Regulation of peripheral circulation: introduction

Ion channels, membrane potential & vascular tone.Intrinsic control of resistance vessels

Metabolic controlAutoregulationEndothelial factorsExtrinsic control of resistance vessels

RMP = resting membrane potential

VSM = vascular smooth muscle

Peripheral resistance vessels are regulated by intrinsic (local) mechanisms, and by extrinsic mechanisms (hormones & the autonomic NS).

Distribution of blood flow among different organs is regulated by myogenic, metabolic, neural, & hormonal effects on arteriolar radius.

Extrinsic actions are superimposed on intrinsic control.

F = DP/R

CO = MAP/TPR

MAP = CO x TPR

Voltage gated Ca++ channels in VSM

HR x SV

Endothelial factors

metabolismAutoregulation (myogenic, metabolic)

Intrinsic

Arteriolar tone

Cardiovascular reflexes

Hormones

Central nervous system

MAP = CO x TPR

Extrinsic

Excitation contraction coupling in vascular smooth muscle

SERCA = sarcoplasmic reticulum Ca++ ATPase

Ca++

Extracellular Ca++

Ca++ stores

Ca++

Ryanodine receptor(SR Ca++ release channel)

Contractile mechanism

Sarcoplasmic recticulum

SR Ca++ ATPase

Ca++

Ca++Na+

L-type Ca++ channels (dihydropyridine receptors) are voltage gated, open with depolarization of cell membrane

No T tubules and no fast Na+ channels.Ca++ enters cells via L-type Ca++ channels.

Membrane potential of VSM controls cell [Ca++] via voltage gated Ca++ channels

Vascular smooth muscle (VSM) exhibits

Intrinsic tone independent of nervous or hormonal input

Sustained graded contraction without action potentials.

Level of intrinsic tone is directly related to resting membrane potential (depolarization increases tone).

Nervous & hormonal control is superimposed on intrinsic tone.

-70 -50 -30 -10 +10

Ope

n pr

obab

ility

of

Ca+

+ c

hann

els

0.2

0.1

0.3

0.4

Resting Membrane Potential (RMP)

L type voltage gated Ca++ channels are activated by depolarization.

VSM RMP = - 40 to - 55 Mv

RMP is a mostly a K+ diffusion potential.

Contraction of VSM depends on intracellular [Ca++]

open K+ channels

K+ efflux

hyperpolarization

inactivates voltage gated L type Ca++ channels

cell [Ca++]

vasodilation

close K+ channels

K+ efflux

depolarization

activates voltage gated L type Ca++ channels

cell [Ca++]

vasoconstrictionEK+ = - 84 mV

ECa++ = + 150 mV

RMP = – 40 to – 55 mV

Level of contraction of VSM is set by intracellular [Ca++]

Ca++ enters VSM cells through voltage gated L type Ca++ channels

K+

-

-- -

- -

Ca++

Vascular smooth muscle cell

-

-

-

-

-

-

Ca++K+

Vasoactive hormones & voltage gated L type Ca++ channels

Vasoconstrictors either

Open Ca++ channels directly or

Depolarize the cell membrane which opens Ca++ channels.

Vasodilators either

close Ca++ channels directly or

hyperpolarize the cell membrane which closes Ca++ channels.

K+ channels in vascular smooth muscle (VSM)

ATP sensitive channel (KATP channel)

↓ [ATP] or ↑ [ADP] → ↑ open probability

Links metabolism to blood flow

Responds to vasoconstrictors and vasodilators

Contributes to resting membrane potential

(some KATP channels are open under resting conditions)

Voltage gated K+ channel (Kv)

Depolarization → ↑ open probability

May contribute to resting membrane potential

Inward rectifying K+ channel (Kir)

At ECF [K+] above normal, Kir channels open

Contribute to vasodilation in muscle during exercise

Despite their name, Kir channels allow outward

diffusion of K+ under physiological conditions.

KATP channel

metabolismhypoxia

K+

ATP, ADP

activates

Activity of the KATP channels links metabolism to blood flow

Hypoxia or increased metabolic rate activate the KATP channel.

K+ efflux hyperpolarizes the cell membrane.

Voltage gated Ca++ channels are inactivated.

VSM dilates.

The SUR domain on the KATP channel is a sulfonylurea receptor or ABC cassette (adenosine binding cassette).

