within 10-15 sec. AP can be doubled

Effects of sympathetic neural regulation on vascular tone

NE binds to α receptors constriction.

E binds to both β and α receptors, but more to β receptors dilation.

150

125

100

75

50

25

0

A

rte

ria

l p

ressu

re (

mm

Hg

)

0 5 10 15 20 min. Effect of total spinal anesthesia on the arterial pressure,

showing a marked decrease in pressure resulting from

loss of vasomotor tone (NE=norepinephrine)

NE inj.

Total spinal anesthesia

Effect of NE on contractility of the heart

Changes in heart rate evoked by stimulation (horizontal bars) of the

vagus (A) and sympathetic (B) nerves in an anesthetized dog.

CV Nervous Regulation

Cardio-inhibitory

activity

NTS

n. IX

Vagus n

Dorsal nc of the Vag n + Nc. Ambiguus

-

CV stim. activity Vagus n – PS preggl. fb.

Adrenal medulla

S postggl. fb.

venules

arterioles

Spinal cord Arterial

baroreceptors

• Baroreceptors /stretch/pressorec.

– are pressure sensitive neurons in the aortic arch and carotid sinus.

– fast (sec.) response to decreased arterial pressure (AP) by concomitantly: - decreasing cardioinhibitory activity - increasing both cardio-acceleratory activity and the vasoconstrictor center

(all in the medulla oblongata)

arterio&venoconstriction

stimulation of the heart: increased HR and contraction

Baroreceptor Reflex

Baroreceptor Reflex

Imp

uls

es/ sec.

fro

m c

aro

tid

sin

us n

n.

0 80 160 240 mmHg

AP effect on carotid baroreceptors response

Baroreceptors response in arterial pressure changes

Max rate at

180 mmHg

Obs: aortic barorec operate

at press 30 mmHg higher

http://cvphysiology.com/Blood%20Pressure/BP012.htm

The “resetting” of the baroreceptors may

attenuate their potency as a control system for

correcting disturbances that tend to change

arterial pressure for longer than a few days at a

time.

Baroreceptors tend to reset in 1-2 days to the

pressure level to which they are exposed.

Ex: if the arterial pressure rises from 100 mmHg

to 160 mmHg, a very high rate of baroreceptor

impulses are at first transmitted. During the next

few minutes, the rate of firing diminishes

considerably; then it diminishes much more

slowly during the next 1-2 days, at the end of

which time the rate of firing will have returned to

nearly normal despite the fact that the mean

arterial pressure still remains at 160 mm Hg.

Conversely, when the arterial pressure falls to a

very low level, the baroreceptors at first transmit

no impulses, but gradually, over 1-2 days, the

rate of baroreceptor firing returns toward the

control level.

150

125

100

75

50

25

0 A

rte

ria

l P

res

su

re (m

m H

g)

2 4 6 8 10 12 min.

Sino-carotidian reflex effect on AP

Carotid arteries

occlusion

Carotid a.

reperfusion

Both vagal nerves blocked

The Baroreceptors Attenuate Blood Pressure

Changes During Changes in Body Posture.

The ability of the baroreceptors to maintain relatively

constant arterial pressure in the upper body is

important when a person stands up after having been

lying down.

Immediately on standing, the arterial pressure in the

head and upper part of the body tends to fall, and

marked reduction of this pressure could cause loss of

consciousness. However, the falling pressure at the

baroreceptors elicits an immediate reflex, resulting in

strong sympathetic discharge throughout the body that

minimizes the decrease in pressure in the head and

upper body.

The Valsalva manoeuvre & the baroreceptor reflex

The patient breathes out forcefully against a closed larynx

- "straining" an increased intrathoracic pressure

decreased venous return, cardiac output and a fall in

blood pressure reduced baroreceptor discharge to the

vasomotor centre peripheral vasoconstriction, and an

increase in heart rate (normal response).

Atrial sensory receptors regulate cardiac and renal function

Bainbridge Reflex

Bainbridge (1915): infusions of blood or saline solution increased the

heart rate, regardless of whether the infusions did or did not raise

the arterial blood pressure; the effect was abolished by cutting both

vagi.

Sensory receptors in both atria, located principally in the venoatrial

junctions, influence heart rate. Their distention sends impulses centrally

in the vagi. The efferent impulses are carried by S and PS fibers to the

SA node.

Stimulation of the atrial receptors also increases urine flow (reduced

secretion of vasopressin/antidiuretic hormone, reduction in renal

sympathetic nerve activity, and the release of atrial natriuretic peptide,

from the atrial tissues in response to atrial contraction and stretch).

Increased venous return stimulates atrial mechanoreceptors which:

– Directly stimulates the SA node to increase its firing rate

– Stimulates the cardioacceleratory center in the medulla oblongata

which causes an increase in sympathetic output to the heart.

Intravenous infusions of blood or electrolyte solutions tend to increase

heart rate via the Bainbridge reflex and to decrease heart rate via the

baroreceptor reflex.

