Inhibition of the Kallikrein-Kinin System and Vascular Reactivity in Bartterʼs Syndrome

To study the significance of the increased activity of the kallikrein-kinin system described in patients with Bartterʼs syndrome, we investigated the pressor response to infused angiotensin II in four patients with the syndrome receiving no treatment and during the administration of aprotinin and of indomethacin. Five normal subjects served as controls. Aprotinin is a proteolytic enzyme that inhibits the formation of kinins by inhibiting plasma and glandular kallikrein. Indomethacin, a prostaglandin-synthesis inhibitor, can also inhibit the kallikrein-kinin system and normalizes vascular responsiveness to angiotensin II in Bartterʼs syndrome. All patients had increased urinary kallikrein and prostaglandin E2 concentrations. Aprotinin significantly decreased the dose of infused angiotensin II required to induce a 20 mm Hg increase in diastolic blood pressure, from 11 ± 4 ng/kg/min to 7.0 ± 2.0 ng/kg/min (mean ± SD; p < 0.05) in normal subjects and from 135 ± 57 ng/kg/min to 70 ± 26 ng/kg/min (p < 0.05) in the patients with Bartterʼs syndrome, without significantly changing plasma renin activity, mean control blood pressure, or urinary prostaglandin E2 concentration. Indomethacin normalized the pressor response to angiotensin II in three patients who had been pretreated for 4 days (pressor dose, 10 ng/kg/min) but not in one patient who received a single oral dose of indomethacin 5 hours before the test. Our results suggest that inhibition of the kallikrein-kinin system alone accounts for approximately a 50% decrease in vascular resistance to the pressor effect of angiotensin II in Bartterʼs syndrome, while additional suppression of prostaglandins entirely normalizes the vascular response to angiotensin II. These observations underscore the importance of the kallikrein-kinin system as a vasodilator in Bartterʼs syndrome and support the concept that this system may contribute to the regulation of blood pressure in human beings.