An extremely high dose of losartan affords superior renoprotection in the remnant model

Background. Rats subjected to 5/6 renal ablation (NX) exhibit large renal amounts of angiotensin II (Ang II) and of its main receptor, AT-1R. At previously used doses, AT-1R blockers (ARB) offer only partial renal protection. A possible explanation for this limited effect is that these doses are insufficient to block most of the abnormally expressed AT-1R. We investigated whether extremely high doses of the ARB, losartan (L), offer better protection than conventional doses in the NX model. Methods. Thirty days after NX, tail-cuff pressure (TCP), albuminuria (UalbV, mg/day), glomerulosclerosis index (GSI), fractional interstitial area (%INT), and macrophage infiltration (MO) were evaluated in a separate group (NXpre). The remaining rats were then subdivided among 4 groups: NX+V, receiving vehicle; NX+L50, treated with L, at the "conventional" dose of 50 mg/kg/day; NX+L500, receiving L, 500 mg/kg/day; and NX+HH, receiving hydrochlorothiazide and hydralazine to lower blood pressure to a similar extent as in group L500. Results. After a month of treatment, blood pressure and renal vascular resistance were lowest in group L500. Glomerular pressure was lowered by a similar extent by L50 and L500, while GFR was similar among groups. UAlbV, TCP, and renal injury were only partially reduced by L50 120 days after renal ablation. By contrast, L500 arrested renal inflammation and glomerular/interstitial injury at pretreatment levels, and promoted regression of hypertension and UalbV, causing no apparent untoward effects. Conclusion. The renal protection afforded by ARB in NX is dose dependent. Maximal protection may require doses several fold higher than those currently employed.