1. We have found that ‘acid’-activation of inactive human plasma renin is a two-phase process. About 30% of activation occurs during dialysis to pH 3·3; the remaining 70% occurs at alkaline pH.
2. The ‘alkaline phase’ of activation has a pH optimum between 7·5 and 8·4. It is inhibited by unacidified plasma and by soya-bean or lima-bean trypsin inhibitors.
3. ‘Cryoactivation’ of inactive plasma renin, which occurs at −4°C and alkaline pH, is also inhibited by soya-bean or lima-bean trypsin inhibitors and by the serine protease inhibitors di-isopropylphosphorofluoridate and benzamidine.
4. Thus endogenous neutral serine proteases participate in the activation of inactive plasma renin in vitro. Their action is prevented in the circulation by inhibitors which are inactivated by acid or cold.