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Kvietys PR. The Gastrointestinal Circulation. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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The Gastrointestinal Circulation.

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Chapter 5Postprandial Hyperemia

5.1. GENERAL CHARACTERISTICS

It is well established that gastrointestinal blood flow increases after meals, a phenomenon referred to as postprandial or functional hyperemia [7,22,42,148,149]. The prevalence of this phenomenon is underscored by the demonstration of a postprandial hyperemia in man [150,151], monkeys [152], dogs [9,153155], cats [156], rats [157], snakes [158], and fish [159]. In general, ingestion of food results in a dual hemodynamic response within the gastrointestinal tract: an initial transient response during anticipation and ingestion of food and a subsequent prolonged response during digestion and absorption.

The anticipatory/ingestion phase is characterized by increases in heart rate, cardiac output, and aortic pressure with only minor changes in gastrointestinal vascular resistance [153,154]. These transient hemodynamic alterations can be (1) blunted by adrenergic blocking agents and (2) mimicked by allowing the animals to see and smell the food, but not allowed to ingest it [153]. Thus, this transient phase represents a sympathetic-driven cephalic phase.

The digestive/absorptive phase is characterized by a gastrointestinal hyperemia. In conscious animals, blood flow in the left gastric, celiac, and superior mesenteric arteries increases within minutes after ingestion of a meal [153,154,160,161]. Left gastric and celiac artery blood flow increases earlier and is transient (10–15 min), while superior mesenteric artery blood flow increases later and is more prolonged (up to several hours). The postprandial hyperemia is detected earlier in the jejunum (within 30 min) than the ileum (by 90 min) [9]. Collectively, these observations indicate that the postprandial hyperemia progresses along the gastrointestinal tract in association with the aboral movement of ingested food. The magnitude (25–200%) and the duration (3–7 h) of the hyperemia appear to depend on the composition of the meal. In general, lipid- and protein-rich meals are more potent than carbohydrate-rich meals in eliciting a hyperemia [152,156]. A cholinergic neural pathway has been proposed to be involved in the gastrointestinal postprandial hyperemia [152,153], but this neurogenic-mediated contribution to the hyperemia may be indirect, rather than direct (see below). In general, the characteristics of the gastrointestinal postprandial hyperemia in animals mimics those observed in humans [162,163].

5.2. LOCALIZATION OF THE POSTPRANDIAL HYPEREMIA

The bulk of experimental evidence indicates that the postprandial hyperemia is localized to that portion of the canine gastrointestinal tract exposed to food or hydrolytic products of food digestion [42,149,164]. Intragastric placement of undigested food increases celiac artery blood flow within minutes, followed by an increase in SMA blood flow [165]. Intrajejunal placement of digested food does not increase celiac artery blood flow, but increases SMA blood flow. These findings are in accord with observations in conscious animals. Further, intrajejunal placement of digested food or hydrolytic products of food digestion increases local blood flow without effecting blood flow to an adjacent segment [165,166]. In general, the nutrient-induced increase in intestinal blood flow appears to be confined to the mucosal layer of the gut wall [9,165,167,168]. However, there is experimental evidence to indicate that intraluminal food (or nutrients) increases blood flow to segments of the small bowel not exposed to chyme [155,156] and that the hyperemic response involves both the mucosal and muscularis layers of the bowel wall [84,157]. The reasons for the discrepancies are not clear, but a role for reflex motor activity in response to luminal nutrients is worth appraisal.

5.3. CONSTITUENTS OF CHYME RESPONSIBLE FOR THE POSTPRANDIAL HYPEREMIA

The constituents of chyme responsible for the postprandial hyperemia in the small intestine and colon are summarized in Figure 5.1 [42]. The constituents of chyme that elicit a local hyperemic response differ in different regions of the intestine. In the upper small intestine ( jejunum), intraluminal placement of digested food, but not undigested food, increases local blood flow (Figure 5.1), with a high fat test meal producing the greatest hyperemic response followed by the high protein and high carbohydrate diets [166,169]. Collectively, these findings indicate that the hydrolytic products of food digestion are responsible for the postprandial hyperemia in the upper small intestine.

FIGURE 5.1. Effects of intraluminal placement of various constituents of chyme on intestinal blood flow.

FIGURE 5.1

Effects of intraluminal placement of various constituents of chyme on intestinal blood flow. Used with permission from Handbook of Physiology, The Gastrointestinal System I, Chapter 39, 1989, pp. 1405–1474.

Intrajejunal placement of amino acids or peptides (at postprandial concentrations) did not affect local blood flow [166]. By contrast, intrajejunal glucose solutions produced a hyperemic response [166,170]. Emulsions of oleic acid (long-chain fatty acid) did not affect blood flow, unless oleic acid was solubilized with bile or bile salts, in which case, it produced a significant hyperemic response [166,171]. The hyperemic response to micellar oleic acid was dose-dependent; 40 mM oleic acid was twice as potent as 20 mM oleic acid. Bile-solubilized caproic acid (short-chain fatty acid) did not induce a hyperemia [172]. Bile (or bile salts) or pancreatic enzymes were ineffective in eliciting a hyperemic response. Collectively, these findings indicate that solubilized hydrolytic products of long-chain lipids and carbohydrates are the primary mediators of the intestinal postprandial hyperemia. However, based on the effects of mixed diets, a synergistic effect of all the hydrolytic products of food digestion cannot be discounted.

In addition to playing a permissive role in the oleic acid-induced hyperemia in the jejunum, bile appears to play an important direct role in the local postprandial hyperemia of the ileum (Figure 5.1). In the ileum, bile induces an increase in blood flow, the effect being mediated by bile salts. This contention is supported by the observations that (1) bile salts, rather than other constituents of bile, can induce a hyperemia similar to that seen with bile and (2) cholestyramine, a bile salt-sequestering agent, prevents the bile-induced ileal hyperemia [37].

A significant amount of carbohydrates (e.g., dietary fiber) can escape absorption in the small intestine and reach the colon where bacterial fermentation converts them to volatile fatty acids. The major volatile fatty acids present in the colon are acetic, propionic, and butyric acids. Intracolonic placement of acetic acid increased local colonic blood flow; butyric or propionic acids were without effect [173].

5.4. MECHANISMS INVOLVED IN THE POSTPRANDIAL HYPEREMIA

Secretory, absorptive, and motor activity are all important functions of the gastrointestinal tract required for efficient assimilation of ingested nutrients. Thus, the mechanisms involved in the postprandial gastrointestinal hyperemia may be quite complex and are not as yet clearly defined. However, several potential mechanisms have been implicated in the hyperemia, including extrinsic and enteric nerves, circulating hormones, and tissue metabolic activity [22,42,149,164].

5.4.1. Extrinsic Nerves

Aside from the initial systemic hemodynamic response during the anticipation/ingestion of food, adrenergic blockade does not influence the postprandial gastrointestinal hyperemia. However, cholinergic nerves have been proposed to be involved in the gastrointestinal postprandial hyperemia [22,42]. The specific neural pathways may be different for the hyperemic response in the stomach and intestines. Vagotomy, but not atropine, blocks the gastric (celiac artery) hyperemia [160,161], while atropine, but not vagotomy, blocks the intestinal (superior mesenteric artery) hyperemia [22,152,153,160]. The role of cholinergic nerves in the gastrointestinal hyperemia, however, may be indirect. Effective assimilation of ingested food is a multistep process. In the stomach, food is partially digested by gastric acid and lipases and then emptied into the small intestine. In the small intestine, progressive digestion and solubilization of the hydrolytic products is facilitated by pancreatic and biliary secretions. All of these processes can be severely blunted by cholinergic blockade. Thus, the cholinergic modulation of the gastrointestinal hyperemia may simply be a result of the inhibition of appropriate processing and delivery of nutrients to absorptive sites. In support of this possibility are the observations that (1) introduction of solubilized products of food digestion into the upper small intestine induces a local hyperemia, while undigested food does not [166], extrinsic denervation of the intestine does not prevent the intestinal hyperemia induced by luminal nutrients [174] and (2) atropine does not block the hyperemic response to predigested food [174,175].

