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 crease in local concentrations of metabolic
environmental conditions and stress (cf. p.74). products such as CO2, H+, ADP, AMP, adenosine,
This implies (a) optimal regulation of cardiac and K+ in the interstitium has a vasodilatory ef-
activity and blood pressure (homeostasis), (b) fect, especially in precapillary arterioles. The
adequate perfusion of all organ systems, and resulting rise in blood flow not only improves
(c) shunting of blood to active organ systems the supply of substrates and O2, but also accel-
(e.g., muscles) at the expense of the resting or- erates the efflux of these metabolic products
gans (e.g., gastrointestinal tract) to keep from from the tissue. The blood flow to the brain and
overtaxing the heart (씮 A). myocardium (씮 p. 212) is almost entirely sub-
Regulation of blood flow to the organs is ject to local metabolic control. Both local meta-
mainly achieved by changing the diameter of bolic effects and O2 deficiencies lead to an up
8

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

blood vessels of the kidney and skin. and local metabolic mechanisms are conflict-
◆ Eicosanoids (씮 p. 271): Prostaglandin (PG) ing (e.g., when sympathetic nervous stimula-
F2α and the thromboxanes A2 (released from tion occurs during skeletal muscle activity),
platelets, 씮 p. 102) and B2 have vasoconstric- the metabolic factors will predominate. Va-
tive effects, while PGI2 (= prostacyclin, e.g. re- sodilatation therefore occurs in the active
leased from endothelium) and PGE2 have va- muscle while the sympathetic nervous system
sodilatory effects. Another vasodilator re- reduces the blood flow to the inactive muscles.
leased from the endothelium (e.g., by brady- Blood flow to the skin is mainly regulated by
kinin; see below) opens K+ channels in vascu- neuronal mechanisms for the purpose of con-
lar myocytes and hyperpolarizes them, leading trolling heat disposal (temperature control;
to a drop in the cytosolic Ca2+ concentration. 씮 p. 226). Hypovolemia and hypotension lead
8

This endothelium-derived hyperpolarizing to centralization of blood flow, i.e., vasocon-

factor (EDHF), has been identified as a 11,12- striction in the kidney (oliguria) and skin (pal-
epoxyeicosatrienoic acid (11,12-EET). lor) occurs to increase the supply of blood to
◆ Bradykinin and kallidin are vasodilatory vital organs such as the heart and central
agents cleaved from kininogens in blood nervous system (씮 p. 220).
plasma by the enzyme kallikrein. Histamine During exposure to extremely low tempera-
also acts as a vasodilator. All three substances tures, the cold-induced vasoconstriction of cu-
influence also vessel permeability (e.g., during taneous vessels is periodically interrupted to
infection) and blood clotting. supply the skin with blood to prevent tissue
damage (Lewis response). Stimulation of noci-
Neuronal Regulation of Circulation ceptor fibers in the skin can cause their axon
Neuronal regulation of blood flow (씮 B1a/b) collaterals to release neuropeptides (sub-
mainly involves the lesser arteries and greater stance P, CGRP) which are responsible for va-
arterioles (씮 p. 190), while that of venous re- sodilatation and skin reddening in the area
turn to the heart (씮 p. 206) can be controlled (axon reflex).
by dilating or constricting the veins (changes in Central regulation of blood flow (씮 C) is the
their blood storage capacity). Both mecha- responsibility of the CNS areas in the medulla
nisms are usually controlled by the sympa- oblongata and pons. They receive information
thetic nervous system (씮 B1a and p. 78ff.), from circulatory sensors (S) or receptors (a) in
whereby norepinephrine (NE) serves as the the high-pressure system (barosensors or
postganglionic transmitter (except in the pressure sensors, SP, in the aorta and carotid
sweat glands). NE binds with the α1 adreno- artery); (b) in the low-pressure system (stretch
ceptors on blood vessels, causing them to con- sensors in the vena cava and atria, SA and SB);
strict (씮 B). Vasodilatation is usually achieved and (c) in the left ventricle (SV). The sensors
by decreasing the tonus of the sympathetic measure arterial blood pressure (SP), pulse rate
system (씮 B1b). This does not apply to blood (SP and SV) and filling pressure in the low pres-
vessels in salivary glands (increased secretion) sure system (indirect measure of blood
or the genitals (erection), which dilate in re- volume). The A sensors (SA) mainly react to
sponse to parasympathetic stimuli. In this case, atrial contraction, whereas the B sensors (SB)
vasoactive substances (bradykinin and NO, re- react to passive filling stretch (씮 C2). If the
spectively) act as the mediators. Some neurons measured values differ from the set-point
release calcitonin gene-related peptide value, the circulatory control centers of the CNS
(CGRP), a potent vasodilator. transmit regulatory impulses through efferent
Neuronal regulation of blood flow to organs nerve fibers to the heart and blood vessels
occurs mainly: (a) via central co-innervation (씮 D and p. 5 C2).
(e.g., an impulse is simultaneously sent from Situated laterally in the circulatory “center”
the cerebral cortex to circulatory centers when is a pressor area (씮 C, reddish zone), the neu-
a muscle group is activated, or (b) via neuronal rons of which (blue arrows) continuously
feedback from the organs whose activity level transmit sympathetic nerve impulses to the 왘

Orthostatic collapse, adrenoceptor blockers, hypertension treatment, shock

 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, sion leads to stiffening of the carotid sinus. This may
conduction and contractility). Their effects on also contribute to decreasing the sensitivity of
Cardiovascular System

vessels are predominantly vasoconstrictive carotid pressosensors in hypertension.

(resting tone). The pressor area is in close con- A temporary increase in venous return (e.g., after an
intravenous infusion) also leads to an increase in
tact with more medial neurons (depressor
heart action (씮 D, right). This mechanism is known
area, light blue area in C). The pressor and as the Bainbridge reflex. The physiological signifi-
depressor areas are connected to the dorsal cance of this reflex is, however, not entirely clear, but
nuclei of the vagus nerve (씮 C, green), the it may complement the Frank–Starling mechanism
stimulation of which reduces the heart rate (씮 p. 204ff.).
and cardiac impulse conduction rate (씮 C,
orange arrows). Hypertension
Homeostatic circulatory reflexes include Hypertension is defined as a chronic increase
8

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

Treatment of heart failure, forms and consequences of hypertension, renal failure

 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