The hemodynamic and pro-inflammatory effects of endothelin-1 (ET-1) in proximal (1^st/2^nd order) and terminal (3^rd/4^th order) arterioles and venules were examined in small intestine submucosa of anesthetized guinea pigs. Vessel diameter (D), red blood cell velocity, and blood flow (Q) were determined in 8 proximal and 8 terminal microvessels prior to and at 20 min of ET-1 suffusion (10^-10,-9,-8M) and then with ET_A receptor blockade with BQ-123 (10^-5M). This protocol was repeated with platelet activating factor (PAF) inhibition (WEB-2086,1.0 mg/kg i.v) (n=16). The ET-1-mediated microvascular responses were also examined with ET_B receptor blockade using BQ-788 (10^-5M; n=11) alone or with ET_A+B receptor blockade with BQ-123+BQ-788 (n=10). Microvascular permeability was assessed by FITC-albumin (25 mg/kg, i.v.) extravasation in 6 series; (a) buffered modified Krebs solution suffusion (n=6), (b) histamine suffusion (HIS, 10^-3M, n=5), (c) ET-1 suffusion (10^-8M, n=5), (d) BQ-123 (10^-5M) plus ET-1 suffusion (n=5), (e) PAF inhibition prior to ET-1 suffusion (n=5), (f) Histamine-1 receptor blockade (diphenhydramine, 20 mg/kg i.v.) prior to ET-1 suffusion (n=5), and (g) ET_B receptor blockade prior to (BQ-788 10^-5M) (n=3) or with ET-1 suffusion (n=3). D and Q decreased at 10^-8M ET-1 and returned to control values with BQ-123 and BQ-123+BQ788 but not with BQ-788 in proximal microvessels. D did not change in terminal microvessels with ET-1 (10^-8M) but decreased with BQ-788 and increased with BQ-123. PAF inhibition did not affect the D and Q responses of proximal microvessels to ET-1, but prevented the fall in Q in terminal microvessels with ET-1. ET-1 increased vascular permeability to about 1/3 of that with HIS; this response was prevented with BQ-123 and WEB-2086 but not with H1-receptor blockade. This is the first evidence that submucosal terminal microvessel flow is reduced with ET-1 independent of vessel diameter changes and that this response is associated with increased microvascular permeability mediated via ET_A receptor stimulation and PAF activation.