Inhibition of phospholipase A<sub>2</sub>attenuates functional hyperemia in the hamster cremaster muscle

Nuttle, Louise C.; Ligon, Alison L.; Farrell, Kathryn R.; Hester, Robert L.

doi:10.1152/ajpheart.1999.276.4.h1289

Cited by 22 publications

(32 citation statements)

References 26 publications

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“…Similar results were also found in patients with type 2 diabetes (14). Because previous studies have supported a critical role of prostaglandin(s) in mediating functional vasodilation (10,19,20,24,30), it is possible that the impaired functional vasodilation in metabolic syndrome may be due to altered AA metabolism. Indeed, previous studies have shown that urinary thromboxane B 2 excretion is enhanced in 12-wk-old OZRs associated with an increased cyclooxygenase-2 expression in kidney (3,15).…”

Section: Discussionsupporting

confidence: 80%

“…Indeed, the role of NO in mediating functional vasodilation in humans and animals is still unclear. Our previous study showed that, in the cremaster muscle, inhibition of cyclooxygenase with indomethacin significantly attenuates functional dilation (19,24), suggesting that prostaglandins play a central role in functional hyperemia (10). Indeed, endothelial-derived prostacyclin (PGI 2 ) has been proposed as playing an important role in regulating local blood flow during exercise through activation of PGI 2 receptors prostacyclin (IP) on vascular smooth muscle cells (20,30).…”

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confidence: 99%

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Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Xiang¹,

Naik²,

Hodnett³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Xiang, Lusha, Jay S. Naik, Benjamin L. Hodnett, and Robert L. Hester. Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 290: R134 -R138, 2006. First published September 15, 2005 doi:10.1152/ajpregu.00295.2005.-These studies tested the hypothesis that in obese Zucker rats (OZRs), a model of metabolic syndrome, the impaired functional vasodilation is due to increased thromboxane receptor (TP)-mediated vasoconstriction and/or decreased prostacyclin-induced vasodilation. Spinotrapezius arcade arterioles from 12-wk-old lean (LZR) and OZR were chosen for microcirculatory observation. Arteriolar diameter (5 LZR and 6 OZR) was measured after 2 min of muscle stimulation in the absence or presence of 1 M SQ-29548 (TP antagonist). Additionally, arteriolar diameter (6 for each group) was measured after application of iloprost (prostacyclin analog; 0.28, 2.8, and 28 M), arachidonic acid (10 M), and sodium nitroprusside (0.1, 1, and 10 M) in the absence or presence of 1 M SQ-29548. A 10 M concentration of adenosine was used to induce a maximal dilation. Basal diameters were not different between LZRs and OZRs. Functional hyperemia and arachidonic acid-mediated vasodilations were significantly attenuated in OZR compared with LZR, and treatment with 1 M SQ-29548 significantly enhanced the dilations in OZRs, although it had no effect in LZRs. Vasodilatory responses to iloprost and sodium nitroprusside (1 and 10 M) were significantly reduced in OZR. Adenosine-mediated vasodilation was not different between groups. These results suggest that the impaired functional dilation in the OZR is due to an increased TP-mediated vasoconstriction and a decreased PGI2-induced vasodilation.obese Zucker rat; prostacyclin; thromboxane; vasoconstriction IT IS WELL ESTABLISHED THAT, during periods of increased skeletal muscle metabolism (such as during exercise), blood flow to the muscle increases (functional hyperemia) because of dilation of local arterioles (functional dilation), and this vasodilatory response is dependent, in some part, on endothelial function (22). However, in patients and animals with metabolic syndrome, endothelial dysfunction may occur early in the pathology of this syndrome (4), possibly contributing to the impaired functional hyperemia seen in metabolic syndrome. For example, patients with type 2 diabetes exhibit an impaired endothelial-dependent vasodilatory response to ACh and a significant impairment of the functional hyperemic response to leg cycle ergometer exercise (14). Our laboratory and others (8,32) have demonstrated that the obese Zucker rat (OZR), a model of metabolic syndrome, have both an attenuated functional and ACh-induced vasodilation in skeletal muscle arterioles. Although the mechanism(s) responsible for the impaired functional dilation remains unclear, these studies reveal a possible relationship between the endothelial dysfunction and the impaired functional vasodilation.The determination of the mechanism(s) responsible...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Xiang¹,

Naik²,

Hodnett³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…2A, black bars). Likewise, mepacrine (10 M), at a three-to tenfold higher concentration than used in other studies to effectively block PLA 2 (1,35), produced a substantial increase in basal contraction Freq but failed to block either the positive inotropic or chronotropic effect of 10 nM SP (Fig. 2B).…”

