Hester, Robert L., and Leah W. Hammer. Venular-arteriolar communication in the regulation of blood flow. Am J Physiol Regulatory Integrative Comp Physiol 282: R1280-R1285, 2002; 10.1152/ajpregu. 00744.2001.-Muscle blood flow is regulated to meet the metabolic needs of the tissue. With the vasculature arranged as a successive branching of arterioles and the larger, Ͼ50 m, arterioles providing the major site of resistance, an increasing metabolic demand requires the vasodilation of the small arterioles first then the vasodilation of the more proximal, larger arterioles. The mechanism(s) for the coordination of this ascending vasodilation are not clear and may involve a conducted vasodilation and/or a flow-dependent response. The close arteriolar-venular pairing provides an additional mechanism by which the arteriolar diameter can be increased due to the diffusion of vasoactive substances from the venous blood. Evidence is presented that the venular endothelium releases a relaxing factor, a metabolite of arachidonic acid, that will vasodilate the adjacent arteriole. The stimulus for this release is not known, but it is hypothesized that hypoxia-induced ATP release from red blood cells may be responsible for the stimulation of arachidonic release from the venular endothelial cells. Thus the venous circulation is in an optimal position to monitor the overall metabolic state of the tissue and thus provide a feedback regulation of arteriolar diameter. vasodilation; venular endothelium; relaxing factor TISSUE BLOOD FLOW is regulated to meet the metabolic needs of each tissue and can change quite dramatically. Increases in tissue metabolism cause increases in blood flow (functional hyperemia), whereas excess oxygen delivery causes a decrease in blood flow. Blood flow to skeletal or cardiac muscle increases proportionally with increases in metabolic rate to ensure adequate delivery of nutrients and removal of waste products. Although the precise mechanisms governing this close relationship between metabolic state of the tissue and blood flow remain to be elucidated, the anatomical arrangement of arteries and veins may provide a unique mechanism allowing the exchange of information or "cross-talk" between the pre-and postcapillary vessels.The vasculature is arranged as a series of blood vessels ranging in size from several millimeters to several micrometers, with the largest contribution of total resistance to blood flow coming from the large "feed" arterioles. Thus, to achieve optimal increases in blood flow during periods of increased muscle metabolism, large decreases in resistance of these arterioles must occur. As these upstream or feed vessels are not necessarily in contact with the metabolically active tissue, mechanisms other than or in addition to direct stimulation by tissue metabolites must be important in functional hyperemia. Mechanisms that have been proposed to regulate the diameter of upstream vessels include 1) conducted vasodilation (14), 2) flow-dependent vasodilation (29), and 3) myogenic vasodilation ...

This study was designed to test the hypothesis that venular administration of ATP resulted in endothelium-dependent dilation of adjacent arterioles through a mechanism involving cyclooxygenase products. Forty-three male golden hamsters were anesthetized with pentobarbital sodium (60 mg/kg ip), and the cremaster muscle was prepared for in vivo microscopy. ATP (100 microM) injected into venules dilated adjacent arterioles from a mean diameter of 51 +/- 4 to 76 +/- 6 microm (P < 0.05, n = 6). To remove the source of endothelial-derived relaxing factors, the venules were then perfused with air bubbles to disrupt the endothelium. Resting arteriolar diameter was not altered after disruption of the venular endothelium (51 +/- 5 microm), and the responses to venular ATP infusions were significantly attenuated (59 +/- 4 microm, P < 0.05). To determine whether the relaxing factor was a cyclooxygenase product, ATP infusion studies were repeated in the absence and presence of indomethacin (28 microM). Under control conditions, ATP (100 microM) infusion into the venule caused an increase in mean arteriolar diameter from 55 +/- 4 to 78 +/- 3 microm (P < 0.05, n = 6). In the presence of indomethacin, mean resting arteriolar tone was not significantly altered (49 +/- 4 microm), and the response to ATP was significantly attenuated (54 +/- 4 microm, P < 0.05, n = 6). These studies show that increases in venular ATP concentrations stimulate the release of cyclooxygenase products, possibly from the venular endothelium, to vasodilate the adjacent arteriole.

Abstract-Indomethacin or glibenclamide treatments attenuate functional dilation of larger-diameter "feed" arterioles paired with venules in hamster cremaster muscle. We tested the hypothesis that release of cyclooxygenase products from venules is important for functional dilation of third-and fourth-order arterioles. We also tested whether ATP-sensitive potassium channels are important during functional dilation of smaller arterioles. The microcirculation of hamster cremaster muscle was visualized with in vivo video microscopy. We measured diameter responses of third-and fourth-order arterioles paired and unpaired with venules in response to 2 minutes of muscle field stimulation (40 s, 10 V, 1 Hz). Control diameters of vessels were 31Ϯ2 (nϭ19), 13Ϯ1 (nϭ12), 12Ϯ2 (nϭ12), and 10Ϯ1 (nϭ12) for paired and unpaired third-order and paired and unpaired fourth-order arterioles, respectively. In all groups, field stimulation resulted in increases in mean control diameter of Ͼ80%. Indomethacin (28 mol/L) superfused on the preparation was used to inhibit cyclooxygenase metabolism, or glibenclamide (10 mol/L) was used to block ATP-sensitive potassium channels. Indomethacin attenuated arteriolar vasodilations to electrical stimulation in paired third-order vessels only, whereas glibenclamide attenuated this vasodilation in all 4 groups. These results support a role for ATP-sensitive potassium channels in functional dilation of arterioles of all sizes regardless of whether or not they are paired with venules. Conversely, a role for cyclooxygenase products is limited to larger "feed arterioles" paired with venules. This study provides further evidence that venules may be the source of prostaglandin release during functional hyperemia. Key Words: indomethacin Ⅲ microcirculation Ⅲ arterioles Ⅲ potassium channels Ⅲ cyclooxygenase O ne of the remarkable characteristics of the microcirculation is the ability of the tissue to "control" local blood flow in such a manner that the metabolic requirements of the tissue are adequately met. For instance, during periods of increased muscle metabolism such as during exercise, blood flow to skeletal muscle increases. In hamster cremaster muscle, functional dilation of larger "feed" arterioles can be attenuated by disruption of the endothelium of venules running parallel to these arterioles, 1 by inhibition of ATPsensitive potassium (K ATP ) channels, 2 and by inhibiting the production of arachidonic acid metabolites. 3,4 Collectively, these studies suggest that during periods of increased muscle metabolism, a metabolite of arachidonic acid is released from the venular endothelium that subsequently diffuses to and dilates the adjacent arteriole.To achieve a maximal increase in blood flow to the tissue, all arterioles within the vascular tree must dilate. As vessels approach the capillary bed, they tend to lose their paired arrangement with venules, and in hamster cremaster muscle, many third-order and the majority of fourth-order arterioles do not have an adjacent venule (see Figure 1). Therefo...

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