OBJECTIVE To determine whether immunoreactive tissue kallikrein levels in cerebrospinal fluid (CSF) of spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)--salt-treated hypertensive rats are elevated compared with normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats. METHODS The present study was designed to test the hypothesis that the activity of the brain tissue kallikrein-kinin system is enhanced in hypertensive states. METHODS Age-matched 18- to 19-week-old SHR and WKY rats, and Sprague-Dawley rats treated for 6 weeks either with 2 mg/kg per day DOCA subcutaneously and 0.9% saline in the drinking water, or with vehicle and tap water to drink, were studied. CSF was collected from a cannula inserted into the cisterna magna, and was frozen until the tissue kallikrein in the samples was measured by radioimmunoassay. Arterial pressure in the SHR and WKY rats was measured directly via a cannula inserted in the femoral artery or by tail-cuff plethysmography. RESULTS In adult 18- to 19-week-old SHR the CSF kallikrein concentration was higher than in WKY rats. The CSF flow rate in SHR was also higher than in WKY rats. The rate of appearance of kallikrein in the CSF of SHR was twice that in WKY rats. Moreover, CSF kininogenase activity in SHR was significantly higher than that in age-matched WKY rats. In DOCA--salt hypertensive rats the CSF kallikrein concentration was higher than in vehicle-treated control rats. Acute elevation of blood pressure with a 120-min intravenous phenylephrine infusion did not change the CSF kallikrein concentration in 50 rats compared with vehicle-treated control rats. This is the first study to quantitate immunoreactive tissue kallikrein in the CSF of rats and to show elevated levels of CSF kallikrein in hypertensive rats compared with normotensive rats. CONCLUSIONS The present data suggest that higher brain kallikrein activity in hypertensive rats may play a role in the development of elevated blood pressure.