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 radiolabelled 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.
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
J
J
Lopez-Belmonte
B J
BJ
Whittle
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005753:Gastric Mucosa / Q000098:blood supply*; D006940:Hyperemia / Q000139:chemically induced / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000418:Albumins; D016232:Endothelins; D011453:Prostaglandins; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin