214 Regulation of the Circulation
The blood flow must be regulated to ensure an ◆ Local metabolic (chemical) effects: An in-
Cardiovascular System
adequate blood supply, even under changing
environmental conditions and stress (cf. p.74).
This implies (a) optimal regulation of cardiac
activity and blood pressure (homeostasis), (b)
adequate perfusion of all organ systems, and
(c) shunting of blood to active organ systems
(e.g., muscles) at the expense of the resting or-
gans (e.g., gastrointestinal tract) to keep from
overtaxing the heart (씮 A).
Regulation of blood flow to the organs is
mainly achieved by changing the diameter of
8
blood vessels. The muscle tone (tonus) of the
vascular smooth musculature changes in re-
sponse to (1) local stimuli (씮 B2a/b), (2) hor-
monal signals (씮 B3 a/b) and (3) neuronal sig-
nals (씮 B1 a/b). Most blood vessels have an in-
termediary muscle tone at rest (resting tone).
Many vessels dilate in response to denerva-
tion, resulting in a basal tone. This occurs due
to spontaneous depolarization of smooth
muscle in the vessels (see also p. 70).
Local Regulation of Blood Flow (Autoregulation)
Autoregulation has two functions:
◆ Autoregulatory mechanisms help to main-
tain a constant blood flow to certain organs
when the blood pressure changes (e.g., renal
vessels constrict in response to rises in blood
pressure; 씮 p. 150).
◆ Autoregulation also functions to adjust the
blood flow according to changes in metabolic
activity of an organ (metabolic autoregulation);
the amount of blood flow to the organ (e.g.,
cardiac and skeletal muscle; 씮 A and p. 212)
can thereby increase many times higher than
the resting level.
Types of autoregulatory mechanism:
◆ Myogenic effects arising from the vascular
musculature of the lesser arteries and arteri-
oles (Bayliss effect) ensure that these vessels
contract in response to blood pressure-related
dilatation (씮 B2a) in certain organs (e.g., kid-
neys, gastrointestinal tract and brain), but not
in others (e.g., skin and lungs).
◆ Oxygen deficiencies generally cause the
blood vessels to dilate. Hence, the degree of
blood flow and O2 uptake increase with in-
creasing O2 consumption. In the lungs, on the
other hand, a low PO2 in the surrounding alve-
oli causes the vessels to contract (hypoxic vaso-
constriction; 씮 p. 122).
Hypoxia, ischemia, organ perfusion abnormalities, centralization of circulation
crease in local concentrations of metabolic
products such as CO2, H+, ADP, AMP, adenosine,
and K+ in the interstitium has a vasodilatory ef-
fect, especially in precapillary arterioles. The
resulting rise in blood flow not only improves
the supply of substrates and O2, but also accel-
erates the efflux of these metabolic products
from the tissue. The blood flow to the brain and
myocardium (씮 p. 212) is almost entirely sub-
ject to local metabolic control. Both local meta-
bolic effects and O2 deficiencies lead to an up
to 5-fold increase in blood flow to an affected
region in response to the decreased blood flow
(reactive hyperemia).
◆ Vasoactive substances: A number of vasoac-
tive substances such as prostaglandins play a
role in autoregulation (see below).
Hormonal Control of Circulation
Vasoactive substances. Vasoactive hormones
either have a direct effect on the vascular
musculature (e.g., epinephrine) or lead to the
local release of vasoactive substances (e.g.,
nitric oxide, endothelin) that exert local para-
crine effects (씮 B).
◆ Nitric (mon)oxide (NO) acts as a vasodila-
tory agent. NO is released from the en-
dothelium when acetylcholine (M receptors),
ATP, endothelin (ETB receptors), or histamine
(H1 receptors) binds with an endothelial cell
(씮 p. 280). NO then diffuses to and relaxes
vascular myocytes in the vicinity.
◆ Endothelin-1 can lead to vasodilatation by
inducing the release of NO from the en-
dothelium by way of ETB receptors (see above),
or can cause vasoconstriction via ETA receptors
in the vascular musculature. When substances
such as angiotensin II or ADH (= vasopressin;
V1 receptor) bind to an endothelial cell, they
release endothelin-1, which diffuses to and
constricts the adjacent vascular muscles with
the aid of ETA receptors.
◆ Epinephrine (E): High concentrations of E
from the adrenal medulla (씮 p. 86) have a
vasoconstrictive effect (α1-adrenoceptors),
whereas low concentrations exert vasodilatory
effects by way of β2 adrenoceptors in the myo-
cardium, skeletal muscle and liver (씮 C). The ef-
fect of E mainly depends on which type of
adrenoceptor is predominant in the organ. α1- 왘
 Plate 8.14 Regulation of the Circulation I 215

