Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of Angiotensin II on gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT₁ receptor antagonist candesartan before cold-restraint stress. AT₁ receptors were localized in the endothelium of arteries in the gastric mucosa, and in all gastric layers. AT₁ blockade increased gastric blood flow 40-50%, prevented gastric ulcer formation by 70-80% after cold-restraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase (TH) mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of necrosis factor (TNF-), that of the adhesion protein ICAM-1 in arterial endothelium and the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE₂. AT₁ receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, anti-inflammatory effects with reduction in TNF-, and ICAM-1 expression leading to reduced neutrophil infiltration, while maintaining the protective glucocorticoid effects and PGE₂ release. Ang II has a crucial role, through stimulation of AT₁ receptors, in the production and progression of stress-induced gastric injury, and AT₁ receptor antagonists could be of therapeutic benefit.