The mechanisms causing the release of plasma inactive renin (PIR) area still unclear. We have investigated the role of the kidney in the release of trypsin-activable PIR from extrarenal sources in the rat, with special reference to the submandibular gland.The activation of PIR was performed by incubation with 20 mg/ml trypsin at 4°C for up to 10 min; the reaction was then terminated by addition of 20 mg/ml of soybean trypsin inhibitor.Bilateral nephrectomy resulted in a gradual, marked, sex-independent increase in PIR concentration, reaching levels 4.5 times higher than basal in 24 h (time 0: 14.8 ± 1.0 ng/ml per h; 24 h: 66.8 ± 3.4 ng/ml per h, mean ± s.d.,P< 0.001). This increase was not altered by the concomitant intravenous infusion of pressor doses of either angiotensin (Ang) II (30 ng/min) or pure mouse submandibular renin (a 20-ng intravenous bolus followed by intravenous infusion at the rate of 50 ng/h) for 4 h, but was completely prevented by prior removal of the submandibular glands, in which no activity of active renin and no inactive renin was detected.These results suggest that the post-nephrectomy increase of PIR is not dependent on feedack mechanisms of the suppressed renin-angiotensin system, but is controlled by the presence of submandibular glands in the rat.