Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting enzyme inhibition alone.
The renoprotective efficacy of the vasopeptidase inhibitor omapatrilat (OMA) was compared with that of enalapril (ENA) in male Munich-Wistar rats subjected to 5/6 nephrectomy. ENA and OMA administered beginning on day 2 after surgery were equally effective in normalizing systolic BP (SBP) and preventing glomerulosclerosis (GS) for 12 wk. Micropuncture studies of rats performed using a similar treatment protocol demonstrated greater reduction of glomerular capillary hydraulic pressure with OMA than with ENA, at similar mean arterial pressures. To investigate whether these glomerular hemodynamic differences might be associated with differences in chronic renoprotective efficacy, additional rats were included in a protocol in which treatment was delayed until 4 wk after surgery (after the onset of hypertension and proteinuria) and continued for a longer period. Both treatments normalized SBP, but OMA resulted in more sustained reduction of proteinuria than did ENA. At week 20, OMA- and ENA-treated rats exhibited less GS than did untreated (control) rats at week 12, but only the difference in control versus OMA values was statistically significant [GS scores: control (12 wk), 36 +/- 4%; ENA (20 wk), 22 +/- 6%; OMA (20 wk), 14 +/- 2%]. The remaining ENA-treated rats were euthanized at 32 wk because of rapidly increasing proteinuria, whereas the remaining OMA-treated rats demonstrated a substantially slower increase in proteinuria until euthanasia at 50 wk. At this extremely late time point, OMA-treated rats exhibited GS scores similar to those of ENA-treated rats at 32 wk and control rats at 12 wk [GS scores: ENA (32 wk), 34 +/- 5%; OMA (50 wk), 38 +/- 8%]. It is concluded that, in this model, OMA affords greater long-term renoprotection than ENA when doses are adjusted to yield equivalent control of SBP.
Taal
Maarten W
MW
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Nenov
Vesselin D
VD
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Wong
Waichi
W
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Satyal
Sharad R
SR
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Sakharova
Olga
O
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Choi
Jeong Hoon
JH
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Troy
Julia L
JL
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Brenner
Barry M
BM
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002908:Chronic Disease; D018450:Disease Progression; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology*; D007674:Kidney Diseases / Q000503:physiopathology*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011677:Punctures; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D015260:Neprilysin