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Cardiovascular Physiology V.

46. The regulation of local blood flow.

47. Factors determining cardiac output, the Guyton diagram.

Ferenc Domoki, November 20 2017.

Control of circulation

Systemic control Local control

Major goal: to maintain

constant pressure gradient

(∆P) chiefly by regulating

mean arterial blood pressure

(MABP)

Major goal: to maintain

adequate blood flow to meet

locally the metabolic and

functional needs of the tissue.

Hemostasis, and immune

functions also affect local

blood flow.

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Common local blood flow regulation responses

1. Autoregulation (constant blood flow despite changing pressure gradient)

2. Active hyperemia (increased blood flow to meet metabolic/functional demands)

3. Reactive hyperemia (increased blood flow following an interruption of flow – ischemia)

4. Decreased local blood flow when vessels are injured – hemostasis

5. Increased local blood flow in inflamed tissues –inflammatory hyperemia

LOCAL CONTROL OF BLOOD FLOW

1. Autoregulation

60 180 mmHg

Flo

w

Kidney

14020 mmHg

Flo

w

Skeletalmuscle

Flow is relatively constant

in a pressure range.

(Note that flow stops at

pressures above 0 mmHg:

Critical closing pressure).

2. Active hyperemia

Increased tissue

metabolism is associated

with enhanced blood

flow: the tissue is capable

of adjusting its own

perfusion.

3. Reactive hyperemia

Hypoxia causes vasodilation.

Flo

w

Time

Occlusion

Hyperemia

Occlusion is followed by

increased flow.

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Control of local blood flow

• Local blood flow will depend on the

regional vascular resistance largely

determined and exclusively regulated by

the diameter of precapillary resistance

vessels.

• All local regulation will thus converge on

the contraction/relaxation of the vascular

smooth muscle in these vessels.

LOCALLY important components of arteriolar smooth muscle tone

RESTING TONE = BASAL TONE

Myogenic tone

Local vascular (endothelial) factors

Local tissue humoral factors

Systemic hormones

Sympathetic vasoconstrictor tone

+ NEUROGENIC TONE

+ PHASIC (not tonic) VASODILATORY INNERVATION CAN

INCREASE BLOOD FLOW LOCALLY

Intrinsic vascular factors!

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Myogenic tone of arteriolar smooth muscle

• Arteriolar smooth muscles maintain spontaneous contraction – myogenic tone

• Bayliss effect: some arteriolar smooth muscles are sensitive to mechanical stretching: they respond with contraction to stretch:blood pressure↑- wall stretch↑ - vasoconstriction – arteriolar resistance ↑

• This simple response tends to stabilize flow when MABP changes

• Bayliss effect is the direct opposite of stress-relaxation observed in venous smooth muscle.

Robert W.Furchgott

Louis J.

Ignarro

Ferid

Murad

THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE, 1998

„for their discoveries concerning

nitric oxide as a signalling

molecule in the cardiovascular

system”

Endothelial factors regulating arteriolar smooth muscle tone

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Endothelial factors regulating arteriolar smooth muscle tone

Dilators

• Nitric oxide

• Prostacyclin

• EDHF (endothelium-derived hyperpolarizing factor)

Constrictor:

• endothelin

Depending on the species, developmental stage, and organ, the presence and the contribution of these factors to the local regulation of arteriolar tone varies greatly

Acetylcholine Acetylcholine

Vascular smooth

muscle (endothelial

cells are removed)

Contraction

Endothelial

lining is intact

Relaxation

The discovery of NO as „ENDOTHELIUM-DERIVED

RELAXING FACTOR (EDRF)

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GqαPLC

IP3

Ca2+Calmodulin

Arg Citrulline + NONOS

GTP cGMP

Guanylyl-cyclase

PKG

Ca2+ decrease

RELAXATION

Inactivation

Phospho-diesterase

NOReceptor Viagra

Endothelial cell Smooth muscle

BIOSYNTHESIS AND ACTION OF NITRIC OXIDE

NITRIC OXIDE SYNTHASE ISOFORMS

NOS:

NOS-1 (nNOS): neural

NOS-2 (iNOS): phagocytes (cytokine-induced NOS, NO is

bactericide here)

NOS-3 (eNOS): endothelial cells

eNOS is stimulated by a number of mediators:

acetylcholine

histamine (H1)

bradykinin

VIP (vasoactive intestinal peptide)

SP (substance P)

NA (NO decreases NA-induced vasoconstriction)

shear stress

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Prostacyclin

PGI2

Prostaglandins

PGD2 PGE2 PGF2α

Thromboxane A2

TXA2

vasodilation vasoconstriction

EICOSANOIDS

MembranePhospholipids

Arachidonic acid

PLA2

PGH2

Cyclooxygenase

COX-1, COX-2

Cortisol

Aspirin

Lipoxins

Leukotrienes

CytochromeP450 products

Inflammation,

Allergic reaction

EDHF?