KATP channel can bind ATP or ADP

ATP

KATP channel

ADP

inactivates activates

Definition of metabolic control

Local blood flow is regulated by the local metabolic level of the tissue.

Increased metabolism produces vasodilators that cause an increase in flow.

The increased flow increases delivery of O2 & nutrients and the removal of CO2 &

waste products to match the new level of metabolism.

Possible vasoactive metabolites include: carbon dioxide, H+, nitric oxide, adenosine, inorganic phosphate ions, interstitial osmolality.

Local metabolic control of blood flow

Metabolism has the opposite effect

Metabolism drives blood flow.

Adenosine may be an important regulator of coronary flow

metabolism

tissue ADP, CO2, H+, lactate, adenosine, O2

vasodilation

blood flow

open KATP channels

Hyperpolarize cell membrane

Close voltage gated Ca++ channels

Kir channels contribute to vasodilation during exercise

During heavy exercise ECF [K+] increases as K+ diffuses out of

cells during repolarization.

Kir channels: Despite their name, these channels allow outward

diffusion of K+ under physiological conditions.

skeletal muscle contraction

ECF [K+]

vasodilation

blood flow

open Kir channels

Hyperpolarize VSM cell membrane

Close voltage gated Ca++ channels

KATP channels are also affected by hormonal signals

KATP channel

Vascular smooth muscle cell

metabolism

hypoxia

vasodilators

receptor

K+ ATP, ADP

cAMP

Gs

vasoconstrictors

receptor

PKC

-

+

Nitric oxide

cGMP

++

Hormones that act via KATP channels

VasodilatorsAdenosine (coronary & renal circulation)EpinephrineNitric oxideANP (atrial natriuretic peptide)VasoconstrictorsAngiotensin IIVasopressinEndothelin

Pressure-flow relationshipsF

low

Pressure

Autoregulation

0 100 200

dilation constriction

Autoregulation: constancy of blood flow when arterial pressure changes.

Flo

w

Pressure

Passive system

Large veins exhibit a passive pressure flow relationship.

Flo

w

Pressure

Rigid system

Doesn’t occur in the circulation.

Myogenic mechanism of autoregulation

An example of autoregulation in vivo:

Standing up increases arterial pressure in the legs as a function of distance below the heart.

Myogenic autoregulation constricts arterioles below the heart.

Constriction maintains flow relatively constant

Also, this myogenic response prevents an increase in capillary pressure & prevents pedal edema.

Myogenic autoregulation is especially effective in the kidney.

pressure

Stretches arterioles

constriction

constant flow

voltage gated Ca++ channels open

cell depolarizes

Activates nonspecific cation channel in VSM cell

Na+ enters cell

Autoregulation: constancy of blood flow when arterial pressure changes.

Pressure has the opposite effect

Metabolic mechanism of autoregulation

Decreased blood pressure and flow have opposite effects. Blood pressure

Blood flow

Tissue PO2 Tissue metabolic vasodilators

Vasoconstriction

Metabolic vasodilators include: low O2, high CO2, [H+], adenosine, PO4, interstitial osmolality.

Autoregulation is a response to changes in blood pressure.

Metabolic control is a response to changes in tissue metabolism.

Flo

w, m

l/min

Pre

ssur

e, m

m H

g

occlusion occlusion occlusion

Reactive hyperemia

Occlusion of an artery is followed by an increase in blood flow above control level when the occlusion is released.

The longer the occlusion, the greater the increase in flow.

During occlusion hypoxia prevails and vasodilator metabolites accumulate.

When flow resumes these metabolites produce vasodilation.

Catecholamines regulating the circulation: norepinephrine

Skeletal muscle and coronary arterioles have beta receptors.

They can be dilated by low dose epinephrine.

Norepinephrine is a constrictor because it has a greater affinity for alpha receptors but it can react with beta receptors.

Neuroeffector Receptor Action

Norepinephrine Alpha Vasoconstriction

Norepinephrine Beta 1 Heart rate Contractility Cardiac

output

Catecholamines regulating the circulation: epinephrine

Secreted from the adrenal medulla.