A. Blood flow to organs

Cardiovascular System
15–25 L/min,

L/(min . kg organ)
depending on fitness
Maximum Relative to
blood flow organ weight

L/min
6
Blood flow Relative to
at rest organ weight

5
Blood flow

8
3

1
ly)
al
e

e
on
scl

tin

scl
ery
mu

ct tes

mu
art
tra troin
al

ys

ac
tic
let

ne

rdi
in
(he er
pa
in
Ske

Bra

Kid
Liv
Ga

Ca
Sk

B. Vasoconstriction and vasodilatation

Pressor area 1a 1b
Neuronal Neuronal
Sympathetic Sympathetic
tonus tonus

Parasympathetic system
(salivary glands, genitalia)
Vessel stretch
PO2
Myogenic reaction Adenosine, PCO2 ,
H+, K+ etc.
Constriction

Dilatation

2a 2b
PO2 NO
local local
PGE2 , PGI2
Endothelin-1 (ETA)
EDHF
PGF2a ,
thromboxane Bradykinin,
kallidin

ADH (V1), Epinephrine (b2) Acetylcholine (M),

epinephrine (a1), ATP,
angiotensin II 3a 3b histamine (H1),
Hormonal Hormonal endothelin-1 (ETB)
216 Regulation of the Circulation (continued)
왘 adrenoceptors are predominant in the
Cardiovascular System
blood vessels of the kidney and skin.
◆ Eicosanoids (씮 p. 271): Prostaglandin (PG)
F2α and the thromboxanes A2 (released from
platelets, 씮 p. 102) and B2 have vasoconstric-
tive effects, while PGI2 (= prostacyclin, e.g. re-
leased from endothelium) and PGE2 have va-
sodilatory effects. Another vasodilator re-
leased from the endothelium (e.g., by brady-
kinin; see below) opens K+ channels in vascu-
lar myocytes and hyperpolarizes them, leading
to a drop in the cytosolic Ca2+ concentration.
8
This endothelium-derived hyperpolarizing
factor (EDHF), has been identified as a 11,12-
epoxyeicosatrienoic acid (11,12-EET).
◆ Bradykinin and kallidin are vasodilatory
agents cleaved from kininogens in blood
plasma by the enzyme kallikrein. Histamine
also acts as a vasodilator. All three substances
influence also vessel permeability (e.g., during
infection) and blood clotting.
Neuronal Regulation of Circulation
Neuronal regulation of blood flow (씮 B1a/b)
mainly involves the lesser arteries and greater
arterioles (씮 p. 190), while that of venous re-
turn to the heart (씮 p. 206) can be controlled
by dilating or constricting the veins (changes in
their blood storage capacity). Both mecha-
nisms are usually controlled by the sympa-
thetic nervous system (씮 B1a and p. 78ff.),
whereby norepinephrine (NE) serves as the
postganglionic transmitter (except in the
sweat glands). NE binds with the α1 adreno-
ceptors on blood vessels, causing them to con-
strict (씮 B). Vasodilatation is usually achieved
by decreasing the tonus of the sympathetic
system (씮 B1b). This does not apply to blood
vessels in salivary glands (increased secretion)
or the genitals (erection), which dilate in re-
sponse to parasympathetic stimuli. In this case,
vasoactive substances (bradykinin and NO, re-
spectively) act as the mediators. Some neurons
release calcitonin gene-related peptide
(CGRP), a potent vasodilator.
Neuronal regulation of blood flow to organs
occurs mainly: (a) via central co-innervation
(e.g., an impulse is simultaneously sent from
the cerebral cortex to circulatory centers when
a muscle group is activated, or (b) via neuronal
feedback from the organs whose activity level
Orthostatic collapse, adrenoceptor blockers, hypertension treatment, shock
and metabolism have changed. If the neuronal
and local metabolic mechanisms are conflict-
ing (e.g., when sympathetic nervous stimula-
tion occurs during skeletal muscle activity),
the metabolic factors will predominate. Va-
sodilatation therefore occurs in the active
muscle while the sympathetic nervous system
reduces the blood flow to the inactive muscles.
Blood flow to the skin is mainly regulated by
neuronal mechanisms for the purpose of con-
trolling heat disposal (temperature control;
씮 p. 226). Hypovolemia and hypotension lead
to centralization of blood flow, i.e., vasocon-
striction in the kidney (oliguria) and skin (pal-
lor) occurs to increase the supply of blood to
vital organs such as the heart and central
nervous system (씮 p. 220).
During exposure to extremely low tempera-
tures, the cold-induced vasoconstriction of cu-
taneous vessels is periodically interrupted to
supply the skin with blood to prevent tissue
damage (Lewis response). Stimulation of noci-
ceptor fibers in the skin can cause their axon
collaterals to release neuropeptides (sub-
stance P, CGRP) which are responsible for va-
sodilatation and skin reddening in the area
(axon reflex).
Central regulation of blood flow (씮 C) is the
responsibility of the CNS areas in the medulla
oblongata and pons. They receive information
from circulatory sensors (S) or receptors (a) in
the high-pressure system (barosensors or
pressure sensors, SP, in the aorta and carotid
artery); (b) in the low-pressure system (stretch
sensors in the vena cava and atria, SA and SB);
and (c) in the left ventricle (SV). The sensors
measure arterial blood pressure (SP), pulse rate
(SP and SV) and filling pressure in the low pres-
sure system (indirect measure of blood
volume). The A sensors (SA) mainly react to
atrial contraction, whereas the B sensors (SB)
react to passive filling stretch (씮 C2). If the
measured values differ from the set-point
value, the circulatory control centers of the CNS
transmit regulatory impulses through efferent
nerve fibers to the heart and blood vessels
(씮 D and p. 5 C2).
Situated laterally in the circulatory “center”
is a pressor area (씮 C, reddish zone), the neu-
rons of which (blue arrows) continuously
transmit sympathetic nerve impulses to the 왘
 Plate 8.15 Regulation of the Circulation II 217

