Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden
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ABSTRACT |
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This study investigated the mechanisms for glucose-induced islet blood flow increase in rats. The effects of adenosine, adenosine receptor antagonists, and vagotomy on islet blood flow were evaluated with a microsphere technique. Vagotomy prevented the islet blood flow increase expected 3, 10, and 20 min after injection of glucose, whereas theophylline (a nonspecific adenosine receptor antagonist) prevented the islet blood flow increase from occurring 10 and 20 min after glucose administration. Administration of selective adenosine receptor antagonists suggested that the response to theophylline was mediated by A1 receptors. Exogenous administration of adenosine did not affect islet blood flow, but local accumulation of adenosine, induced by the adenosine uptake inhibitor dipyridamole, caused a doubling of islet blood flow. In conclusion, the increased islet blood flow seen 3 min after induction of hyperglycemia is caused by the vagal nerve, whereas the increase in islet blood perfusion seen at 10 and 20 min after glucose administration is caused by both the vagal nerve and adenosine.
adenosine; microcirculation; microspheres; pancreas; vagus nerve
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INTRODUCTION |
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THE PANCREATIC ISLETS are metabolically very active and have a high oxygen consumption, which is coupled to nutrient-stimulated insulin release (20, 22, 49). To ensure an adequate supply of oxygen, the islets have a high basal blood flow, which can be increased when insulin release is stimulated, e.g., by hyperglycemia (7, 25). This blood perfusion increase has been shown to depend on the vagus nerves (28, 43). Teleologically, the increased islet blood flow can be envisaged as reflecting an attempt to increase the availability of the islet hormones. Previous studies of islet blood perfusion after glucose administration have been focused mainly on the increase during the first few minutes after glucose administration, i.e., during the time when islet metabolism begins to increase. However, islet blood flow remains elevated for 25 min after a bolus dose of glucose (25) and as long as hyperglycemia is maintained during chronic glucose infusions (42). We have recently observed (unpublished observation) that hyperglycemia increases islet blood flow in the denervated transplanted whole pancreas in rats 10 min after induction of hyperglycemia, whereas no such effect is seen at earlier time points (29). This suggests that, in addition to the nervous induction of islet blood hyperperfusion during hyperglycemia, there are also other factors involved in the glucose-induced islet blood flow increase.
Of interest in this context is the finding that islet cells metabolically activated by glucose have an increased ATP production (45). It could be anticipated that the simultaneously increased ATP-consuming processes of insulin synthesis and exocytosis may yield increased local adenosine concentrations. Formed adenosine has also been suggested to be a mediator in metabolically induced vasodilation when ATP utilization outstrips supply (13, 15, 24). Indeed, adenosine has been suggested to be involved in the metabolic regulation of blood flow in the heart, brain, skeletal muscle, and intestines (2, 3, 13, 16, 23, 24, 50). It is therefore tempting to speculate that adenosine, especially in view of its formation during glucose metabolism, can also be involved in the regulation of pancreatic islet blood flow. The aims of the present investigation were, therefore, to evaluate whether adenosine is involved in glucose-stimulated islet blood flow and to what extent such effects might depend on the formation of nitric oxide. To separate any effects of adenosine from those mediated by the nervous system, the experiments were designed to evaluate the dynamics of these processes.
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MATERIALS AND METHODS |
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Animals. Male Sprague-Dawley rats obtained from a local breeding colony (Biomedical Center, Uppsala, Sweden) and weighing ~325 g were used in all experiments. The animals had free access to tap water and pelleted rat food. Approval of the experiments had been obtained from the local animal ethics committee.
Surgical preparation.
The rats were anesthetized with an intraperitoneal injection of
pentobarbital sodium (60 mg/kg body wt; Apoteket, Umeå, Sweden), heparinized, tracheostomized, and placed on a heated operating table to
maintain a body temperature of 37°C. Polyethylene catheters were
inserted into the ascending aorta, via the right common carotid artery,
into the right femoral artery and into both femoral veins. The aortic
catheter was connected to a pressure transducer (PDCR 75/1; Druck,
Groby, UK) to allow constant monitoring of the mean arterial blood
pressure. The catheters in the veins were used to administer drugs and
to continuously infuse Ringer solution (5 ml · kg1 · h
1), respectively.
