The involvement of endogenous vasopressin in the actions of indomethacin following the concurrent administration of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on acute intestinal microvascular permeability has been investigated in the rat. Administration of indomethacin (10 mg/kg, s.c.) or L-NAME (10 mg/kg, s.c.) alone did not affect jejunal and ileal vascular permeability after 1 h, as determined by the leakage of radiolabelled serum albumin. In contrast, when indomethacin (10 mg/kg, s.c.) was injected concurrently with L-NAME (2-10 mg/kg, s.c.), significant dose-dependent plasma leakage occurred in the jejunum. Pretreatment with L-arginine (300 mg/kg s.c.) 15 min prior to L-NAME prevented these changes in microvascular permeability. Moreover, pretreatment with the vasopressin pressor-receptor antagonist, d(CH2)5Tyr(Me)AVP (0.01-0.2 μg/kg, s.c.) dose-dependently attenuated such damage. These findings suggest that following indomethacin administration, the early inhibition of NO synthase leads to acute microvascular injury involving vasopressin in the rat jejunum. This suggests a protective role of NO, formed by constitutive NO synthase, counteracting effectively the deleterious actions of endogenous vasopressin.