In pentobarbital-anesthetized rats a comparison was undertaken of the blood pressure lowering effect of nitroglycerin (glyceryl trinitrate, GTN) administered by different routes: jugular vein (i.v.), portal vein (p.v.), peritoneal (i.p.), intrajejunal (i.j.), and sublingual (s.l.). The potency of GTN given by these routes was approximately i.v.:s.l.:i.p.:p.v.:i.j. = 100:20--10:10--5:5:5--2.5. Application of GTN to the visceral peritoneum (i.p.) caused a greater and more prolonged lowering of blood pressure than an injection into the portal vein. We conclude that the capacity of the liver to degrade the active agent during the first passage can be overcome and that a blood pressure response to enterally absorbed GTN could be caused by a prehepatic site of action, i.e., on the splanchnic venous system.