Vagotomy and glucose administration. The abdominal cavity of some animals was opened with a midline incision. The vagus nerve fibers were identified immediately below the diaphragm and divided. Special care was taken to identify and divide the hepatic branch at its origin from the anterior vagal trunk and the celiac branches from the posterior trunk (31). These denervations were performed with the aid of a microscope to facilitate visualization of all nerve fibers. Approximately 20 min after the vagotomy, an intravenous injection of 1 ml of saline or 30% (wt/vol) D-glucose was given. Blood flow measurements were then performed 3, 10, or 20 min after the injection.
Administration of adenosine receptor antagonists and glucose. The animals were treated with 1 ml of saline or 30% (wt/vol) D-glucose intravenously 3, 10, or 20 min before blood flow measurements. Furthermore, the animals were given an intravenous injection of 0.2 ml of saline or theophylline (6 mg/kg body wt; Sigma Aldrich, St. Louis, MO) 3 min before the blood flow measurements. Among its other pharmacological effects, theophylline is a nonspecific adenosine receptor antagonist (46). To exclude possible effects of theophylline-induced phosphodiesterase inhibition, we administered the theophylline analog 3-propylxanthine (6 mg/kg body wt; Sigma), which has only minimal adenosine antagonist properties but intact phosphodiesterase effects (1), to separate animals. Blood flow measurements were then performed 10 min after administration of saline or glucose (see Blood flow measurements).
Separate animals, given saline or glucose, as described, 10 min before the blood flow measurements, were instead injected intravenously with 0.2 ml of either 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 300 µg/kg body wt; Sigma Aldrich), 3,7-dimethyl-1-propargylxanthine (DMPX; 150 µg/kg body wt; Sigma Aldrich), or the vehicle dimethyl sulfoxide (DMSO; Sigma Aldrich) 10 min before blood flow measurements. DPCPX and DMPX inhibit A1 and A2 receptors, respectively (35).Adenosine infusions.
These animals were injected intravenously with 0.2 ml of either saline
or NG-methyl-L-arginine methyl ester
(L-NAME, 10 mg/kg body wt; Sigma Aldrich) 15 or 16 min
before the blood flow measurements. L-NAME is a nonspecific
nitric oxide synthase inhibitor and thereby prevents any nitric
oxide-mediated changes in blood flow induced by adenosine. A 10-min
infusion (0.1 ml/min) with saline or adenosine (0.6 mg · kg1 · min
1; Sigma
Aldrich) was commenced 5 min after administration of saline or
L-NAME. Pilot experiments with administration of adenosine at a dose of 0.2 mg · kg
1 · min
1 were also
performed (n = 8), but no consistent effects on blood perfusion were observed (data not shown). Immediately, or 1 min, after
the end of the 10-min infusion, the blood perfusion of the whole
pancreas and the islets was measured with microspheres (see Blood
flow measurements). We chose to measure the blood flow at these
two time points, because adenosine produced a hypotension, which was
followed by a rebound hypertension immediately after the infusion was
ended (see RESULTS and Table 3 for further details).
Dipyridamole administration. The rats were injected intravenously with 0.2 ml of saline or dipyridamole (1 mg/kg body wt; Sigma Aldrich) 10 min before blood flow measurements with microspheres. Dipyridamole prevents the reuptake of released adenosine into cells by blocking the low Michaelis-Menten system for adenosine transport (32, 41, 48) and thereby induces a local accumulation of this substance, which is proportional to the released quantity.
Blood flow measurements. Whole pancreatic and islet blood flows were measured with a nonradioactive microsphere technique, as previously described in detail (26, 27). Briefly, ~1.5 × 105 nonradioactive microspheres (NEN-Trac; Du Pont Pharmaceuticals, Wilmington, DE), with a diameter of 11 µm, suspended in 0.2 ml of saline were injected via the catheter in the ascending aorta. Starting 5 s before the microsphere injections and continuing for 60 s, an arterial reference sample was obtained from the catheter in the right femoral artery at a rate of ~0.25 ml/min. The exact withdrawal rate was determined in each case by weighing the sample.
