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Chronic Angiotensin II Infusion But Not Bradykinin Blockade Abolishes the Antiproteinuric Response to Angiotensin-Converting Enzyme Inhibition in Established Adriamycin Nephrosis

FRITS H. WAPSTRA^*, GERJAN NAVIS^*,, PAUL E. DE JONG^* and DICK DE ZEEUW^*,

^* Groningen Institute of Drug Studies (GIDS), Department of Medicine, Division of Nephrology, University Hospital and Groningen School of Medicine, The Netherlands.
Groningen Institute of Drug Studies (GIDS), Department of Clinical Pharmacology, University Hospital and Groningen School of Medicine, The Netherlands.

Correspondence to Dr. Gerjan Navis, Department of Nephrology, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Phone: +31 5036 12621; Fax: +31 5036 19310; E-mail: g.j.navis{at}int.azg.nl

Abstract. Angiotensin-convernting enzyme (ACE) inhibition reduces proteinuria in established adriamycin nephrosis. To investigate whether the reduction in proteinuria is due to decreased generation of angiotensin II (AngII) or to decreased degradation of bradykinin, four series of experiments in established adriamycin nephrosis were performed. In the first series, 2 mg/kg lisinopril reduced BP from 117 ± 4 to 67 ± 2 mmHg and proteinuria from 335 ± 66 to 57 ± 10 mg/24 h after 2 wk of treatment. Subsequent continuous intraperitoneal infusion of AngII (250 ng/kg per min) for 2 wk partially restored proteinuria to 180 ± 42 mg/24 h, whereas BP increased to 97 ± 3 mmHg. Subsequent withdrawal of AngII restored the antiproteinuric effects of lisinopril, whereas subsequent withdrawal of lisinopril restored proteinuria to pretreatment values. In the second series, AT1 receptor blockade induced a fall in BP and proteinuria similar to that by lisinopril. In the third series, lisinopril reduced BP from 121 ± 5 to 68 ± 2 mmHg and proteinuria from 355 ± 90 to 101 ± 10 mg/24 h. Subsequent intraperitoneal infusion of bradykinin antagonist (HOE 140; 1 mg/kg per 24 h) for 2 wk did not affect BP (72 ± 2 mmHg) or proteinuria (92 ± 15 mg/24 h). In the fourth series, bradykinin (3 mg/kg per 24 h) was infused for 2 wk to mimic decreased bradykinin breakdown. This did not affect proteinuria, but induced a fall in BP from 114 ± 3 to 93 ± 4 mmHg. The BP-lowering effect of exogenous bradykinin was completely reversed by 1 wk infusion of HOE 140 (93 ± 4 to 113 ± 4 mmHg), while proteinuria remained unchanged. In conclusion, the antiproteinuric effect of ACE inhibition appears to be independent of bradykinin in this model, supporting a main role for reduction of AngII in the antiproteinuric action of ACE inhibition.

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