C. Central regulation of blood flow

Cardiovascular System
1 Cerebral cortex

Limbic Hypothalamus Tempe-

system rature

Respiratory
“center”

8
Pressor area

Circulatory “center”
in pons and
medulla oblongata Parasympathetic
nerve
Depressor area
Vagal nuclei
IXth
Inhibition cranial nerve

Sympathetic
nervous system Vagus
nerve (X)

Sympathetic trunk

2
Spinal cord
Inhibits
cardiac action
Carotid
sinus
SP
Aortic pressure Increases
cardiac action Common
SP AP carotid
artery

Aorta
Ventricular Veins
pressure SP

SV AP

Vasoconstriction
(a1 adrenoceptors)
Venous pulse SA
SA SB AV node
AP Arterioles SA node
SB
(After Paintal)

Heart
2 Afferent action potentials (AP) SV
from circulatory sensors
218 Regulation of the Circulation (continued)
왘 heart to increase its activity (heart rate,
conduction and contractility). Their effects on
Cardiovascular System
vessels are predominantly vasoconstrictive
(resting tone). The pressor area is in close con-
tact with more medial neurons (depressor
area, light blue area in C). The pressor and
depressor areas are connected to the dorsal
nuclei of the vagus nerve (씮 C, green), the
stimulation of which reduces the heart rate
and cardiac impulse conduction rate (씮 C,
orange arrows).
Homeostatic circulatory reflexes include
8
signals along afferent nerve tracts (씮 D3a/b)
that extend centrally from the pressosensors in
the aorta and carotid sinus (씮 C, green tracts).
The main purpose of homeostatic control is to
maintain the arterial blood pressure at a stable
level. Acute increases in blood pressure
heighten the rate of afferent impulses and acti-
vate the depressor area. By way of the vagus
nerve, parasympathetic neurons (씮 C, orange
tract) elicit the depressor reflex response, i.e.,
they decrease the cardiac output (CO). In addi-
tion, inhibition of sympathetic vessel innerva-
tion causes the vessels to dilate, thereby reduc-
ing the peripheral resistance (TPR; 씮 D4a/b).
Both of these mechanisms help to lower acute
increases in blood pressure. Conversely, an
acute drop in blood pressure leads to activation
of pressor areas, which stimulates a rise in CO
and TPR as well as venous vasoconstriction
(씮 C, blue tracts), thereby raising the blood
pressure back to normal.
Due to the fast adaptation of pressosensors
(differential characteristics, 씮 p. 314ff.), these
regulatory measures apply to acute changes in
blood pressure. Rising, for example, from a
supine to a standing position results in rapid
redistribution of the blood volume. Without
homeostatic control (orthostatic reflex; 씮 p. 7,
E and p. 206), the resulting change in venous
return would lead to a sharp drop in arterial
blood pressure. The circulatory centers also re-
spond to falling PO2 or rising PCO2 in the blood
(cross-links from respiratory center) to raise
the blood pressure as needed.
In individuals with chronic hypertension, the input
from the pressosensors is normal because they are
fully adapted. Therefore, circulatory control centers
cannot respond to and decrease the high pressures.
On the contrary, they may even help to “fix” the
blood pressure at the high levels. Chronic hyperten-
Treatment of heart failure, forms and consequences of hypertension, renal failure
sion leads to stiffening of the carotid sinus. This may
also contribute to decreasing the sensitivity of
carotid pressosensors in hypertension.
