Effects of angiotensin receptor blockers on ambulatory plasma Renin activity in healthy, normal subjects during unrestricted sodium intake.
BACKGROUND
Plasma renin activity (PRA), measured under controlled conditions, is a marker of the degree and persistence of renin-angiotensin system blockade.


METHODS
Two similarly designed five-way crossover studies evaluated angiotensin II type 1 (AT1) receptor blockade-induced changes in PRA in quietly seated, ambulatory volunteers who were ingesting uncontrolled diets. At weekly intervals, PRA was measured during the 24 h after administration of placebo, olmesartan medoxomil (20 or 40 mg), or valsartan (80 or 160 mg) (Study CS866-445), or placebo, olmesartan medoxomil (40 mg), valsartan (160 or 320 mg), or irbesartan (300 mg) (Study CS866-448). The primary end point was change in PRA relative to placebo from predose to 24 h postdose (DeltaPRA24).


RESULTS
In the 20 subjects who completed each study, there was a direct relationship between baseline PRA and DeltaPRA24 for all doses. Subjects with low PRA (<0.65 ng/mL/h) exhibited very low absolute increases in PRA. The DeltaPRA(24) increased significantly with olmesartan medoxomil 20 mg (P<.01) and 40 mg (P<.001) and valsartan 160 mg (P<.05) but not with valsartan 80 mg. In the second study (in which baseline PRA was lower), DeltaPRA24 increased with olmesartan medoxomil 40 mg (P<.0001), valsartan 320 mg (P<.01), and irbesartan 300 mg (P<.01) but not with valsartan 160 mg. The DeltaPRA24 was greatest with olmesartan medoxomil 40 mg and was dose-related for olmesartan medoxomil but not for valsartan.


CONCLUSIONS
The greater DeltaPRA24 with olmesartan medoxomil 40 mg indicates a more prolonged AT1 receptor blockade than with valsartan 80, 160, or 320 mg or irbesartan 300 mg. A routine, clinic ambulatory PRA level can be used as a biochemical marker of the persistence and degree of AT1 receptor blockade in subjects without suppressed PRA levels.
Phase IV Research, Daiichi Sankyo, Inc., Parsippany, New Jersey 07054, USA. mjones@daiichisankyo-us.com
Michael R
MR
Jones
Jean E
JE
Sealey
John H
JH
Laragh
D000293:Adolescent; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000652:urine; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001713:Biphenyl Compounds / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D000068557:Olmesartan Medoxomil; D011379:Prognosis; D011863:Radioimmunoassay; D012016:Reference Values; D012083:Renin / Q000097:blood* / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D016037:Single-Blind Method; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*; D013777:Tetrazoles / Q000008:administration & dosage; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D001713:Biphenyl Compounds; D007093:Imidazoles; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D000068557:Olmesartan Medoxomil; D000068756:Valsartan; D012083:Renin; D014633:Valine; D000077405:Irbesartan