Journal of Surgical Research 93, 182–196 (2000) doi:10.1006/jsre.2000.5862, available online at http://www.idealibrary.com on RESEARCH REVIEW Regulation of Intestinal Blood Flow Paul J. Matheson, Ph.D.,*,†,1 Mark A. Wilson, M.D., Ph.D.,*,†,‡ and R. Neal Garrison, M.D.*,†,‡ *Center for Excellence in Applied Microcirculatory Research and ‡Department of Surgery, University of Louisville, Louisville, Kentucky 40292; and †Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40206 Submitted for publication July 29, 1999 arteries is typically 20–25% of cardiac output in the The gastrointestinal system anatomically is posi- unfed state [2]. There is extensive overlap or collateral tioned to perform two distinct functions: to digest and circulation in the distal vascular distributions of these absorb ingested nutrients and to sustain barrier func- arteries. During nutrient absorption, blood flow in each tion to prevent transepithelial migration of bacteria of these arteries is increased sequentially as the diges- and antigens. Alterations in these basic functions con- tive chyme passes over the mucosal surface supplied by tribute to a variety of clinical scenarios. These pri- mary functions intrinsically require splanchnic blood the particular arteries [3]. Following nutrient absorp- flow at both the macrovascular and microvascular lev- tion, the blood flow to each segment returns to baseline els of perfusion. Therefore, a greater understanding of levels as the chyme moves past that region of the the mechanisms that regulate intestinal vascular per- digestive tract [4, 5]. This postprandial increase in fusion in the normal state and during pathophysiolog- blood flow is independent of organ distention and is ical conditions would be beneficial. The purpose of solely dependent on the composition of the chyme [6, 7]. this review is to summarize the current understand- The intraorgan distribution of blood flow within the ing regarding the regulatory mechanisms of intestinal tissue layers of the intestine is not uniform [3] and blood flow in fasted and fed conditions and during appears to correspond to the functional importance of pathological stress. © 2000 Academic Press the tissue layer. In unfed animals at rest, blood flow to Key Words: regional blood flow; postprandial hyper- the mucosal layer is about 70–80% of total flow, while emia; septic shock; hemorrhagic shock; cardiogenic the muscular and serosal layers collectively receive shock; circulation; nitric oxide; adenosine; adrenergic. 15–25% of organ flow and the submucosal layer is perfused by less than 5% [3]. Of the mucosal blood flow, VASCULAR ANATOMY AND DISTRIBUTION OF approximately 60% perfuses the vessels that terminate INTESTINAL BLOOD FLOW as end loops and that supply the epithelial cells in the intestinal villi. The remaining 40% supply flow to the The gastrointestinal system of mammals is supplied crypts and goblet cells [3]. The arterial microvascular by three direct branches of the aorta: the celiac artery, branching pattern of the intestinal microvasculature, the cranial or superior mesenteric artery, and the cau- described by Bohlen and Gore [8, 9], is diagrammed in dal or inferior mesenteric artery [1]. The celiac artery Fig. 1. Following the ingestion of a meal, blood flow supplies blood flow to the stomach, liver, and spleen, increases by as much as 200% above baseline levels while the superior mesenteric artery, the largest single and persists for 2 to 3 h. This increase in flow is shifted branch of the abdominal aorta, supplies the entire to the mucosal layer by a process of capillary recruit- small intestine, proximal portions of the colon, and the ment where existing but closed vessels open. The con- pancreas. The inferior mesenteric artery delivers blood trol mechanism of this recruitment process is unknown flow to the distal colon. Total blood flow through these for the intestinal microcirculation. In the resting or 1 To whom correspondence should be addressed at Veterans Af- unfed state only 20–30% of capillaries are normally fairs Medical Center, 800 Zorn Avenue, Research Bldg. 19, Louis- perfused [1, 3]. The intestinal mucosa is the site of ville, KY 40206. E-mail: [email protected]. nutrient absorption; the submucosa, which consists of 0022-4804/00 $35.00 182 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved. MATHESON, WILSON, AND GARRISON: REGULATION OF INTESTINAL BLOOD FLOW 183 imal to the site where the mucosal–submucosal and muscular lymph systems unite [13, 14]. As lymph col- lects in the submucosal arcade, the contraction of the longitudinal and circular muscular layers during the digestion of chyme propels the lymph out from the intestinal layers and into the outflow lymph vessels [13, 14]. These outflow lymph