The rats were killed after the reference sample was secured, and the pancreas and both adrenal glands were removed, blotted, and weighed. The microsphere contents present in these organs were determined separately (26). The pancreatic islets were visualized with a freeze-thaw technique, and the number of microspheres in the islets and exocrine parenchyma was counted as previously described (26). The adrenal glands were used as a control to ascertain a complete mixture of the microspheres in the arterial circulation, and only those animals with differences in total microsphere content of <10% between the two glands were included in the study. This criterion led to the exclusion of a total of five animals. The microsphere content of each of the arterial reference samples was determined by transferring the samples to glass microfiber filters (pore size <0.2 µm) and counting the microspheres in a stereo microscope. The organ blood flow values were calculated according to the formula: Qorg = Qref × Norg/Nref, where Qorg denotes organ blood flow (ml/min), Qref the withdrawal rate of the reference sample (ml/min), Norg the number of microspheres present in the organ, and Nref the number of microspheres present in the reference sample.Measurements of blood glucose and serum insulin concentrations. Arterial blood samples were obtained after the reference blood sample was secured and were later analyzed for blood glucose (Medisense; Baxter Travenol Laboratories, Deerfield, IL) and serum insulin concentrations [Pharmacia insulin RIA kit (Pharmacia-Upjohn Diagnostics Sverige, Uppsala, Sweden); rat insulin (Novo Nordisk, Bagsværd, Denmark) as a standard].
Statistical analysis. All values are given as means ± SE. For normally distributed data, probabilities of chance differences between the experimental groups were calculated with one-way ANOVA with Bonferroni's correction; otherwise a nonparametric ANOVA with Dunn's correction was applied (Sigmastat for Windows; SPSS, Erkraft, Germany). When only two groups were compared, Student's unpaired t-test was used. A value of P < 0.05 was considered to be statistically significant.
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RESULTS |
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Effects of vagotomy or administration of theophylline on the
response to glucose.
Blood glucose and serum insulin concentrations were increased at 3, 10, and 20 min after glucose injection in otherwise untreated animals
(Table 1). Vagotomy further increased
blood glucose concentrations as measured after 10 and 20 min in
glucose-treated rats and also increased blood glucose concentrations in
saline-treated rats (Table 1). Serum insulin concentrations were not
influenced by the vagotomy in any of the groups, except for a decreased
concentration in the glucose-injected rats 3 min after glucose
administration (Table 1). Blood glucose concentrations were unaffected
by theophylline administration in both saline- and glucose-treated
rats, with the exception of a slightly higher value seen 20 min after
saline treatment (Table 1). The insulin response to saline or glucose administration was unaffected by theophylline at the time points studied (Table 1). In the vagotomized animals, mean arterial blood
pressure was increased 3 min after glucose administration and 20 min
after saline administration (Table 1). An increase in mean arterial
blood pressure was also seen in theophylline-injected animals 3 min
after saline administration (Table 1).
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Effects of selective adenosine receptor inhibitors on the response
to glucose.
Mean arterial blood pressure, blood glucose, or serum insulin
concentrations were not affected by DMPX (A2 receptor
antagonist) or DPCPX (A1 receptor antagonist) compared with
saline- or glucose-injected rats given only the vehicle DMSO (Table
2).
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Effects of adenosine.
Infusion of adenosine induced an increase in both blood glucose and
serum insulin concentrations, which was seen both immediately after the
infusion and 1 min later (Table 3).
Pretreatment with L-NAME, a nitric oxide synthase
inhibitor, did not affect this response in blood glucose to adenosine.
However, L-NAME prevented the increase in serum insulin
concentrations induced by adenosine, although not affecting the rebound
increase in insulin concentration seen 1 min after the adenosine
infusion was ended. In saline-infused rats, L-NAME
pretreatment effected a slight decrease of both blood glucose and serum
insulin concentrations. The mean arterial blood pressure was markedly
decreased by the adenosine infusion, but a rebound hypertension was
consistently seen after the infusion was ended (Table 3).
L-NAME markedly increased mean arterial blood pressure in
otherwise untreated control rats but only partially prevented the
adenosine-induced decrease in blood pressure. A rebound hypertension
was seen also in L-NAME-treated rats.
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Effects of dipyridamole.
No effects on mean arterial blood pressure, blood glucose, or serum
insulin concentrations were seen after administration of dipyridamole
(data not shown). Whole pancreatic blood flow remained unaffected
[0.48 ± 0.04 vs. 0.48 ± 0.08 ml · min1 · g pancreas
1 in
dipyridamole (n = 7)- and saline-injected
(n = 6) rats, respectively], whereas islet blood flow
was doubled after dipyridamole injection [88 ± 10 vs. 43 ± 5 µl · min
1 · g pancreas
1
in dipyridamole (n = 7)- and saline-injected
(n = 6) rats, respectively; P < 0.001 with Student's unpaired t-test].
