Angiotensinogen depletion by high renin levels in hypertensive rats: no evidence for tonic stimulation of angiotensinogen by angiotensin II.
OBJECTIVE
Data concerning the effect of angiotensin II (Ang II) on plasma angiotensinogen levels are conflicting. Although Ang II is reported to stimulate the biosynthesis of angiotensinogen, plasma angiotensinogen is often depleted by renin when the level of renin, and therefore Ang II, increases. In the present study we used the Ang II subtype 1 (AT1) receptor antagonist losartan to investigate whether rising plasma Ang II levels stimulate angiotensinogen production to counteract the falling plasma angiotensinogen levels caused by increasing renin activity in plasma.


METHODS
Angiotensinogen was measured in plasma from two previously reported studies in which 6-week-old stroke-prone spontaneously hypertensive rats (SHRSP) or Dahl salt-sensitive (Dahl-S) rats were fed high-salt diets (4 and 8% sodium chloride, respectively) for 10-12 weeks with or without losartan.


RESULTS
As reported previously, plasma renin was suppressed during the first 4 weeks of the high-salt diet but then paradoxically increased in both strains. When plasma renin increased, plasma angiotensinogen levels fell to 45 and 62% of the baseline value. The plasma renin concentration was negatively correlated with plasma angiotensinogen both in SHRSP and in Dahl-S rats (r = -0.76, P < 0.001 and r = -0.60, P < 0.001, respectively). In Dahl-S rats losartan treatment was associated with lower levels of plasma angiotensinogen but caused greater increases in plasma renin. When differences in renin were taken into account, plasma angiotensinogen levels were not different in losartan-treated and untreated Dahl-S rats. Similarly to Dahl-S rats, plasma angiotensinogen fell in SHRSP when renin increased, but SHRSP had higher plasma angiotensinogen levels during losartan treatment because plasma renin concentration was lower.


CONCLUSIONS
The present study shows, in two strains of hypertensive rat, that an increase in plasma renin levels is associated with a fall in plasma angiotensinogen levels. Concurrent treatment with an Ang II AT1 receptor antagonist does not augment this fall, except to the extent that renin rises further. The results provide no evidence for a significant tonic stimulatory effect of Ang II on plasma angiotensinogen levels.
Gahnem
F
F
Department of Medicine, Cornell University Medical College, NY 10021, USA.
Camargo
M J
MJ
von Lutterotti
N
N
Laragh
J H
JH
Sealey
J E
JE
D000284:Administration, Oral; D000804:Angiotensin II / Q000097:blood* / Q000187:drug effects; D000808:Angiotensinogen / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004032:Diet; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood* / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D001713:Biphenyl Compounds; D007093:Imidazoles; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin; D019808:Losartan