?

EICOSANOIDS IN CIRCULATION

Eicosanoids are general inter- and intracellular signal molecules

that can be produced virtually by every cell.

Circulation:

1. Endothelial PGI2: continuous vasodilator tone in arteries.

It inhibits aggregation of platelets. (Receptor → cAMP)

2. PGE2: putative mediator of metabolically induced

vasodilation. (Receptor → cAMP)

3. TXA2: vasoconstrictor released from platelets.

(Receptor → IP3/Ca)

ASPIRIN can prevent coagulation/thrombosis:

COX COX

TXA2 PGI2 PGI2

cc. 4 hoursASPIRIN

COX COX

TXA2 PGI2 PGI2

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EDHF: not yet identified

• There is an EDRF present in many vessels even when NO or prostacyclin is fully inhibited

• Its chemical identity is unknown, eicosanoids, reactive oxygen species, myoendothelial gap junctions are suspects

• It activates potassium channels on vascular smooth muscle, causing hyperpolarization and relaxation

ENDOTHELIN

• Paracrine vasoconstrictor peptide produced by endothelial cells.

• ET1, ET2, ET3. Circulation: ET1.

• Az ET1 is the currently known, most potent vasoconstrictor.

• Receptor: ET-A (IP3/Ca).

• Stimulus: angiotensin, catecholamine, hypoxia, thrombin, shear stress

Thus, the local regulators of blood flow can directly induce dilation or constriction of the arterioles by acting on the

vascular smooth muscle, OR they can act indirectly by releasing vasodilator or vasoconstrictor substances from the vascular endothelium. Some mediators have both

effects.

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LOCALLY important components of arteriolar smooth muscle tone

RESTING TONE = BASAL TONE

Myogenic tone

Local vascular (endothelial) factors

Local tissue humoral factors

+ PHASIC (not tonic) VASODILATORY INNERVATION CAN

INCREASE BLOOD FLOW LOCALLY

Intrinsic vascular factors!

Local vasodilator tissue metabolites

• Released from active cells or from cells of

energy distress

• Hypoxia, carbon dioxide, lactic acid,

acidosis, potassium ions

• NO

• PGE2

• adenosine

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InosineS-adenozyl-

homocisteine

Coffein

A

Na+

A

ATP

A A

cAMP↑

A2

Adenosine

Vasodilation

Smooth muscle cell

Tissue cell

LOCALLY important components of arteriolar smooth muscle tone

RESTING TONE = BASAL TONE

Myogenic tone

Local vascular (endothelial) factors

Local tissue humoral factors

+ PHASIC (not tonic) VASODILATORY INNERVATION CAN

INCREASE BLOOD FLOW LOCALLY

Intrinsic vascular factors!

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LOCALLY important VASODILATORY autonomic innervation

• Parasympathethic innervation (Ach, VIP,

NO) of salivary glands, external genitalia,

pial vessels

• Sympathetic innervation of skeletal muscle

arterioles (Ach, maybe not in humans)

• Enteral nervous system innervation of

arterioles in GI tract glands (Ach, VIP, NO)

Long-term changes in local blood flow: Angiogenesis

• Chronic elevation of metabolic activity, or hypoxia triggers angiogenesis

• HYPOXIA triggers humoral factors (vascular endothelial growth factor, fibroblast growth factor, angiopoietins)

• Steps: next slide

• Capillary density is determined by MAXIMUM flow need, not average flow need (muscle)

• Opposite phenomenon: arteriolar/ capillary rarefaction

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The cellular steps involved in angiogenesis.

Clapp C et al. Physiol Rev 2009;89:1177-1215

©2009 by American Physiological Society

Autoregulation

• Present in every organ (except pulmonary circulation), however, most pronounced in the cerebral, coronary and renal circulation.

