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13 Physiology of the Mesenteric Circulation 111
Artery
m
25
Resistance
vessels
Arteriole
Precapillary
eres
sphinct
Exchange
vessels
Cells
Capillaries
Capacitance
essels
v
Fig. 13.4 The mesenteric microcirculation is comprised of three major components: microscopic
arteries and arterioles (resistance vessels), capillaries (exchange vessels) and microscopic veins
(capacitance vessels). Blood flow to the capillaries is regulated by the precapillary sphincters
Venu le
40 m
V
ein
Pressure
P
1
drop
Volume
–
P
P
2
1
=
F
R
P
2
r
flowrate
F
Resistance
to flow
R
8L
=
R
Rr
4
L
Fig. 13.5 Derivation of Poiseuille’s equation with Blood flow (F) equal to the change in pressure
(P1–P2) divided by resistance (R). In addition, resistance is equal to 8ηL/pr
constants, η represents fluid (blood) viscosity, L the length of the vessel, and r the radius of the
vessel
4
where 8 and p are
112 S. Hashmi et al.
most distinctive effects occur as a result of increasing or decreasing blood vessel
diameter, i.e. vasodilation or vasoconstriction, respectively. As the equation above
demonstrates, vasoconstriction and vasodilation have a profound effect on vascular
resistance. This becomes a clinically important factor in the setting of low
mesenteric blood pressure from systemic hypotension in which blood flow is
maintained at an adequate range by vasoconstricti on.
The Intrinsic System
The intrinsic system autoregulates the mese nteric blood flow via the metabolic and
myogenic pathways.
Metabolic Pathway
This mainly describes the direct vasodilator effect on mesenteric blood vessels
caused by tissue hypoxia and accumulation of metabolic byproducts.
Oxygen Demand and Supply
The major variable regulating blood flow in the metabolic pathway is tissue oxygenation. As in most vascular beds in the body, tissue hypoxia causes an increase in
mesenteric blood flow via direct vasodilation. When tissue oxygenation is restored,
blood vessel diameter returns to the resting state. Augmented oxygen demand in the
mesentery occur when there is increased secretion, absorption, or motility of the
gastrointestinal tract. Conversely, factors such as temperature reduction causes a
decrease in tissue metabolism and oxygen demand, thus leading to vasoconstriction.
Oxygen supply in the mesentery may be pathologically low as a result of
decreased cardiac output or mesenteric ischemia.
Metabolic Byproducts
The accumulation of metabolic byproducts—especially CO2and adenosine—leads
to vasodilation within the mesentery. During digestion, the transport of nutrients such
as glucose amino acids and free fatty acids from the intestinal lumen to the enterocytes lining the intestinal mucosa is an active process requiring oxygen. As a result of
energy metabolism required for many forms of nutrient absorption and other small
intestinal processes, lactic acid, CO
, hydrogen ions, prostaglandins, histamine,
2
adenosine and bradykinin, are produced. These products cause vasodilation via
relaxation of precapillary sphincters and a decrease in vascular resistance. This in
turn leads to an increase in blood flow allowing for improved delivery of oxygen to
the tissues. The production of these metabolites also results in local hyperemia. This
form of hyperthermia should not to be confused with reactive hyperemia, a transient
increase in blood temperature occurring after a period of occlusion of blood flow.
13 Physiology of the Mesenteric Circulation 113
Intraluminal Hyperosmolarity
The intr aluminal fluid containing dietary-derived nutrients is hyperosmolar and has
a high sodium content. Sodium absorp tion leads to a high intracellular sodium
concentration. This in turn activates Na
2+
Ca
concentration which in turn stimulates nitric oxide-mediated relaxation of
+
/Ca2+exchanger, increasing intracellular
vascular smooth muscle. Mesenteric vasodilation is mediated via activation of nitric
oxide synthase (Figs. 13.6 an d 13.7).
