EFFECT OF ACUTE AND CHRONIC LOSARTAN THERAPY ON ACTIVE AND INACTIVE RENIN AND ACTIVE RENIN GLYCOFORMS

Plasma active renin consists of multiple glycoforms, which are differe ntially stored and secreted by the kidney, have varying plasma half-li ves, and appear to have differing effects on renal sodium and water me tabolism. Acute stimulation of renal renin secretion results in a disp roportionate increase in plasma concentrations of the less negatively charged renin glycoforms and a decrease in the plasma half-life of act ive renin. The effects of chronic stimulation have not been well studi ed. We studied the effect of acute and chronic (42 days) stimulation o f the renin angiotensin system with the AT(1) selective angiotensin II receptor antagonist losartan on plasma active renin, active renin gly coforms separated by isoelectric focusing, and inactive renin in 11 es sential hypertensive patients. A single 50 mg dose of losartan signifi cantly increased plasma active renin concentration (ARC) from a pretre atment baseline of 3.2 +/- 1.1 to 7.2 +/- 2.3 ng AI/mL/h, 4 h postdose . This was primarily due to an increase in plasma concentrations of th e less negatively charged active renin forms. After 42 days of losarta n monotherapy, plasma ARC at losartan trough had increased significant ly to 7.8 +/- 3.1 ng AI/mL/h, although the proportions of active renin forms were identical to baseline. Plasma ARC also increased significa ntly from 7.8 +/- 3.1 to 14.9 +/- 6.0 ng AI/mL/h acutely after the los artan dose on day 42 primarily due to increased plasma concentrations of less negatively charged active renin forms. Although plasma inactiv e renin concentrations did not change acutely after losartan dosing on day 1 or 42 they did increase from 27.3 +/- 7.8 before losartan day 1 to 37.0 +/- 13.7 ng AI/mL/h (P = .14) before losartan day 42. Thus, b oth acute and acute on chronic stimulation of renal renin secretion in creased circulating ARC and shifted the profile of circulating renin t oward the less negatively charged forms but did not change inactive re nin concentrations. Chronic stimulation of renal renin secretion with losartan increased plasma concentrations of both active and inactive r enin, but did not alter the proportions of active renin forms. Since t he less negatively charged active renin forms have relatively short pl asma half-lives, acute, but not chronic renal renin secretion is assoc iated with a change in plasma renin half-life. Chronic stimulation of renal renin secretion with losartan presumably increased renin gene ex pression and resulted in increased constitutive secretion of inactive renin, increased constitutive secretion of negatively charged active r enin forms, and increased renal storage of less negatively charged ren in forms that were then available for acute regulated release.