TCV 116 prevents progressive renal injury in rats with extensive renal mass ablation.
OBJECTIVE
The objective of this study was to determine the renal protective effects of TCV 116, a novel, non-competitive, angiotensin II type 1 (AT1) receptor antagonist, in rats with 5/6 renal mass ablation.


METHODS
Adult male Wistar rats were subjected to 5/6 nephrectomy and treated continuously with either TCV 116 (group I, n = 8; group III, n = 9) or vehicle (group II, n = 8; group IV, n = 8). The development of elevated systolic blood pressure, 24-h urinary protein excretion, glomerular hemodynamics and glomerular morphology were compared among groups.


RESULTS
Systolic blood pressure rapidly reached hypertensive levels in group II, increasing from 175 +/- 8 mmHg after 3 weeks to 221 +/- 15 mmHg after 12 weeks, whereas group I rats remained normotensive (101 +/- 8 to 112 +/- 6 mmHg). Similarly, urinary protein excretion increased from 45 +/- 11 to 104 +/- 18 mg/day in group II, but remained low (6.9 +/- 1 to 19 +/- 4 mg/day) in group I. After 12 weeks, there was an average of 42 +/- 6% glomerulosclerosis in group II, but only 1.6 +/- 0.5% in group I. After 4-6 weeks, a markedly elevated glomerular capillary pressure (62 +/- 1.2 mmHg) was observed in group IV, but the pressure was normal in group III (50 +/- 1.1 mmHg).


CONCLUSIONS
These data show that TCV 116 prevents the development of systemic hypertension, glomerular capillary hypertension, proteinuria and glomerulosclerosis in rats with reduced renal mass. We therefore conclude that the renal protection associated with angiotensin I converting enzyme inhibitors and other pharmacologic blockers of the renin-angiotensin system arises chiefly from blockade of AT1 receptor-mediated hemodynamic effects.
Mackenzie
H S
HS
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Troy
J L
JL
Rennke
H G
HG
Brenner
B M
BM
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007238:Infarction / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000517:prevention & control*; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C077793:candesartan cilexetil