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 differentially stored and secreted by the kidney, have varying plasma half-lives, and appear to have differing effects on renal sodium and water metabolism. Acute stimulation of renal renin secretion results in a disproportionate increase in plasma concentrations of the less negatively charged renin glycoforms and a decrease in the plasma half-life of active renin. The effects of chronic stimulation have not been well studied. We studied the effect of acute and chronic (42 days) stimulation of the renin angiotensin system with the AT1 selective angiotensin II receptor antagonist losartan on plasma active renin, active renin glycoforms separated by isoelectric focusing, and inactive renin in 11 essential hypertensive patients. A single 50 mg dose of losartan significantly increased plasma active renin concentration (ARC) from a pretreatment 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 the less negatively charged active renin forms. After 42 days of losartan monotherapy, plasma ARC at losartan trough had increased significantly to 7.8 +/- 3.1 ng AI/mL/h, although the proportions of active renin forms were identical to baseline. Plasma ARC also increased significantly from 7.8 +/- 3.1 to 14.9 +/- 6.0 ng AI/mL/h acutely after the losartan dose on day 42 primarily due to increased plasma concentrations of less negatively charged active renin forms. Although plasma inactive 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, both acute and acute on chronic stimulation of renal renin secretion increased circulating ARC and shifted the profile of circulating renin toward the less negatively charged forms but did not change inactive renin concentrations. Chronic stimulation of renal renin secretion with losartan increased plasma concentrations of both active and inactive renin, but did not alter the proportions of active renin forms. Since the less negatively charged active renin forms have relatively short plasma half-lives, acute, but not chronic renal renin secretion is associated with a change in plasma renin half-life. Chronic stimulation of renal renin secretion with losartan presumably increased renin gene expression and resulted in increased constitutive secretion of inactive renin, increased constitutive secretion of negatively charged active renin forms, and increased renal storage of less negatively charged renin forms that were then available for acute regulated release.
Opsahl
J A
JA
School of Medicine, University of Minnesota, Minneapolis, USA.
Goldberg
M R
MR
Katz
S A
SA
D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007525:Isoelectric Focusing; D019808:Losartan; D008297:Male; D008875:Middle Aged; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D012083:Renin; D019808:Losartan