Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model.
OBJECTIVE
Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria.


METHODS
Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4-160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy.


RESULTS
No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80-120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses.


CONCLUSIONS
ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.
Tominaga
Naoto
N
Institute of Medical Sciences, Tokai University, Kanagawa, Japan. tominaga1213@kbd.biglobe.ne.jp
Robert
Annie
A
Izuhara
Yuko
Y
Ohtomo
Shuichi
S
Dan
Takashi
T
Chihara
Kazuo
K
Kurokawa
Kiyoshi
K
Van Ypersele de Strihou
Charles
C
Miyata
Toshio
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006973:Hypertension / Q000150:complications; D016014:Linear Models; D008297:Male; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine