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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 4Extrinsic Vasoregulation: Neural and Humoral

4.1. NEURAL

4.1.1. Postganglionic Sympathetic

Neural regulation of small intestinal and colonic blood flow is generally achieved at the level of the submucosal arterioles, which are predominantly innervated by sympathetic fibers emanating from the celiac, superior mesenteric, and inferior mesenteric ganglia (Figure 4.1); parasympathetic innervation is negligible [118,119]. Sympathetic neural input is rather complex consisting of both divergent and convergent pathways, but in general, different fibers innervate specific portions of the microcirculation, i.e., arterioles and venules. Activation of sympathetic nerves elicits vasoconstriction of small mesenteric arteries primarily due to release of ATP and norepinephrine [120]. ATP appears to be more important with low-frequency stimulation of the nerves, while norepinephrine plays a greater role with high-frequency stimulation. By contrast, activation of sympathetic nerves induces vasoconstriction of submucosal arterioles primarily by release of ATP; a role for norepinephrine, if any, is in presynaptic modulation of neurotransmitter release [118].

FIGURE 4.1. Schematic of the extrinsic and intrinsic innervations of submucosal arterioles in the guinea pig small intestine.

FIGURE 4.1

Schematic of the extrinsic and intrinsic innervations of submucosal arterioles in the guinea pig small intestine. NE, norepinephrine; SOM, somatostatin; Ach, acetylcholine; VIP, vasoactive intestinal polypeptide; NPY, neuropeptide Y; SP, substance P; (more...)

During prolonged stimulation of the postganglionic sympathetic nerves, the resistance vessels begin to dilate with the result that gastrointestinal blood flow returns toward control levels despite continued nerve stimulation, a phenomenon termed “autoregulatory escape [121,122].” Autoregulatory escape has also been noted in mesenteric resistance vessels in vivo with norepinephrine administration: the more distal small diameter arterioles exhibiting a more pronounced response [123].Autoregulatory escape is generally believed to be due to intrinsic metabolic mechanisms overriding the neurogenic constriction [62]. This contention is supported by the observations that (1) autoregulatory escape is more pronounced in the more metabolically active mucosa than the muscularis [124],(2) gastric oxygen consumption is maintained during autoregulatory escape in the stomach [125], and (3) blockade of adenosine bioavailability attenuates the autoregulatory escape [126]. Sympathetic stimulation also induces venular constriction in the intestine and mesenteric venules [122,123]. However, unlike the response in resistance vessels, autoregulatory escape does not occur in venules [127]. From a systemic homeostasis point of view, this selective autoregulatory escape of resistance vessels within the gastrointestinal microcirculation is important. For example, during blood loss, the sympathetic-induced sustained venoconstriction allows for expulsion of a significant volume of blood into the systemic circulation, while resistance vessel escape allows for sufficient oxygen delivery to maintain organ function.

4.1.2. Sensory C Fibers

Sensory C fibers, whose cell bodies are located in the dorsal root ganglia (Figure 4.1), also have efferent limbs impinging on submucosal arterioles. When these nerves are activated by ligands (capsaicin) of the vanilloid receptor (TRPV1), they induce dilation of the submucosal arterioles via the co-release of SP and CGRP [118,128]. Species and/or regional differences seem to exist along the gastrointestinal tract, i.e., CGRP is the predominant peptide in sensory neurons of the rat stomach [129], while in the human colon, SP is the predominant neurotransmitter [130]. Further, although SP and CGRP have been the most studied neurotransmitters of these neurons, there is potential for a wider array of neurotransmitters [131]. CGRP can act directly on vascular smooth muscle to induce relaxation or can act via an interaction with the endothelium to induce an NO-mediated vasodilation [132]. Of interest is the fact that these capsaicin-sensitive C fibers are nociceptors responding to noxious chemical, mechanical, or thermal stimuli [133]. Thus, in addition to activating a local reflex vasodilation, they also pass on nociceptive information to the CNS.

In addition to the classical view that the afferent limbs of sensory C fibers are located within the mucosal interstitium, there is evidence that mesenteric resistance vessels may also be richly innervated with these C fibers [131,134]. This arteriolar neural reflex arc may modulate both the myogenic and metabolic intrinsic vasoregulatory mechanisms within the gastrointestinal tract. For example, the myogenic vasoconstriction in isolated mesenteric arteries is substantially blunted by ablation (capsaicin) of sensory C fibers, an effect also noted in arteries in which the endothelium was removed [134]. Based on pharmacologic and genetic blockade approaches, it was proposed that elevation of luminal pressure results in the generation of 20-HETE by smooth muscle, which subsequently activates TRPV1 (vanilloid receptor) on C fibers in the arteriole. The release of SP from the nerve terminals of these fibers interacts with NK1 receptors on smooth muscle cells causing contraction. This challenge to the current dogma that the myogenic response is an intrinsic property of vascular smooth muscle [52] cannot be readily dismissed, since a role for sensory C fibers has also been demonstrated in the myogenic response of isolated cerebral arteries [135]. C fibers have also been implicated in vasodilator responses in the gastrointestinal tract generally attributed to intrinsic metabolic regulatory mechanisms. Using capsaicin as a probe, these sensory C fibers have been implicated in reactive hyperemia in the intestine [136] and skin [137] as well as autoregulatory escape in the intestine [138] and the stomach [139]. These latter studies did not identify the neurotransmitters involved or characterize the reflex arc. Clearly, further studies are required to determine the circumstances under which these sensory fibers elicit vasodilation or vasoconstriction and why nociceptor nerves are involved in intrinsic vasoregulatory phenomenon.

4.1.3. Enteric Nerves

Gastrointestinal vasodilator neurons, whose cell bodies are located in the enteric ganglia, have been identified (Figure 4.1). The neurogenic vasodilation induced by these neurons is not affected by extrinsic denervation of the sympathetic supply or removal of the myenteric plexus [118,140].These neurons contain acetylcholine (Ach) and vasoactive intestinal polypeptide (VIP). In the small intestine, the intrinsic vasodilation has been attributed to acetylcholine release from nerve terminals and subsequent NO generation from endothelium, while in the colon, VIP is the predominant neurotransmitter. These fibers can be activated by mechanical or chemical stimuli to induce vasodilation [118].

4.2. CIRCULATING VASOACTIVE SUBSTANCES

The major endogenous circulating substances that impact on gastrointestinal microvascular tone are catecholamines, vasopressin, and angiotensin II. Basal intestinal microvascular tone is attributed to the endogenous circulating levels of these substances. There may be some species variability in their relative contributions to vascular tone, i.e., norepinephrine and vasopressin being more important in the rat [141], while vasopressin and angiotensin II are predominant in the cat [142]. Further, there appears to be a redundancy in the vasopressin and angiotensin II systems, i.e., when one is inhibited, the other compensates to maintain tone [142].

Exogenous administration of catecholamines induces either vasoconstriction or vasodilation depending on whether the predominant effect is on α- or β-adrenergic receptors. Norepinephrine, a predominantly α-adrenergic agonist, causes vasoconstriction and a decrease in intestinal blood flow [34,143,144]. As described above, during prolonged infusion of norepinephrine, the intestinal resistance vessels exhibit “autoregulatory escape.” Epinephrine at low doses induces vasodilation via β-adrenergic receptors and at high doses, vasoconstriction via α-adrenergic receptors [143,145,146].

In general, vasodilators increase Kf,c, while vasoconstrictors decrease Kf,c [28,42]. For example, isoproterenol increases intestinal blood flow and Kf,c, the increase in blood flow being directly correlated to the increase in Kf,c [147]. Since isoproterenol does not affect capillary permeability, the increase in Kf,c must be due to an increase in capillary exchange capacity (surface area). This observation, coupled to the responses of other vasodilators and vasoconstrictors, indicate that vascular elements controlling capillary surface area (precapillary sphincters) possess specific receptors for a wide variety of vasoactive agents [42]. Some vasodilators can increase microvascular permeability (e.g., histamine, bradykinin), while some vasoconstrictors (e.g., angiotensin II) can decrease permeability. Thus, unless estimates of capillary permeability are available, caution should be used in attributing changes in Kf,c solely to corresponding changes in capillary surface area.

The effects of vasoactive agents on gastrointestinal oxygen uptake are variable and dependent on either their (1) direct effects on tissue metabolism or (2) indirect effects on oxygen delivery and /or capillary density [69]. Figure 4.2 depicts the relationship between gastrointestinal oxygen uptake and blood flow (or O2 delivery) and circumstances that alter this relationship. Based on this theoretical template, a vasodilator that increases oxidative metabolism will take pathway A. For example, dinitrophenol, an uncoupler of mitochondrial oxidative phosphorylation, increases both blood flow and oxygen consumption [66]. A vasodilator that does not affect oxidative metabolism (e.g., isoproterenol) will take pathway B. Vasoconstrictors tend to reduce gastrointestinal oxygen uptake as depicted by pathway G, unless they also decrease capillary density, in which case they follow pathway F. For example, vasopressin and norepinephrine decrease blood flow, capillary density, and oxygen uptake [34]. By contrast, epinephrine can decrease blood flow and increase capillary density, yet not affect oxygen consumption (pathway H) [69]. Interestingly, after blockade of β-receptors, epinephrine decreased blood flow and oxygen uptake presumably by decreasing capillary density (pathway F) [145].

FIGURE 4.2. Relationship between oxygen uptake and blood flow (oxygen delivery).

FIGURE 4.2

Relationship between oxygen uptake and blood flow (oxygen delivery). The curves depicted represent a composite of those shown in Figure 3.4. Alterations in tissue oxidative metabolism shift the curve vertically, while alterations in perfused capillary (more...)

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53091

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