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DISCUSSION |
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In the present experiments, we confirmed previous findings (25) that a bolus intravenous glucose injection leading to initial blood glucose concentrations exceeding 20 mmol/l preferentially increases islet blood flow as measured at 3, 10, and 20 min after injection. A previous abdominal vagotomy prevented the islet blood flow increase at all of these time points. The new and somewhat surprising finding in the present study was that the glucose-induced islet blood flow increase, as recorded at 10 and 20 min after glucose injection, could also be inhibited by blocking adenosine receptors with theophylline. The tentative interpretation of these findings is that, even though an intact vagus nerve is needed for glucose to initially stimulate islet blood flow, adenosine adapts the blood flow to more long-term local needs. It can indeed be envisaged that the nervous system initiates an anticipatory increase in islet blood flow in preparation for the expected increase in islet metabolism and hormonal release. To adjust this increased blood perfusion to the actual needs of the islets, the hyperperfusion of blood may then be maintained by increases in local metabolite concentrations, which affect only islet arterioles without influencing total pancreatic blood flow.
Purinergic receptors are known to be present in the pancreas and to
affect both the vascular response of the pancreatic vascular bed and
insulin and glucagon release (4, 11, 12, 21, 34, 40).
Furthermore, adenosine can be taken up by -cells (48)
and is likely to be present in the extracellular space of the islets
during glucose metabolism. Indeed, the prevention of uptake of
endogenously produced adenosine has been shown to affect islet function
(48). The possibility that theophylline may induce other
effects in the islets leading to a secondary change in islet blood flow
cannot be completely ruled out. However, the unchanged islet blood flow
after administration of 3-propylxanthine, which inhibits
phosphodiesterase but has almost no adenosine antagonist properties, to
hyperglycemic animals suggests that phosphodiesterase effects are
unimportant in this context. Furthermore, the effects of administration
of selective A1 and A2 receptor antagonists indicated that the theophylline effects were caused by adenosine receptor antagonism. Surprisingly, we found that administration of a
selective A1 receptor antagonist completely abolished the increased islet blood perfusion seen after glucose administration, whereas an A2 antagonist did not. Previous studies on the
influence of adenosine on the splanchnic circulation, including the
pancreas, have unequivocally demonstrated that the vasodilating effects are mediated by A2 receptors (18, 24).
However, a vasodilator response mediated by A1 receptors
exists in other vascular beds, e.g., the diaphragm (14)
and other skeletal muscle (8, 9, 38).
Intravenous infusion of exogenous adenosine led to a pronounced
increase in total pancreatic blood flow, whereas islet blood flow
remained unchanged. The former finding confirms previous experiments in
vivo (24) and in vitro (19, 21). When uptake of adenosine was prevented with dipyridamole, however, only islet blood
flow increased, whereas total pancreatic blood flow remained unaffected. The discrepancies between these findings when adenosine or
dipyridamole are given are likely to reflect differences in local
availability of adenosine to islet afferent arterioles. The islet
arterioles deviate from intralobular pancreatic arteries and usually
provide its tributaries only to the endocrine tissue, whereas the small
arteries supplying the exocrine tissues are more numerous and totally
separate from the former (7, 44). The arterioles
presumably branch into capillaries after entering the -cell core of
the islets, meaning that the distal portion of the arterioles is
surrounded by islet cells, i.e., they are likely to be influenced by
substances produced locally within the islets (6). In view
of this vascular anatomical organization, it is likely that the
generalized intrapancreatic vasodilation induced by exogenous adenosine
administration opens up more arterioles in the exocrine than in the
endocrine parenchyma. This leads to a steal of blood from the islets to
the acini due to the higher number of arterioles in the latter. Indeed,
similar findings have been made in the gut after administration of
adenosine (17, 39) and in the pancreas after injection of
other general vasodilators such as terbutaline (25).
Dipyridamole, on the other hand, leads to an increase in local
adenosine concentrations, which are proportional to the amount of the
substance formed within the tissues. The islets are highly
metabolically active and therefore release more adenosine than the
exocrine parenchyma (22). Furthermore, it can be
speculated that the islets under basal conditions, in view of their
higher partial pressure of oxygen (10), contain less adenosine. The sensitivity of the islet vasculature to adenosine may
therefore be higher, although this notion is conjectural.