Myogenic Pathway
a. The myogenic pathway involves the phenomenon known as the Bayliss effect in
which vasoconstriction is produced by stretching of vascular smooth muscle cells
(Fig. 13.8). More specifically, an elevated intravascular pressure causes a reactive
stretching of vascular smooth muscle cells. This leads to depolarization of
mechanosensitive sodium (Na
voltage-gated calcium (Ca
triggering vascular smooth muscle contraction and vasoconstriction.
+
) channels and subsequent activation of
2+
) channels. This allows the influx of calcium ions
Adenosine and NO
Glucose
Lymph
drainage
Blood flow
Na
CLUT 2
+
Nutrient
Absorption
Epithelium
2b
A
2a
Vascular
smooth
muscle
cells
ATP
ADP
ADO
Nutrient absorption
produces metabolic
A
2a
dilation & release of NO
A
2a
(direct or indirect)
ADO
vasodilators
& A
mediated
+
+
2b
A
2b
A
NO
Endothelium
Fig. 13.6 A schematic representation of dietary factors in mesenteric vasodilation. Dietary
sodium and glucose absorption increase ATP utilization stimulating production of vasodilators
such as adenosine and nitric oxide. This is a proposed mechanism for post-prandial mesenteric
vasodilation
114 S. Hashmi et al.
Fig. 13.7 Feedback mechanisms involved in the regulation of mesenteric blood flow based on
nutrient absorption and metabolism
In contrast, a low intravascular pressure will lead to a reactive vasodilation,
restoring blood flow. This effect is based on the Law of Laplace which proposes
that smooth muscle tension is directly proportional to the intravascular pressure and
vessel radius. Hence, an increase in blood pressure leads to a decrease in vessel
radius (vasoconstriction) in order to maintain the same amount of tension.
Laplace’s equation: T ¼ p r
T = smooth muscle tension, p = intravascular pressure and r = vessel radius.
In the setting of blood pressure fluctuations, the function of the myogenic
pathway is to maintain constant blood flow to the mesentery via vasoconstriction or
vasodilation.
13 Physiology of the Mesenteric Circulation 115
Pressure
Bayliss effect
Diameter
A
Fig. 13.8 a Graphic representation of the Bayliss effect in which an increase in pressure in blood
vessels leads to a decrease in diameter of the vessel (vasoconstriction) b The Bayliss effect is
mediated by smooth muscle cells within blood vessels
Time
B
Lumen
Endothelium
Smooth
muscle
Adventitia
Extrinsic System
The extrinsic system functions as an additional regulator of the mesenteric circulation. It comprises central cardiovascular control, autonomic autoregulation, and
neurohumoral control.
Central Cardiovascular Control
The components of cardiac cardiovascular control include cardiac output, systemic
arterial blood pressure, venous return, and circulating blood volume. Any significant change in one or more of these parameters will cause a resultant change in
mesenteric blood flow. For example, in cases with severe blood loss diminished
circulating blood volume and subsequent decrease in venous return will occur.
These factors produce a reduction of mesenteric blood flow.
Autonomic Neuro-Regulation
Sympathetic Nervous System (SNS) Stimulation
Postganglionic vasomotor fibers originate from the celiac, superior mesenteric, and
inferior mesenteric ganglia. These are distributed along the branches of the corresponding mesenteric arteries. These terminate on vascular smooth muscle of
specific portions of the microcirculation (such as the microscopic arteries, arterioles,
venules, and microscopic veins). Physiological and pathological stresses, such as
exercise and hemorrhage result in potent stimulation of the sympathetic neurons.
116 S. Hashmi et al.
Stimulation of postganglionic sympathetic fibers cause the release of adenosine
triphosphate (ATP) and noradrenaline. The resulting transient vasoconstriction
leading to expulsion of blood from capacitance vessels and reduction of mesenteric
blood flow. Strangely, within minutes of prolonged stimulation, the resistance
vessels dilate leading to return to near-normal levels of flow. This is followed by a
third phase consisting of reactive hyperemia causing a transient increase in blood
flow. This triphasic pattern describes a phenomenon called “autoregulatory escape.”
