Effect of combining an ACE inhibitor and an angiotensin II receptor blocker on plasma and kidney tissue angiotensin II levels.
Increased angiotensin II (AII) activity has been recognized as a risk factor for progression of kidney disease. There is increasing clinical evidence that combining an angiotensin-converting enzyme (ACE) inhibitor with an AII receptor blocker (ARB) reduces proteinuria and blood pressure in patients with renal disease, although the mechanism of this synergistic effect remains poorly defined. This study tested whether the combination of an ACE inhibitor and an ARB reduces plasma AII (AIIp) and kidney tissue AII (AIIk) beyond what is observed with either of these two agents alone. Mean arterial pressure, glomerular filtration rate, AIIp, and AIIk were measured in four groups of Wistar rats after 2 weeks of a low-salt diet and 1 week of treatment with captopril (2.4 mg/d), losartan (1.7 mg/d), combination captopril+losartan (1.7 mg/d of captopril, 0.7 mg/d of losartan), or no treatment (control). Administration of captopril, losartan, and captopril+losartan produced statistically significant reductions in mean arterial pressure (control, 130 +/- 4 mm Hg; captopril, 92 +/- 5 mm Hg; losartan, 88 +/- 4 mm Hg; captopril+losartan, 104 +/- 5 mm Hg) and mild reductions in glomerular filtration rate (control, 3.1 +/- 0.1 mL/min; captopril, 2.2 +/- 0.3 mL/min; losartan, 1.7 +/- 0.3 mL/min; captopril+losartan, 2.3 +/- 0.3 mL/min) when compared with control rats, but no significant differences were observed among the treated groups. Captopril and captopril +losartan reduced AIIp significantly when compared with control (captopril, 43 +/- 8 pg/mL; captopril+losartan, 47 +/- 5 pg/mL; control, 134 pg/mL) and with losartan (99 +/- 2 pg/mL). AIIk values were reduced in captopril (254 +/- 18 pg/g kidney weight) and losartan (292 +/- 33 pg/g kidney weight) when compared with control (1,235 +/- 79 pg/g kidney weight). Captopril+losartan (136 +/- 17 pg/g kidney weight) reduced AIIk to values significantly lower than captopril or losartan alone. Higher doses of captopril (5 mg/d and 7.5 mg/d) or losartan (4 mg/d and 6 mg/d) alone did not reduce AIIk to the levels observed with combination low doses of captopril+losartan. Combining low doses of ACE inhibitor plus ARB reduces AIIk more than higher doses of either agent alone. This reduction in AIIk with ACE inhibitor plus ARB provides a mechanism to understand the synergism of this combination in reducing proteinuria and blood pressure. The reduction in AIIk with ACE inhibitor plus ARB may have important implications in long-term organ protection in hypertension and renal disease.
Komine
Norikuri
N
Division of Nephrology/Hypertension, VA San Diego Healthcare System and University of California, San Diego, La Jolla, CA 92161, USA.
Khang
Ser
S
Wead
Lucinda M
LM
Blantz
Roland C
RC
Gabbai
Francis B
FB
D000804:Angiotensin II / Q000097:blood / Q000187:drug effects* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D012982:Sodium, Dietary / Q000008:administration & dosage
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D012982:Sodium, Dietary; D000804:Angiotensin II; D002216:Captopril; D019808:Losartan