A temporary increase in venous return (e.g., after an
intravenous infusion) also leads to an increase in
heart action (씮 D, right). This mechanism is known
as the Bainbridge reflex. The physiological signifi-
cance of this reflex is, however, not entirely clear, but
it may complement the Frank–Starling mechanism
(씮 p. 204ff.).
Hypertension
Hypertension is defined as a chronic increase
in the systemic arterial blood pressure. The
general criterion for diagnosis of hypertension
is consistent elevation of resting blood pres-
sure to ⬎ 90 mmHg and/or ⬎ 140 mmHg dias-
tolic and systolic, respectively (씮 p. 208). Un-
treated or inadequately managed hyperten-
sion results in stress and compensatory hyper-
trophy of the left ventricle which can ulti-
mately progress to left heart failure. Individuals
with hypertension are also at risk for arterio-
sclerosis and its sequelae (myocardial infarc-
tion, stroke, renal damage, etc.). Therefore, hy-
pertension considerably shortens the life ex-
pectancy of a large fraction of the population.
The main causes of hypertension are (a) increased
extracellular fluid (ECF) volume with increased
venous return and therefore increased cardiac out-
put (volume hypertension) and (b) increased total pe-
ripheral resistance (resistance hypertension). As hy-
pertension always leads to vascular changes result-
ing in increased peripheral resistance, type a hyper-
tension eventually proceeds to type b which, regard-
less of how it started, ends in a vicious circle.
The ECF volume increases when more NaCl (and
water) is absorbed than excreted. The usually high in-
take of dietary salt may therefore play a role in the
development of essential hypertension (primary
hypertension), the most common type of hyperten-
sion, at least in patients sensitive to salt. Volume hy-
pertension can even occur when a relatively low salt
intake can no longer be balanced. This can occur in
renal insufficiency or when an adrenocortical tumor
produces uncontrolled amounts of aldosterone, re-
sulting in Na+ retention.
Other important cause of hypertension is
pheochromocytoma, a tumor that secretes epi-
nephrine and norepinephrine and therefore raises
the CO and TPR. Renal hypertension can occur due
to renal artery stenosis and renal disease. This results
in the increased secretion of renin, which in turn
raises the blood pressure via the renin–angiotensin–
aldosterone (RAA) system (씮 p. 186).
 Plate 8.16 Regulation of the Circulation III 219

D. Circulatory reflexes

Cardiovascular System
Carotid and aortic Atrial (Bainbridge) reflex
sinus reflex (depressant) (excitatory)

IX X X

8
4b 4a 3a 3b 3c 4c
Efferent Afferent Afferent Efferent

SP
2b
SP
2a

SA node
AV node
2d
SV
2c

Vasodilatation Stretch
receptors
1. Venous return rises
Arterial blood pressure rises Stimulus Atrial pressure rises
Pressosensors in:
a) Aorta 2.
Sensors d) Atrial and venous
b) Carotid artery stretch sensors
c) Left ventricle

a) Glossopharyngeal nerve (IXth nerve) 3.

c) Vagus nerve (Xth nerve)
b) Vagus nerve (Xth nerve) Afferent path
a) Stimulation of
parasympathetic system 4. c) Stimulation of
b) Inhibition of Efferent path sympathetic system
sympathetic system

Bradycardia
Vasodilatation 5. Tachycardia,
Response myocardial contractility
increases
Cardiac output Peripheral resistance
decreases decreases

Arterial blood pressure decreases 6. Cardiac output rises

Goal achieved