The actual change in heart rate induced by such infusions is the result

of these two opposing reflex actions.

Bainbridge reflex

Ventricular sensory receptors affect cardiac function

in a reflex way

Sensory receptors located in the ventricular endocardium initiate

reflex effects similar to those elicited by the arterial baroreceptors

diminishes heart rate and peripheral vascular resistance.

The receptor discharge pattern parallels the changes in ventricular

pressure. Impulses originating in these receptors are transmitted to

the medulla oblongata via the vagus nerves.

Other sensory receptors in the epicardial regions of the ventricles,

are stimulated by various mechanical and chemical stimuli, but their

physiological functions are not clear.

Chemoreceptor reflexes

- Stim. of chemoreceptors by decreased O2, pH and increased CO2

- The chemosensitive cells are located in the 2 mm sized chemoreceptor

organs (two carotid bodies, one of which lies in the bifurcation of each

common carotid artery, and usually one to three aortic bodies adjacent to

the aorta).

- The chemoreceptors excite nerve fibers that, along with the baroreceptor

fibers, pass through Hering’s nerves and the vagus nerves into the

vasomotor center of the brain stem.

- Each carotid or aortic body is supplied with an abundant blood flow

through a small nutrient artery, so the chemoreceptors are always in

close contact with arterial blood and sense arterial pressure falls below a

critical level, when they become stimulated .

- The signals transmitted from the chemoreceptors excite the vasomotor

center, and this response elevates the arterial pressure back toward

normal.

- Chemoreceptor reflex is not a powerful arterial pressure controller until

the arterial pressure falls below 80 mm Hg becomes important at the

lower pressures to prevent further decreases in arterial pressure.

CNS ischemic response: control of arterial pressure by

the brain’s vasomotor center in response to diminished

brain blood flow

When blood flow to the vasomotor center in the lower brain stem becomes

decreased severely enough to cause nutritional deficiency/cerebral ischemia,

the vasoconstrictor and cardioaccelerator neurons in the vasomotor center

respond directly to the ischemia and become strongly excited.

When this excitation occurs, the systemic arterial pressure often rises to a

level as high as the heart can possibly pump.

This effect is believed to be caused by failure of the slowly flowing blood to

carry CO2 away from the brain stem vasomotor center stimulate

sympathetic vasomotor nervous control areas.

The ischemic effect on vasomotor activity can elevate MAP dramatically (up

to 250 mm Hg) for as long as 10 minutes. The degree of sympathetic

vasoconstriction caused by intense cerebral ischemia is often so great that

some of the peripheral vessels become totally or almost totally occluded.

The kidneys often entirely cease their production of urine because of renal

arteriolar constriction in response to the sympathetic discharge.

CNS ischemic response is an emergency pressure control system, a

powerful activator of the sympathetic vasoconstrictor system !

Cushing Reaction to Increased Pressure Around the Brain - a

special type of CNS ischemic response that results from increased

pressure of the cerebrospinal fluid around the brain in the cranial vault.

-cerebrospinal fluid pressure rises to equal the arterial pressure, it

compresses the whole brain, as well as the arteries in the brain, and

cuts off the blood supply to the brain initiates a CNS ischemic

response arterial pressure rise to a level higher than the

cerebrospinal fluid pressure blood flows once again into the vessels

of the brain to relieve the brain ischemia -> the blood pressure comes

to a new equilibrium level slightly higher than the cerebrospinal fluid

pressure, thus allowing blood to begin to flow through the brain again.

The Cushing reaction helps protect vital centers of the brain from loss

of nutrition if the cerebrospinal fluid pressure ever rises high enough to

compress the cerebral arteries.

Long-term Humoral Regulation 1) Vasoactive substances released in the blood/proximity of vascular

smooth mm effect on AP & local blood flow

Biogenic amines:

-E (MSR, a1R–vc, b2R-vd, b1R-↑HR & contractility)

-serotonin (local vc)

-histamine (local vd)

Peptides:

-Angiotensin II (vc) - AT1A rec

-Endothelins (the most powerful vc)

-ANP (vd)

-Kinins (vd): bradykinins

- Vasopressine/ADH (vc. at high level)

Prostaglandins:

-vd: PGI2, PGE2; vc: TxA2

Nitric oxide (vd)

2) Non-vasoactive substances effective circulating volume: kidney,

by regulating total-body Na content effect on MAP, CO

Renin-ANG II-aldosterone axis, AVP, ANP

B. Systemic Regulation

Renin-ANG II-aldosterone axis

Factors that affect cardiac output

Integrated regulation

Filling time

Filling pressure

Vasc compliance

preload

contractility

afterload

EDV ESV Intrinsic

Regul Extrinsic

Regul

CO Total Peripheral

Resistance

Systemic

Reg

Local

Reg

Stroke

Volume HR

MAP

Humoral

factors

ANS

Venous return

- Regulation ?