The mesenteric circulation receives approximately 20% to 30% of the cardiac output at rest, which may increase by up to 50% after meals.6 As such, the mesenteric circulation receives approximately three times more blood per unit weight than most other body tissues. This blood flow is partly to satisfy the absorptive function of the intestine and perfuse the liver via the portal vein, but it also represents a reservoir function from which blood can be mobilized to other sites (vital organs) at times of stress or increased demand. This preferential shunting of blood to vital organs, if acute or severe, can “sacrifice” the mesenteric circulation, leading to low-flow and ischemic injury. The more metabolically active mucosal layer receives 70% of blood flow, only 30% supplying the muscularis and serosal layers, placing the intestinal mucosa at greatest risk from ischemic injury.6 Within the intestinal villus, passive exchange of oxygen typically occurs between the afferent arteriole and efferent venule, effectively bypassing the capillary network at the villus tip, a phenomenon called oxygen countercurrent exchange. In health, high partial pressures of oxygen ensure that the metabolic needs of the villus mucosa are met despite this shunting, but in deoxygenated states this shunting adversely affects oxygen delivery to the mucosal tip, making it most vulnerable to ischemic injury. A number of extrinsic and intrinsic factors regulate the mesenteric blood flow, leading to a complex interaction between neural, hormonal, and paracrine effectors that regulate the vascular smooth muscle tone in the mesenteric bed and control local blood flow. Vasoactive mediators alter the vascular smooth muscle (VSM) tone of multiple small afferent arterioles, collectively known as resistance vessels, changing their cross-sectional area and blood flow (Table 86-2). The interaction between extracellular agonist (first messenger) and VSM receptor leads to accumulation of intracellular second messengers, such as cyclic adenosine monophosphate (cAMP), Ca2+, and cyclic guanosine monophosphate (cGMP). These second messengers directly or indirectly alter the cytosolic concentration of Ca2+ and dictate whether VSM contracts.7 A functioning cardiovascular system is essential because the mesenteric circulation is often sacrificed to maintain blood flow to vital organs at times of detrimental alterations in cardiac output, blood volume, or arterial blood pressure. Increased sympathetic nervous activity associated with cardiogenic, septic, or hypovolemic shock can further compound flow-related ischemia by inducing intense vasocontriction within the mesenteric bed. High-volume hemorrhage (>35% of blood volume) leads to disproportionate visceral vasoconstriction compared with the reduction in cardiac output.8 When activated postganglionic sympathetic nerves fibers release norepinephrine, stimulating α2-adrenergic receptors on VSM of precapillary arterioles (which are the resistance vessels), this results in vasoconstriction and reduced intestinal blood flow. Some compensation is provided by the simultaneous stimulation of vasodilatory β2-adrenergic receptors on VSM by norepinephrine.9 However the net effect is a rapid reduction in flow followed by a gradual return to prestimulation blood flow levels, a phenomenon known as autoregulatory escape. Exogenously administered norepinephrine similarly can cause nonocclusive mesenteric ischemia (NOMI). Parasympathetic nerves induce vasodilation due to the effect of specific neurotransmitters acetylcholine (ACh, increases cGMP and NO), vasoactive intestinal protein (VIP, increases cAMP), and adenosine triphosphate (ATP). Primary sensory nerves also play a role because their activity through C fibers can inhibit sympathetic impulse flow through the spinal cord or sympathetic ganglia. Indeed, direct antidromic vasodilation can occur as C fibers release neuropeptides, including substance P, calcitonin gene–related peptide, and VIP, in response to luminal signals. Humoral (endocrine) messengers also can affect the mesenteric blood flow, most notably adrenal catecholamines in states of systemic stress, shock, or secreting tumor (pheochromocytoma). Similarly vasocontrictive effects are seen with renal-derived angiotensin II in congestive heart failure and pituitary-derived vasopressin in shock, respectively. Ingested meals and gastrointestinal luminal peptides stimulate a postprandial increase in mesenteric blood flow. This vasodilatory response is regulated, in part, by the increased metabolic activity in the tissues, leading to local accumulation of vasoactive metabolites such as amines, peptides, prostanoids, and adenosine in the presence of a reduced oxygen concentration. Adenosine itself, increasing as a result of energy-dependent processes, may vasodilate in a paracrine fashion. A number of hormones are also released in response to luminal contents, including gastrin, cholecystokinin, and secretin, with net vasodilatory effects.10 Somatostatin, released by the mucosal D cells, induces mucosal vasoconstriction, and synthetic analogs (e.g., octreotide) can induce ischemia.