Response to angiotensin inhibition in rats with sustained renovascular hypertension correlates with response to removing renal artery stenosis.
OBJECTIVE
Sustained (late-phase) renovascular hypertension is associated with lower plasma renin activity than is the early phase. It is not clear to what extent this reduced plasma renin activity reflects diminished influence of the renin-angiotensin system. It also is not clear whether this change in the character of the disease influences the effectiveness of surgical removal of the renal artery stenosis in reversing hypertension. Using an animal model of sustained (> or =10 weeks after renal artery clipping) two-kidney, one-clip renovascular hypertension, we hypothesized that the magnitude of the depressor response to selective angiotensin II receptor blockade with losartan would reflect the influence of the renin-angiotensin system on hypertension and enable us to predict the depressor response to subsequent surgical removal of the clip.


METHODS
The left renal arteries of 20 male Sprague-Dawley rats weighing 150 to 200 gm were fitted with a silver clip (0.23 mm internal diameter). Systolic blood pressure was measured by means of tail-cuff plethysmography for 10 weeks. Rats were then given losartan orally (30 mg/kg a day) for 1 week while blood pressure was monitored. After an additional week to allow recovery, 13 rats underwent surgical unclipping, and seven underwent sham repair. Blood pressure again was monitored over the final week.


RESULTS
All two-kidney one-clip rats had hypertension 10 weeks after clipping (mean systolic blood pressure 206 +/- 10 mm Hg). Losartan decreased systolic blood pressure by 36 +/- 6 mm Hg. The response was variable, ranging from 3 to 66 mm Hg, and overall blood pressure did not normalize (170 +/- 8 mm Hg). Subsequent surgical unclipping decreased systolic blood pressure by 46 +/- 9 mm Hg. Again the response was variable, ranging from 10 to 99 mm Hg, although overall blood pressure did not normalize (164 +/- 7 mm Hg). The decrease in blood pressure after unclipping showed a high correlation with the blood pressure decrease after losartan administration (r = 0.861, p < 0.001). Resting plasma renin activity (before intervention) was 16 +/- 4 ng angiotensin I per milliliter per hour and was not predictive of the response to either losartan or surgical unclipping. The rats subjected to sham operations had no statistically significant changes in blood pressure. Histologic evaluation showed patent renal arteries without appreciable stenosis or intimal hyperplasia after removal of the clips.


CONCLUSIONS
In sustained two-kidney, one-clip renovascular hypertension, the depressor response to angiotensin II receptor blockade is attenuated, suggesting that late-phase hypertension becomes increasingly angiotensin II-independent. In our model, the extent to which sustained renovascular hypertension becomes refractory to 7 days of angiotensin II blockade is highly predictive of the ultimate outcome of surgical repair of renal artery stenosis.
Pipinos
I I
II
Division of Vascular Surgery, Henry Ford Hospital, Detroit, Mich 48202, USA.
Nypaver
T J
TJ
Moshin
S K
SK
Careterro
O A
OA
Beierwaltes
W H
WH
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D006978:Hypertension, Renovascular / Q000473:pathology / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051381:Rats; D012078:Renal Artery Obstruction / Q000473:pathology / Q000503:physiopathology*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D012083:Renin; D019808:Losartan