Beneficial effects of a serine protease inhibitor in peripheral vascular disease

Kallikrein, a serine protease known to generate bradykinin (a vasodilating peptide) in alkaline conditions, also generates angiotensin II (a vasoconstricting peptide) in weak acidic conditions. Based on this previous observation, the present study was performed to determine whether ischemic muscle tissue, in which the regional pH must decrease, produces angiotensin II by kallikrein or a similar enzyme, and whether nafamostat (NAF), a serine protease inhibitor, improves local hemodynamics under ischemic conditions caused by exercise in patients with ischemic peripheral vascular disease. NAF was administered intravenously to 20 patients with peripheral vascular disease. Lower-limb thermograms and blood flow were measured before and after exercise. Femoral venous blood of affected limbs was obtained to measure viscosity and humoral variables (i.e., pH, lactate, angiotensin II and bradykinin). Walking distance and subjective symptoms were also recorded. As a control, the same patients repeated this test with saline infusion on a separate day. NAF significantly increased maximal walking distance, improved subjective symptoms during exercise, and attenuated exercise-induced venous lactate and blood viscosity increases, and pH reduction. The blood viscosity increase correlated with the lactate increase. Pretreatment with NAF also resulted in a higher lower-limb skin temperature, and a greater increase of blood flow in the lower limbs after exercise than did pretreatment with saline. The results suggest that kallikrein-like serine protease may exacerbate ischemic symptoms. Changes in plasma bradykinin and angiotensin II in the femoral vein were not detectable, probably because of the lower levels of these peptides in the peripheral circulation.