• Based on the parallel increase or decrease of LOCAL vascular resistance with changes in arterial blood pressure

• Mechanisms of acute autoregulation: 1. myogenic (Bayliss effect)2. metabolic (accumulation/washout of vasodilatory metabolites)3. functional (in the kidney autoregulation of glomerular filtration produces the flow autoregulation)

• Long-term autoregulation (weeks to months): new vessel growth (angiogenesis) – vessel degeneration –arteriolar and capillary rarefaction

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Active/Reactive hyperemia

Long-term activation of the tissue leads to excess capillarization: angiogenesis!

Hemostasis-induced vasoconstriction

• Loss of functional endothelium: decreased release of NO, prostacyclin and EDHF

• Vasodilator mediators acting via endothelium will be ineffective or their effect will reverse (for instance Ach)

• Thrombin induces release of constrictor endothelin

• Platelets release vasoconstrictors: serotonin, catecholamines, thromboxane

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Inflammation-induced vasodilation

1. Histamine

2. Bradykinin and kallidine (Lys-bradykinin)

3. PGE2

4. Neurogenic inflammation (Substance P,

Neurokinin A, Calcitonin-gene related

peptide)

INFLAMMATION:

Vasodilation

Increased permeability

Itching/pain

Tissue damage

Immune reaction

Histamine

H1-R(IP3/Ca)

H2-R(cAMP)

HISTAMINE

HISTAMINE IS THE

MOST IMPORTANT

INFLAMMATORY

MEDIATOR.

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KININS

Tissue

kallikrein

Plasmakallikrein

Inactivepeptides

Kininase I

Kininase II =

ACE

XII XIIa Clotting

Prekallikrein

HMW kininogen

LMW kininogen

Bradykinin

Lysil-Bradykinin

Bradykinin and Lysil-bradykinin are both effective.

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PAIN

To spinal cord

Trauma

Histamin

Local

Inflamma-

tion

Chemosensitive

C-fibres

CNS:

PAIN

Axon collaterals:

FLARE

Vasodilation +Local edemaCGRP/SP

LOCAL ERYTHEMA

EDEMA

Chemosensitive

Pain receptors

(C-fibres) release

neuropeptides:

•Calcitonin gene-

related peptide

(CGRP)

•Substance P (SP)

NEUROGENIC INFLAMMATIONTRIPLE RESPONSE: local erythema + local edema + flare

Mast cell:Histamin

TRAUMA

vasodilationvasodilation

FLARE FLARE

AXON-REFLEX

IP3/C

a2

+ ↑

NO

IP3/Ca2+ ↑

cAMP↓

cAMP↑

NO

ENDOTHELIAL CELLMUSCLE

Contraction

Relaxation

Contraction

Endothelin-1

ET-A

TXA2

TP

Serotonin

5HT2a

5HT2a

Bradykinin B1

B1

Neurokinin A NK2

NK2

Acetylcholine M1

M1

α2 Noradrenaline α1

α1

Histamine H1

H1

H2 CGRP ?? VIP ??

AdenosineA2

A1

PGE2

PGI2IPEP1-4

LOCALLY ACTING VASOACTIVE SUBSTANCES

NK1

Substance P NK1

cGMP↑

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CARDIAC OUTPUT „regulation”

Factors determining cardiac output:

1. The heart

2. Blood volume

3. Venous compliance

4. Total peripheral resistance

Cardiac output does NOT have a homeostatic regulation as

arterial blood pressure, rather the complex interactions of the

above factors will determine the cardiac output.

Guyton model: the graphic representation of factors determining Cardiac Output

• Cardiac function curve: effect of atrial

pressure on cardiac output (Frank-

Starling)

• Systemic vascular function curve: effect of

atrial pressure on venous return (modified

by blood volume, TPR, venous

compliance)

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Effect of atrial pressure on cardiac output (Frank-Starling mechanism)

Systemic vascular function curve: effect of atrial pressure on venous return

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Mean vascular filling pressure (MFP)

Increasing cardiac output will decrease central venous pressure

MFP

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Exchanging the two axes will yield the vascular function curve

MFP

Merging the two curves will show the „steady state” equilibrium cardiac output of

the system

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Effect of sympathetic tone on the cardiac function curve

Sympathetic stimulation

Sympathetic inhibition

Effect of venous compliance/blood volume on the vascular function curve

Decreased blood volume

Increased compliance

(venodilation)

Increased blood volume

Decreased compliance

(venoconstriction)

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Effect of total peripheral resistance on the vascular function curve

MFP

Increased TPR

Decreased TPR

Guyton diagram at work: cardiac output change during exercise

Sympathetic stimulation of the heart

Sympathetic venoconstriction

Decreased total peripheral resistance