Combined therapy of cilazapril and losartan has no additive effects in ameliorating adriamycin-induced glomerulopathy.
OBJECTIVE
Effects of the blockade of renin-angiotensin system (RAS), by angiotensin-converting enzyme inhibitor (ACEi), type 1 angiotensin II receptor blocker (ARB), or a combination of both, were evaluated in Adriamycin (ADR)-induced glomerulopathy.


METHODS
Male Sprague-Dawley rats (180-250 g) were induced of glomerulopathy by treatment with ADR (2 mg/kg, i.v.). Six weeks later, they were treated with cilazapril (1 mg/kg/day) and/or losartan (10 mg/kg/day) for an additional 6 weeks.


RESULTS
The urinary excretion of protein progressively increased following the treatment with ADR, which was prevented by ACEi, ARB, and a combination of both. Similarly, the glomerulopathy assessed by glomerulosclerosis index was also ameliorated by ACEi or ARB. However, combined therapy of both ACEi and ARB was without an additional effect (Control 1.4 +/- 0.4%, ADR 10.7 +/- 2.7%**, ACEi 0.8 +/- 0.4%, ARB 2.6 +/- 1.0%, ACEi+ARB 1.7 +/- 1.5%, ** p < 0.01 vs. Control). The expression of transforming growth factor-beta(1) was increased following the treatment with ADR (1.4 +/- 0.07-fold, p < 0.05 vs. Control), however, the degree of which was similarly blunted by either ACEi, ARB, or the combination of both. The expression of type 1 angiotensin II receptor mRNA increased following the treatment with ADR, the degree of which was further upregulated by ACEi and decreased by ARB to the control level (ADR 1.3 +/- 0.06-fold*, ACEi 1.8 +/- 0.05-fold***, ARB 1.0 +/- 0.04-fold, * p < 0.05 and *** p < 0.001 vs. Control). The combined therapy of ACEi and ARB still showed an upregulation of type 1 angiotensin II receptor mRNA, however, of which degree was mitigated compared with that induced by ACEi alone (ACEi+ARB 1.5 +/- 0.04-fold, ** p < 0.01 vs. Control). On the contrary, the expression of type 2 angiotensin II receptor mRNA was downregulated following the treatment with ADR, which was similarly restored to the control level by ACEi, ARB, and a combination of both (ADR 0.5 +/- 0.08-fold**, ACEi 1.0 +/- 0.06-fold, ARB 1.0 +/- 0.05-fold, ACEi+ARB 1.0 +/- 0.05-fold, ** p < 0.01 vs. Control).


CONCLUSIONS
It is suggested that combined therapy of ACEi and ARB with relatively high or maximal doses of each drug has no additive or synergistic benefits on the progression of ADR-induced glomerulopathy. Effects of RAS blockade may in part be related to differential regulation of type 1 and type 2 angiotensin II receptors.
Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea. kimhj@hanyang.ac.kr
Ho-Jung
HJ
Kim
Jun-Ho
JH
Ryu
Sang-Woong
SW
Han
Ile Kyu
IK
Park
Seung Sam
SS
Paik
Moon Hyang
MH
Park
Doo Jin
DJ
Paik
Ho-Sam
HS
Chung
Soo Wan
SW
Kim
Jong Un
JU
Lee
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017315:Cilazapril / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009402:Nephrosis, Lipoid / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D011507:Proteinuria / Q000188:drug therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017315:Cilazapril; D004317:Doxorubicin; D019808:Losartan