THE PRESERVATION OF BRADYKININ BY PHENOTHIAZINES IN VITRO.

Chlorpromazine and phenoxybenzamine have been shown to potentiate the actions of bradykinin in vivo. To test whether this phenomenon could be due to inhibition of the enzymatic destruction of bradykinin, bradykinin was incubated with either tissue extracts or with carboxypeptidase B. Bradykinin was rapidly destroyed by acetonedried powders of brain and serum of various animals as well as by purified carboxypeptidase B. The rate of disappearance of bradykinin activity was decreased in the presence of phenothiazine derivatives, phenoxybenzamine and hydroxyzine, but not by compounds of a larger group including other psychotropic drugs, tranquillizers and ganglionic and adrenergic blocking agents. Spectrophotometric studies of the hydrolysis of hippuryl-L-arginine confirmed the presence of a carboxypeptidase B-like activity in brain. The substances that acted as inhibitors of bradykinin destruction were also enzyme inhibitors as measured by this technique. Previous incubation of carboxypeptidase B with phenothiazines and zinc ions greatly reduced the enzymatic inhibition by the phenothiazines, which indicated a possible chelating action by these inhibitors on the metalo-enzyme carboxypeptidase B.