Purinergic Signalling in Pancreatic Islet Endothelial Cells - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 214

12.3.6 Islet Blood Flow Regulation

As mentioned above the pancreatic islets possess an autonomous blood flow reg-
ulation (Fig. 12.1). Although the islets constitute only approximately 1% of the
pancreas they account for 5-10% of total pancreatic blood flow [9, 45]. The
mechanisms for regulation of islet blood flow are complex and multifactorial, but
especially influenced by the ambient blood glucose concentration [9, 45]. Other
factors of importance include metabolism- and endothelium-derived factors, such
as adenosine, ATP and nitric oxide, as well as neurogenic modulation by sensors
located to vascular bed of the brain, intestines and liver [17, 45, 72]. The islet
blood flow is closely coupled to the -cell glucose metabolism and the accom-

panying release of insulin. After food intake, the glucose receptors in the brain
[46], intestine [15] and liver [16] transiently stimulate the islet blood flow, mainly
through the parasympathetic nerves [46]. During hyperlipidemia there is instead
an activation of the sympathetic nervous system, which increases islet blood flow
mainly through

β

β 3 -adrenoceptors (unpublished observation). However, within a few
minutes glucose-stimulation of the -cell metabolism generates islet blood flow

increase, with adenosine as the main vasodilator [17]. We have recently been able
to perfuse single islets with intact afferent arterioles (Fig. 12.2) [51, 52, 67]. The
results confirm that adenosine has a direct dilatory effect on arterioles [51]. So
far preliminary studies on intraluminally administered ATP have demonstrated a
vasoconstrictive effect when given at 100

β

M (Fig. 12.3). This contrasts to the
ATP-effects in skeletal muscle circulation, where it mediates exercise hyperaemia
[21, 61].
It is known that endothelial cells in capillary networks communicate via gap junc-
tions [42]. As a consequence pulses of depolarization are conducted both up and
downstream in the capillaries [62] and propagate to the arterioles and/or venules
[3]. It can be envisaged from the islet microvasculature that electrical coupling
between endothelial cells enables the capillaries to regulate the islet blood flow
by conducted responses to the arterioles. If this holds true, external ATP may
affect islet blood flow differently depending on whether it exerts the predomi-
nant action on endothelial cells or VSM. As mentioned above, we have observed
adenosine-induced vasodilation in isolated islet arteriolar VSM [51].
Purinoceptor regulation of islet microcirculation may involve release of
ATP from erythrocytes by mechanical deformation [77] and deoxygenation of
haemoglobin [43]. Together with ATP release from granulocytes [23], this is likely
to be a major determinant for the deranged microcirculation induced by hypoxia
and non-specific inflammation early after islet transplantations. Similar responses
are seen in damaged skeletal muscle [27, 76]. Non-specific inflammatory responses,
associated with local hyperemia, are amplified by immunological processes asso-
ciated with rejection. Accordingly, ATP may influence islet microcirculation in the
immediate post-transplantation period. Infiltration of leukocytes is frequently seen
with insulitis in the initial stages of type 1 diabetes. This insulitis is coupled to a
marked increase in islet blood flow [14, 18], and may well reflect the local release
of ATP.

μ