Gastric vasoconstrictor actions of leukotriene C4, PGF2 alpha, and thromboxane mimetic U-46619 on rat submucosal microcirculation in vivo

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Abstract
The gastric vasoconstrictor actions of the arachidonate lipoxygenase products leukotrienes B4, C4, and D4 and the prostanoids prostaglandin F2 alpha (PGF2 alpha) and the endoperoxide analogue U-46619 have been investigated in vivo in the submucosal microcirculation of the anesthetized rat using direct microscopy. Topical application of PGF2 alpha (1-100 microM) to the exposed submucosa reduced vessel diameter of the venules, with peak vasoconstriction occurring within 1 min and remaining during the 3-min period of administration. Constriction of the arterioles by PGF2 alpha was less pronounced. U-46619 (1-1,000 nM), a thromboxane mimetic, induced vasoconstriction in both arterioles and venules, reaching plateau responses within 1.5-2.0 min of application. Leukotriene C4 (25-400 nM) induced vasoconstriction in the venules, which was more pronounced than in the arterioles, reaching peak responses within 1-1.5 min, which were unaffected by indomethacin administration. No significant vasoactive action with leukotrienes B4 or D4 in the submucosal microcirculation could be detected. With both leukotriene C4 and U-46619 intense focal vasoconstriction in the venules was observed, leading to sluggish blood flow or stasis within the vessel. In contrast, norepinephrine had no significant action on submucosal venules at concentrations that substantially reduced arteriolar vessel diameter. Such potent vasoconstrictor actions of leukotriene C4 and U-46619 in the gastric submucosa identify this leukotriene and thromboxane A2 as potential endogenous proulcerogenic agents and suggest that these arachidonate products could play a role in microcirculatory events accompanying gastric damage.