The involvement of endothelial dysfunction, nitric oxide and prostanoids in the rat gastric microcirculatory responses to endothelin‐1

1 The role of endothelial dysfunction in the gastric microcirculatory responses during local endothelin-1 (ET-1) infusion has been investigated in the pentobarbitone-anaesthetized rat. Furthermore, the involvement of prostanoids or nitric oxide (NO) in these actions has been investigated by the use of indomethacin to inhibit cyclo-oxygenase and NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NO synthase. 2 Close-arterial infusion of ET-1 (1–10 pmol kg−1 min−1 for 10 min) induced a dose-dependent increase in the gastric leakage of radiolabeled albumin, used as an index of endothelial cell dysfunction. 3 Close-arterial infusion of a submaximal dose of ET-1 (5 pmol kg−1 min−1 for 10 min) significantly increased gastric albumin leakage after 2 min infusion, which reached maximal levels after 10 min, and only slowly declined during the 30 min observation period. 4 By contrast, gastric blood flow, as assessed by laser Doppler flowmetry, did not significantly increase until after 5 min of infusion of ET-1 (5 pmol kg−1 min−1 for 10 min), reaching a maximum after 17 min, and was sustained for the 30 min observation period. 5 Pretreatment with l-NAME (2 mg kg−1, i.v.) or indomethacin (5 mg kg−1, i.v.) significantly reduced both the hyperaemic response to ET-1 and the increase in gastric albumin leakage, and in combination abolished these responses. 6 These results suggest that locally released NO and prostanoids mediate the gastric vasodilator response to close arterial infusion of ET-1. This hyperaemia is preceded by changes in gastric albumin extravasation and hence may be initiated as a response to direct endothelial injury by ET-1.