It should be noted that administration of the nitric oxide synthase inhibitor L-NAME markedly decreased whole pancreatic and islet blood flow in control animals, whereas an increase in islet blood flow and an unchanged pancreatic blood flow were seen instead when L-NAME was given in conjunction with adenosine. These findings suggest, first, that adenosine does not affect the pancreatic vasculature by stimulating A2 receptors on the endothelial cells, thereby inducing the formation and release of nitric oxide (33, 36). This is in accord with previous findings in the rat isolated mesenteric arterial bed (37). Second, it implies that nitric oxide is not necessary for the adenosine-induced vasodilation to occur. This is of interest, because we have previously demonstrated a pronounced dependence of an intact nitric oxide production especially to maintain islet blood perfusion (43). The finding of an increased islet blood flow after combined adenosine and L-NAME administration suggests that adenosine does indeed exert a direct effect also on the islet vasculature that is potent enough to overcome the otherwise prominent blood flow decrease induced by the lack of nitric oxide.
A pronounced rebound hypertension was seen after the adenosine infusion
was discontinued, probably reflecting a widespread systemic
vasoconstriction. The mechanisms behind this are unknown, even though
it can be suspected that it is, at least partially, caused by increased
sympathetic activity. When we examined to what extent this influenced
the circulation of the pancreas, we found a marked decrease in total
pancreatic, but not in islet, blood flow. Incidentally, this lends some
support to the notion that the sympathetic nervous system is involved
in this response, since we have previously shown that islet blood
perfusion is less sensitive to -adrenergically mediated
vasoconstriction than the exocrine pancreas (30). These
experiments also confirmed our previous findings that islet blood flow
remains fairly constant despite changes in perfusion pressure, i.e., it
is autoregulated to a much higher degree than that of the whole
pancreas (25). However, in the
L-NAME-pretreated rats, the decrease in whole pancreatic
blood flow during rebound hypertension was more pronounced, and a very
marked decrease in islet blood flow was observed. The islet blood flow
values seen were among the lowest so far recorded in adult rats,
suggesting a synergistic effect between inhibited nitric oxide
production and the mechanisms behind the rebound vasoconstriction.
Infusion of adenosine led to hyperglycemia in all animals. This is
likely to reflect the glucagon release induced by adenosine (18,
47). The hyperinsulinemia seen in the animals is probably due to
the hyperglycemia per se. However, adenosine in itself may further
stimulate the effects on insulin release by agents increasing -cell
cAMP concentrations (5) and may thus contribute to insulin
release by potentiating effects of glucagon. The increased insulin
concentrations are unlikely to affect islet blood flow (25), whereas the hyperglycemia would rather tend to
increase islet blood flow without affecting total pancreatic blood
flow, since its magnitude is at the threshold for stimulation of islet blood flow (25). Because an unchanged islet blood flow was
seen after adenosine infusion in control rats, we deem it unlikely to
be of major importance.
It is concluded that the initial increase in islet blood flow seen after induction of hyperglycemia is caused by the nervous system, as previously suggested (25), whereas the maintenance of the increased blood perfusion demands an additional, metabolically mediated signal. Adenosine seems to be of importance in this context, most probably by actions on A1 receptors. These findings once again emphasize the versatility of the mechanisms behind the glucose-induced islet blood flow response and thereby further underline that this response is of crucial importance for normal islet function.
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ACKNOWLEDGEMENTS |
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The skilled technical assistance of Astrid Nordin is gratefully acknowledged.
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FOOTNOTES |
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The study was supported by grants from the Swedish Medical Research Council (72X-109), the Juvenile Diabetes Research Foundation, Novo Nordic Research Fund, the Swedish-American Diabetes Research Program funded by the Juvenile Diabetes Research Foundation and the Wallenberg Foundation, the Swedish Diabetes Association, the Swedish Society of Medicine, Svenska Barndiabetesfonden, Jeanssons Foundation, Magnus Bergvalls Foundation, Thurings Foundation, Lars Hiertas Memorial Foundation, Goljes Memorial Foundation, and the Family Ernfors Fund.
Address for reprint requests and other correspondence: P.-O. Carlsson, Dept. of Medical Cell Biology, Biomedical Center, Box 571, SE-751 23 Uppsala, Sweden (E-mail: Per-Ola.Carlsson{at}medcellbiol.uu.se).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
April 30, 2002;10.1152/ajpendo.00044.2002
Received 1 February 2002; accepted in final form 25 April 2002.
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