The cavernous carotid artery, that portion of the internal carotid artery that lies within the intracranial cavernous sinus, is covered by arterial (luminal surface) and venous (external surface) endothelium. The reactivity of the isolated canine, cavernous carotid artery, precontracted with 10(-5) M 5-hydroxytryptamine, was studied by using in vitro perfusion and superfusion to evaluate the effects of vasoactive stimuli applied to the internal or external surface. Acetylcholine (10(-8)-10(-4) M), thrombin (0.01-1 U/ml) or calcium ionophore A23187 (10(-8) - 10(-6) M) on the luminal side produced concentration-dependent relaxations which were reduced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or by removing either the internal or both endothelia. Thrombin or ionophore A23187 on the external side produced concentration-dependent contractions which were reduced by removing either the external or both endothelia, and by meclofenamate (10(-5) M). Acetylcholine on the external side, produced a concentration-dependent contraction that was unaffected by meclofenamate or by removing the external or both endothelia. Sodium nitroprusside (10(-7) - 10(-5) M) induced similar relaxation on both sides and regardless of whether the arteries were with or without endothelium. These results suggest firstly, that the cavernous carotid artery responds to acetylcholine, thrombin or calcium ionophore A23187 by relaxing or contracting when these agents act on the luminal or the external surface respectively. Secondly, the arterial endothelium mediates relaxation to these three substances by releasing NO, whereas the venous endothelium mediates contraction to thrombin and ionophore A23187 by releasing a cyclooxygenase product.(ABSTRACT TRUNCATED AT 250 WORDS)