It is believed to be caused by intrinsic metabolic mechanisms (see above) producing
an overriding of the sympathetic neurogenic constriction. The overall effect is
reduction in blood flow to the mesentery while maintaining adequate perfusion to
organs such as the brain, heart and lungs.
Parasympathetic Nervous System (PNS) Stimulation
The PNS has a less prominent role in controlling mesenteric blood flow. Activation
of the parasympathetic system occurs via innervation from the vagal and pelvic
nerves resulting in increases in intestinal motility and secretion. Thus, fibers from
the PNS do not have direct vasomotor effects. However, activation of muscarinic
receptors via acetylcholine triggers release of nitric oxide (NO). Stimulation of NO
receptors results in vascular smooth muscle relaxation which in turn produces an
increase in mesenteric blood flow. Activation of visceral muscle and secretory units
may also have an indirect effect of increasing mesenteric blood flow.
Neurohumoral Control
There are two main groups of vasoactive substances contributing to neurohumoral
control.
The first group includes classical vasoconstrictor agents of the body. They can
be endogenously released or exogenously administered as pharmacologic agents.
Catecholamines
These are released in response to stresses, such as strenuous exercise. They can also
be administered exogenously in cases of shock. Higher levels of catecholamines
cause an increase in vascular resistance in the same manner as sympathetic
activation.
Angiotensin II
The renin-angiotensin system is activated in response to reduction in the extracellular fluid volume. This leads to increased production of angiotensin II, which in
turn causes a direct vasoconstriction of the mesenteric vasculature.
13 Physiology of the Mesenteric Circulation 117
Vasopressin
Loss of blood volume and hyperosmolarity result in the release of vasopressin
(anti-diuretic hormone) from the posterior pituitary gland. This leads to mesenteric
vasoconstriction and reduction of portal venous pressure.
The second group includes circulating paracrine and autocrine mediators. Histamine, bradykinin and prostaglandins (A, D, E and I) cause direct vasodilation as
mentioned above in the metabolic control section. Prostaglandin F
, however,
2a
causes direct vasocon striction. In contrast to the direct effect of the aforementioned
vasoactive substances, the gastrointestinal peptides cholecystokinin, secretin, and
gastrin mediate an indirect vasodilatory effect through prompting gastrointestinal
motility. Those peptides are endogenously and locally released during digestion
(Table 13.1).
The algorithm in Fig. 13.9 summarizes intrinsic and extrinsic control mechanisms of mesenteric blood flow.
Table 13.1 Endogenous vasoactive mediators of the mesenteric circulation
Constrictors Dilators
I. Vasoactive metabolites
#PCO
2
"PO
2
"pH #pH
II. Autonomic neuro-regulation
Sympathetic stimulation Parasympathetic stimulation
III. Neurohumoral control
Catecholamines (adrenaline and
noradrenaline)
Angiotensin II
Vasopressin
IV. Circulating paracrine and autocrine mediators
Constrictor prostaglandin (F
a
Gastrointestinal peptides indirectly mediate mesenteric vasodilation by promoting gastrointestinal
motility. Reused with permission from Matheson PJ, Wilson MA, Garrison RN. Regulation of
intestinal blood flow. J Surg Res. 2000;93(1):182–196. Copyright © Elsevier 2000
2a)
"PCO
2
#PO
2
Lactic acid
Adenosine
Nitric oxide
Dilator prostaglandins (A, D, E and I)
Histamine
Bradykinin
Gastrointestinal peptides (cholecystokinin, secretin
and gastrin)
a
118 S. Hashmi et al.
Fig. 13.9 Summarizes the main classes of intrinsic and extrinsic control mechanisms of
mesenteric blood flow
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.
Part IV
Role of Mesentery in Systemic
Medical Diseases