Addition of AT1 blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis.
BACKGROUND
Angiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy response, particularly for individuals with a poor response to ACE inhibition. We studied whether co-treatment with an angiotensin II subtype 1 (AT1) receptor antagonist (AII-A) improves the individual antiproteinuric response of maximal ACE inhibition in established adriamycin nephrosis.


METHODS
Rats were instituted on lisinopril (75 mg/L) six weeks after disease induction. After two weeks rats were re-stratified for residual proteinuria to continue this regimen, to a higher dose of lisinopril (150 mg/L) or to co-treatment with the AII-A L 158,809 for another four weeks. Groups on monotherapy AII-A and vehicle served as controls (all groups N=15).


RESULTS
Lisinopril lowered proteinuria by 63% from 741 to 246 g/day (range of percentage change -90 to +2%). Neither increasing the dose of the ACE inhibitor nor addition of AII-A to ACE inhibition improved the antiproteinuric efficacy on a group or individual level: non-responders remained non-responders. All drug categories reduced hard end-points of focal glomerulosclerosis to a similar degree.


CONCLUSIONS
ACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level.
Bos
Hendrik
H
Department of Clinical Pharmacology, Faculty of Medical Sciences and Groningen University Institute of Drug Exploration (GUIDE), University of Groningen, Groningen, The Netherlands.
Henning
Robert H
RH
De Boer
Eric
E
Tiebosch
Anton T M G
AT
De Jong
Paul E
PE
De Zeeuw
Dick
D
Navis
Gerjan
G
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy*; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C070967:L 158809; D004317:Doxorubicin; D017706:Lisinopril