5.4.2. Enteric Neural Reflexes

There also appears to be some support for the role of local enteric nerves in the postprandial hyperemia. The postprandial gastric hyperemia is prevented by anesthetizing (oxethazaine) the gastric mucosa [161]. Mechanical stimulation of the small intestinal mucosa elicits a local vasodilation that is mediated by a noncholinergic, nonadrenergic (NANC) enteric reflex, which can be blocked by tetrodotoxin [176,177]. The mechanical stimulation of the mucosa with a plastic object has been taken to simulate the movement of chyme along the intestine [149]. However, the results of studies with digested food, or hydrolytic products thereof, cast doubt on the potential role of enteric nerves in the postprandial intestinal hyperemia. As mentioned above, intrajejunal placement of digested food, but not undigested food, induces a local hyperemic response [166]. Thus, unlike mechanical stimulation of the mucosa with coarse foreign material, a simple mechanical interaction of foodstuff with the mucosa does not induce a hyperemia. Introduction of digested food, glucose, or micellar oleic acid into isolated jejunal segments produces a local hyperemia, which is not affected by tetrodotoxin or hexamethonium [174]. The ability of local anesthesia of the mucosa to inhibit the local hyperemia to hydrolytic products of food digestion may also be indirect. For example, the hyperemic response to hydrolytic products of food digestion could be blocked by dibucaine, an effect attributed to the inhibition of transport processes of the mucosa rather than decreased activity of local nerves [80,174].

5.4.3. Circulating Hormones

Various gastrointestinal hormones and neuropeptides are released into the circulation postprandially, including gastrin, secretin, cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), neurotensin, and substance P. Since all of these peptides are vasodilators in the gastrointestinal circulation, it has been proposed that one or more of them may contribute to the postprandial hyperemia [22,149,156]. However, in general, their role in the postprandial intestinal hyperemia has been dismissed based on the fact that their vasodilator effects are only apparent when they are administered at doses 10–100 times greater than those measured in the circulation postprandially [149,178181]. However, circulating levels of these hormones may only represent a fraction of the levels in the interstitium where they are generated adjacent to intestinal resistance vessels. To illustrate this point is the case of VIP [181]. To elicit a jejunal hyperemia, VIP had to be administered at 10 times the concentration measured in the venous effluent from jejunal segments containing micellar oleic acid. Yet, antisera to VIP reduced the hyperemic response to micellar oleic acid. Another reason for eliminating a role for a given hormone released after meals is its effects on intramural blood flow distribution [149]. For example, intravascular administration of neurotensin to achieve postprandial concentrations, increased muscularis, but not mucosal, blood flow in the ileum [182]. This is analogous to excluding adenosine as potential mediator of metabolic regulation based on arterial infusion to a multicompartmental organ (see 3.4.2). Thus, although it is generally accepted that circulating gastrointestinal peptides play a minor role (if any) in the postprandial hyperemia, their potential paracrine contribution has not been systematically addressed.

5.4.4. Tissue Metabolic Activity

An increase in splanchnic oxygen consumption (O2 demand) and blood flow (O2 delivery) after a meal has been demonstrated in man [151]. The increase in blood flow is presumed to be a result of the increased O2 requirements for efficient digestion and absorption of ingested food. Secretory and absorptive activity is generally confined to the mucosa, while propulsive motor activity is the responsibility of the muscularis. In general, gastric mucosal blood flow increases with enhanced acid secretion [78] and intestinal mucosal blood flow increases during absorption of nutrients, [166] while muscle blood increases during enhanced rhythmic contractions of the gut [11]. Thus, the postprandial (functional) gastrointestinal hyperemia is a rather complex phenomenon involving alterations in the relative distribution of blood flow between the mucosal and muscularis compartments at any given time. Thus, investigative approaches have tended to isolate these activities (solute transport vs motility) when addressing the role of metabolic factors in the postprandial hyperemia.

Solute Transport. Gastric oxygen consumption (O2 demand) increases during stimulation of acid secretion by secretagogues (e.g., gastrin, histamine) [65,78,183,184]. Oxygen uptake of the small and large intestine increases during absorption of nutrients or transportable solutes [56,76,80,173]. Indeed, a direct correlation between the rate of solute transport and local oxygen consumption has been demonstrated in isolated preparations of the stomach [184,185], small intestine [39,170], and colon [56].

In most cases, there is an increase in regional blood flow associated with enhanced functional activity; however, there are some exceptions. While histamine-induced gastric acid secretion is associated with an increase in gastric blood flow, pentagastrin-induced gastric acid secretion may not be associated with a local hyperemic response [186]. Similarly, glucose absorption by the intestine can increase oxygen uptake, yet have variable effects on blood flow [39]. According to the metabolic theory, an increase in tissue oxygen demand can be met by changes in either blood flow (resistance vessel regulation) or oxygen extraction (exchange vessel regulation). One determinant of whether resistance vessel or exchange vessel regulation predominates is the level of existing oxygen extraction or (AV )O2 (Figure 5.2) [44]. If the prevailing (AV )O2 is low, then the increase in postprandial oxygen demand is met primarily by increases in O2 extraction. If the prevailing (AV )O2 is high, then the postprandial oxygen demand is met by increases in intestinal blood flow. Another confounding factor is the vasoactive properties of the agent used to enhance functional (metabolic) activity. For example, histamine is a potent secretagogue and vasodilator, and increasing doses of histamine increase both gastric oxygen uptake and blood flow. Thus, according to the relationship between oxygen uptake and blood flow (or O2 delivery), histamine should follow pathway A of the relationship depicted in Figure 4.2.

