Histargin

It was previously shown that autoregressive modeling can be used for feedback analysis in the body. We used this method to investigate the dynamic changes in and around the renin-angiotensin system in vivo induced by angiotensin-converting enzyme (ACE) inhibition. Long-term studies were performed on rabbits, which were given a daily injection of one of the following ACE inhibitors: captopril, foroxymithine, or histargin. For comparison, other rabbits received injections of saline or the renin inhibitor pepstatin. Autoregressive coefficients were computed from the raw data thus observed and were used to simulate the impulse-response function proper to each animal. The response of each animal estimated in this way exposed the effects of ACE inhibitors in vivo which were obscured by the feedback regulation of the renin-angiotensin system. Also, it was suggested that histargin has a peculiar action, blocking the negative feedback that would be elicited by the usual ACE inhibition. Feedback analysis seems to be essential to elucidate the in vivo effects of enzyme inhibitors.

Carboxypeptidase N (kininase I, EC 3.4.17.3) was found in human placenta and purified 600-fold. The enzyme was solubilized from membrane fractions with Triton X-100 and was purified by affinity chromatography with histargin, a potent inhibitor of this enzyme. The pH optimum of the enzyme was 7.8. The Km values for L-hippuryl-L-lysine and bradykinin were 1.25 and 0.43 mmol/l, respectively. The apparent molecular mass (Mr) of the enzyme determined by gel filtration was estimated to be 280,000, which is identical to that of the human serum enzyme. We propose that the placenta is a major source of carboxypeptidase N and thus may be involved in the physiological control of fetal circulation by regulating the kallikrein-kinin and renin-angiotensin systems.

We investigated, with use of a technique of feedback analysis, the dynamic changes in and around the renin-angiotensin system in vivo induced by ACE inhibition. Prolonged studies were performed over a half year on rabbits, which were treated by daily injections of saline or one of the inhibitors as follows: captopril, foroxymithine, histargin and pepstatin. In spite of the apparently bizarre movements of the raw data, the analysis with autoregressive modelling unveiled the different modes of feedback regulations of the renin-angiotensin system under the influence of the various inhibitors. In order to interpret the in vivo actions of enzyme inhibitors, it seems essential to take feedback regulations into consideration.