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

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.

Prostaglandin F 2α elevates blood pressure and promotes atherosclerosis

“…S5 A-F). PGF 2␣ is a vasoconstrictor in vitro (23), and the dose-dependent elevation of BP in anesthetized WTs evoked by infusion of PGF 2␣ is abrogated in FP Ϫ/Ϫ mice ( Fig. 4 B and C).…”

The protective effects of sulphasalazine against ethanol‐induced gastric damage in rats

“…The protective mechanisms of the drug against stress-induced ulceration are thought to be largely due to inhibition of stomach lipoxygenase activity (Sircar et al, 1983; and of leukotriene C4 (LTC4) synthetase in particular (Bach et al, 1985). Indeed, in the rat gastric mucosa, some of the effects elicited by exogenous LTC4 resemble those produced by ethanol (Guth et al, 1984;Szabo et al, 1985;Whittle et al, 1985). Recently, it has been reported that ethanol stimulates the formation of LTC4 resulting in damage to the rat gastric mucosa (Dreyling et al, 1986;Peskar et al, 1986).…”

Neuronal and endothelium‐derived mediators in the modulation of the gastric microcirculation: integrity in the balance

“…In addition, pretreatment with a 5-lipoxygenase inhibitor had no effect on the mucosal injury, showing that local release of vasoconstrictor leukotrienes (Whittle et al, 1985) did not contribute to the mucosal damage with ET-I (Whittle & Esplugues, 1988). An increase in PAF formation by the gastric mucosa has been reported to be stimulated by ET-1, along with activation of the fibrinolytic system, while a PAF receptor antagonist attenuated mucosal injury induced ET-1 (Kurose et al, 1992).…”