Because plasma levels of protein C (PC) or activated protein C (APC) are altered in certain diseases associated with vascular dysfunction, and APC has therapeutic potential in preventing microvascular coagulation in severe sepsis, potential vascular effects of PC and APC were compared to those of the vasoactive peptide, thrombin. Thrombin was a more potent relaxant agonist than contractile agonist in aorta. Unlike thrombin, cumulatively administered APC (10(-9)-10(-7) M) did not exert vascular effects in rat or rabbit aorta. Noncumulative challenge of PC (10(-7) M) and APC (8 x 10(-8) M) also did not contract rat or rabbit aortae, either with or without endothelium. Likewise, the same concentrations of PC and APC also did not relax norepinephrine-induced (10(-7) M) vascular tone in either rat or rabbit aortae. Thus, in contrast to thrombin, PC and APC failed to modulate vascular tone, suggesting that the therapeutic use of APC is unlikely to be accompanied by any direct effects on vascular motility.