FIGURE 5.2. Relationships between changes in intestinal arteriovenous oxygen difference (upper panel) and blood flow (lower panel) in response to increases in oxygen demand imposed by instillation of digested food in the lumen.

FIGURE 5.2

Relationships between changes in intestinal arteriovenous oxygen difference (upper panel) and blood flow (lower panel) in response to increases in oxygen demand imposed by instillation of digested food in the lumen. Solid circles represent responses when (more...)

According to the metabolic theory, the link between oxygen demand and intrinsic regulation of resistance and exchange vessels is provided by local changes in tissue pO2 and /or adenosine. Application of glucose to the mucosal surface reduces villus pO2 and increases blood flow to the villus via the submucosal arteries [84]. Further, the glucose-induced hyperemia is diminished when villus pO2 is stabilized by exogenous delivery of O2 via the luminal aspect of the mucosa [83]. However, submucosal arteries also dilate during luminal application of glucose, even though perivascular pO2 in this region is unchanged. In the case of adenosine, it is released from the small intestine (into the draining vein) when digested food is placed in the lumen [88]. However, blockade of adenosine bioactivity produced equivocal results with respect to attenuating the hyperemic response to luminal digested food [89,90].

NO has also been implicated in the postprandial gastrointestinal hyperemia. Blockade of eNOS blunts both the gastric hyperemia associated with pentagastrin-induced acid secretion [97,106] and the intestinal hyperemia associated with glucose absorption [187]. In the small intestine, glucose absorption is associated with increases in NaCl hyperosmolarity at the level of the submucosal arterioles and larger feeding arteries [188]. The hyperosmolarity-induced vasodilation in the submucosal vessels is partially inhibited by blockade of eNOS [104]. Based on pharmacologic blockade approaches, it has been proposed that an increase in intracellular Ca++ levels via the Na+/Ca++ exchanger is crucial for the hyperosmolarity-induced increase in endothelial cell production of NO [105]. Collectively, the information available on the role of NO in the absorptive hyperemia provides a potential feedback link by which microvascular adjustments are regulated during intermittent periods of absorptive activity. Specifically, the increased NaCl hyperosmolarity would lead to NO production and resistance vessel dilation. The vasodilation would then wash out the hyperosmolarity and remove the stimulus for NO production, thereby closing the feedback loop.

Motor Activity. Although in isolated visceral smooth muscle (Taeniae coli) enhanced contractile activity is associated with increases in oxygen consumption [189], in isolated perfused preparations of the small intestine, increases in motility have unpredictable effects on blood flow and oxygen consumption [190192]. This may be a result of the capricious nature of motor activity in the small intestine, being of the rhythmic or tonic type or a combination of both at any given time. Rhythmic contractions can passively affect blood flow through intermittent compression of blood vessels, decreasing blood flow during the contractile phase and increasing blood flow during the relaxation phase [193]. Tonic contractions tend to decrease small intestinal blood flow due to vessel compression. When the influence of tonic contractions is minimized, a positive correlation is obtained between the level of intestinal motility and oxygen consumption [38]. When a vasoconstrictor (met-enkephalin) was used to stimulate motility, the increase in oxygen uptake was met entirely by an increase in (AV )O2. Alternatively, when a vasodilator (acetylcholine) was used, the increase in oxygen demand was met by increases in blood flow. Thus, according to the relationship between oxygen uptake and blood flow (or O2 delivery) depicted in Figure 4.2, met-enkephalin follows pathway I, while acetylcholine follows pathway A.

Little is known regarding the mediators which link the oxygen requirements of enhanced motor activity to the regulation of resistance or exchange vessels. However, based on studies in other vascular beds supplying muscular tissue, such as heart and skeletal muscle [194,195], tissue pO2, adenosine, and NO may be likely candidates. Studies are warranted to directly address this issue.

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53094

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