vessels exhibit typical characteristics of lymph vessels including rhythmic contractions and unidirectional valves, which function to propel the lymph and to prevent retrograde flow back toward the intestinal layers. These larger lymph vessels are lined with endothelial cells and smooth muscle cells that produce mediators of smooth muscle tone in response to different nutrients or metabolic products present in the lymph [12, 13]. The role of lymph-derived mediators in regulation of resting vas- cular tone or postprandial hyperemia is not known, but FIG. 1. Outline of the intestinal microvasculature emphasizing involvement has been implicated in some studies [16]. the mucosal blood supply with the inflow (A1), transitional (A2), and premucosal (A3) arteriolar structure as well as outflow (V1) and transitional (V2) venules. FACTORS THAT REGULATE RESTING VASCULAR TONE glandular cells, produces serous and mucous secre- tions, as well as newly formed, immature enterocytes; In the unfed resting state, numerous mechanisms and the muscular layers provide contractile force for exist that control vascular tone in the microvessels of intestinal mixing and propulsion of the chyme. In gen- the gastrointestinal circulation. Table 1 provides a eral, blood flow to these three layers is autoregulated summary of mechanisms and mediators that might by metabolic factors such as decreased PO , pH, or contribute to resting tone, and Fig. 2 provides a theo- 2 retical scale to indicate the relative contribution of the osmolarity and increased PCO2 or adenosine. These mechanisms serve to maintain or increase blood flow to different vasoactive mediators as a function of position meet the tissue’s need for oxygen and nutrient delivery in the arterial tree. Constriction of large arteries and Ͼ ␮ and waste removal [10]. arterioles ( 50 m) is primarily under the influence of In addition to vascular perfusion, the organs of the neural regulation from the vasomotor center of the gastrointestinal system contain numerous lymph ves- sels [11–14]. The gastrointestinal lymphatic circula- tion is anatomically divided into two separate parti- tions, which remain separate until they exit from the intestine near the mesenteric arcade vessels [12–14]. These two lymphatic circulations are termed the mucosal–submucosal lymph system and the muscular lymph system [12]. The mucosal–submucosal lymph circulation functions to drain the absorbed nutrients and metabolic by-products from the villi during diges- tion. These villus lymph vessels, termed lacteals, do not have smooth muscle cells. However, it is thought that the muscularis mucosa, which lines the villi be- neath the epithelial cells, can contract in synchrony with the relaxation of the muscular layers of the intes- tine, thereby propelling lymph from the villi into the submucosal arcade of lymph capillaries [15]. The en- teric nervous system coordinates the contractions of villi in this process to optimize lymph drainage from FIG. 2. Theoretical contribution to vascular tone of the media- the intestine and to facilitate nutrient entry into the tors from the classification system outlined in Table 1 as a function circulation [12, 13]. of their position in the vascular tree. Neural and humoral agents might contribute more to the tone of large conduit blood vessels, The contraction of the muscularis mucosa occurs while paracrine and metabolic mediators contribute proportionally along the length of the villus and propels lymph toward more to the smaller microvessels due to limited diffusion into sys- the submucosal arcade vessels, which are located prox- temic blood. 184 JOURNAL OF SURGICAL RESEARCH: VOL. 93, NO. 1, SEPTEMBER 2000 TABLE 1 Potential Vasoactive Mediators of the Enteric Circulation Constrictors Dilators Neural Mediators 1 Sympathetic tone (Adrenergic) 2 Sympathetic tone 2 Parasympathetic tone (Cholinergic) 1 Parasympathetic tone Neuropeptide Y Substance P Vasoactive intestinal polypeptide (VIP) Calcitonin gene-related peptide (CGRP␣) Circulating Humoral Mediators Catecholamines (except in liver and muscle) Catecholamines (only in liver and muscle) Angiotensin II Histamine Vasopressin Bradykinin Serotonin Activated complement (C3a, C5a) Activated complement (C5a) Adrenomedullin Circulating Paracrine and Autocrine Mediators Endothelin-1 (vascular smooth muscle cells) Endothelium-derived relaxing factor (EDRF, NO) Platelet-activating factor Endothelium-derived hyperpolarizing factor (EDHF) Constrictor prostaglandins (F2␣) Dilator prostaglandins (I2 or prostacyclin) Endothelin-1 (endothelial cells) “Metabolic” Vasodilators 1 PO2 2 PO2 2 PCO2 1 PCO2 1 pH 2 pH 2 Metabolites (Kϩ, lactate, adenosine, etc.) 1 Metabolites medulla oblongata through preganglionic sympathetic during the digestion