Release controlled by sympathetic nerves

Cardiac actions

Heart rate

Contractility

Cardiac output

Vascular

Constricts

Kidney

Splanchnic bed

Skin

Dilates heart & skeletal muscle (low dose)

Angiotensin & vasopressin

Angiotensin IIGenerated by angiotensin converting enzyme in blood in response to secretion of renin from kidneys. Renin secretion is stimulated by:

Arterial pressure or blood volumeLow salt diet

Vasoconstrictor, increases TPRRetains salt (kidneys)VasopressinSecreted from posterior pituitary in response to

Arterial pressure or blood volumeDehydrationPainFear

VasoconstrictorRetains water (kidneys)

Vasoconstricting effects of sympathetic nerves, angiotensin and vasopressin are synergistic

Parasympathetic effects on blood flow

Neuroeffector Receptor Action

Acetylcholine Muscarinic Blood flow

Salivary glands

Gastrointestinal glands

Erectile tissue

Effects of acetylcholine on blood flow are indirect.

Ach acts on the endothelium to release nitric oxide.

NO diffuses to VSM & is a vasodilator.

Endothelium , shear stress & nitric oxide synthesis

Vascular smooth muscle relaxation

Flow Shear stress

Ca++

L-arginine

Ca++ + Calmodulin Nitric oxide synthase

Nitric oxide (NO)

Blood Flow

NOS is a calmodulin -dependent enzyme

endothelium

Nitric oxide is needed for maintenance of normal blood pressure. Pharmacological inhibition of nitric oxide synthase increases MAP into the hypertensive range.

Circulatory response to hypotension

Sympathetic nerve activity

Arteriolar constriction

total peripheral resistance

flow (GI tract, kidney, liver, resting muscle).

Baroreflex

secretion of epinephrine

Constriction: skin, GI tract, kidneyDilation: skeletal muscle, heart

Hypotension, hemorrhage, dehydration, pain, fear

+

Maintain systemic arterial pressure.

+

Integration of sympathetic and metabolic control of circulation

In general:

At rest, blood flow is controlled primarily by a low level of sympathetic tone.

Increased work (muscle contraction, secretion, digestion, absorption etc) increases tissue metabolism.

Blood flow increases to match the new level of metabolism.

Blood flow decreases in inactive tissue due to increased sympathetic tone.

Effects of epinephrine on vascular smooth muscle are less important than sympathetic activity.

Aim: to measure upper leg muscle work and metabolism during leg exercise.

Cycle ergometer sets work intensity

Blood pressure cuff minimizes flow to lower leg

Femoral arterial & venous blood sampled

Upper Leg QO2 versus work intensity

Work Intensity, Watts

Upp

er L

eg Q

O2, L

/min

0

0.2

0.4

0.6

0.8

20 40 60

Work drives oxygen consumption

Graph shows leg blood flow as a function of work intensity

Maximal cardiac output is the limiting factor in aerobic exercise.U

pper

Leg

Blo

od F

low

, L/m

in

Work Intensity, Watts

20 40 600

2

4

6VO2 = (F)(O2A- O2V)

VO2 may be increased by

increasing flow &

increasing oxygen extraction

Maximum flow = 2L/min per kilogram of muscle.

If projected to the whole body, this flow would be equivalent to CO = 50 - 60 L/min. The capacity of skeletal muscle to receive blood is greater than the maximal cardiac output.

VO2 is increased by increasing oxygen extraction and blood flow

Femoral A -V O2 Difference versus work intensity

Work Intensity

Fe

mo

ral A

-V d

iffe

renc

e, m

lO2

/10

0 m

l blo

od

0

4

8

12

16

20 40 60

Exercising the other leg: decreases flow increases extractionWhen both legs are exercised, flow is controlled by the balance of opposing sympathetic and metabolic effects

VO2 = (F)(O2A- O2V)O2A- O2V

Summary

Arteriolar resistance determines distribution of flow between organs.

Vascular smooth muscle (VSM) has basal tone independent of nerves & hormones.

Tone of VSM is regulated by gradual changes in RMP & cell [Ca++].

Stretch depolarizes VSM & increases tone (myogenic response).

Increased local metabolism dilates VSM (metabolic regulation).

Autoregulation maintains constant flow when pressure changes (brain, heart, kidney,

skeletal muscle).

Local metabolic control predominates in heart & brain.

Muscle blood flow in active tissue is a balance between sympathetic (constrictor) &

metabolic (dilator) effects.

Neural control predominates in the splanchnic region and skin.

Sympathetic nerves, angiotensin II and vasopressin potentiate each other’s effects.