Section: Resultsmentioning

confidence: 62%

“…2B), and the TxA 2 synthase inhibitor imidazole. Although we do not have independent confirmation of the effectiveness of these inhibitors, we used a threefold higher dose of indomethacin that completely blocked the SP action in guinea pig lymphatics (39), a three-to tenfold higher dose of mepacrine than required to block PLA 2 in other studies (1,35), and the same dose of imidazole that blocked SPinduced lymphatic chronotropy in guinea pig (39). It should be noted that flow-dependent diastolic relaxation in the rat thoracic duct was independent of COX activity as well (13).…”

Section: Discussionmentioning

confidence: 99%

Modulation of lymphatic muscle contractility by the neuropeptide substance P

Davis¹,

Lane²,

Davis³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Davis MJ, Lane MM, Davis AM, Durtschi D, Zawieja DC, Muthuchamy M, Gashev AA. Modulation of lymphatic muscle contractility by the neuropeptide substance P. Am J Physiol Heart Circ Physiol 295: H587-H597, 2008. First published June 6, 2008 doi:10.1152/ajpheart.01029.2007.-Substance P (SP) is a neuropeptide associated with sensory innervation of lymphoid tissue and a suspected modulator of lymphatic function in inflammation. Only a few studies have examined the effects of SP on lymphatic contraction, and it is not clear to what extent SP acts directly on the lymphatic muscle and/or endothelium or indirectly through changes in intraluminal filling pressure secondary to increases in capillary permeability/ filtration. We tested the effects of SP on the spontaneous contractions of rat isolated mesenteric lymphatic vessels under isometric and isobaric conditions, hypothesizing that low concentrations would stimulate lymphatic pumping by enhancing lymphatic muscle contraction in a manner complementary to the effect of increased preload. Under isometric conditions, SP (10 nM) dramatically enhanced lymphatic chronotropy and inotropy. Unlike guinea pig lymphatics, SP actions were not blocked by cyclooxygenase or PLA2 inhibition. In the absence of SP, ramp increases in isometric preload resulted in ϫϳ1.6 increases in contraction amplitude (Amp) and ϫϳ1.7 increases in frequency (Freq). SP increased Freq by ϫϳ2.4, Amp by ϫϳ1.9, and the Amp-Freq product (AFP) by ϫϳ3.5. Under isobaric conditions, the pressure elevation from 0.5 to 10 cmH2O in the absence of SP decreased Amp by ϫϳ0.6 and increased Freq by ϫϳ1.8. SP caused a modest increase in Amp, a robust increase in Freq at all pressures, and shifted the AFP-pressure relationship upward and leftward. Therefore, SP has substantial positive inotropic and chronotropic effects on rat lymphatic muscle, improving pump efficiency independent of the effects of preload and broadening of the working range of the lymphatic pump. neurokinin; edema; inflammation; lymphatic pump; inotropy; chronotropy; thromboxane A2 SUBSTANCE P (SP) is an 11-amino acid neuropeptide (36) often associated with cells of lymphoid tissue (15,19,21,22,46,47). SP is released from enteric nerves, sensory nerves, and inflammatory cells (27,41,45,52). Correspondingly, SP receptors are expressed on endothelium and muscle of blood and lymphatic vessels, on nerves innervating those vessels, and on associated immune and inflammatory cells (31,36,44).SP appears to have both direct and indirect effects on vascular targets. For example, SP is a powerful stimulator of endothelium-dependent nitric oxide production (28), evoking vasodilation and increasing local blood flow. In addition, SP enhances vascular permeability (18,25) and stimulates the release of cytokines and chemokines (4, 36) that would indirectly elicit vasodilation and increase vascular permeability. These vascular effects of SP would collectively increase flow/ pressure in capillaries and post-capillary venules and lead to increases in transcapillary fluid ...

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“…In these studies, functional hyperemia in the hamster cremaster muscle was inhibited by global administration of the cyclooxygenase inhibitor indomethacin (19,34) or by the phospholipase A 2 inhibitor, quinacrine (39), which blocks the liberation of arachidonic acid from the cell membrane. As these inhibitors were applied to the whole cremaster muscle, it is possible that the arachidonic acid metabolites were coming from locations other than the venular endothelium.…”

Section: Physiological Role For Venular-arteriolar Communicationmentioning

confidence: 99%

Venular-arteriolar communication in the regulation of blood flow

Hester

Hammer

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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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 ...

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Inhibition of phospholipase A₂attenuates functional hyperemia in the hamster cremaster muscle

Cited by 22 publications

References 26 publications

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Modulation of lymphatic muscle contractility by the neuropeptide substance P

Venular-arteriolar communication in the regulation of blood flow

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Inhibition of phospholipase A2attenuates functional hyperemia in the hamster cremaster muscle

Cited by 22 publications

References 26 publications

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Modulation of lymphatic muscle contractility by the neuropeptide substance P

Venular-arteriolar communication in the regulation of blood flow

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Product

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Inhibition of phospholipase A₂attenuates functional hyperemia in the hamster cremaster muscle