Blood pressure-independent effect of long-term treatment with the soluble heme-independent guanylyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage

Nitric oxide formation is impaired in chronic renal failure. The renoprotective effects of a nonhypotensive dose of HMR1766, a direct activator of the heme enzyme soluble guanylyl cyclase was studied in comparison to an ACE- i in the remnant kidney model. Male Sprague- Dawley rats were subtotally nephrectomized ( SNX) or sham operated ( sham) and left untreated or started on treatment with HMR1766 or ACE- i in non- hypotensive doses. BP, albumin excretion and parameters of renal damage were analyzed. After a 12- week study, urinary albumin excretion was significantly higher in untreated SNX than in sham; this increase was prevented by ACE- i and ameliorated by HMR1766. Relative kidney and left ventricular weight were significantly higher in untreated SNX compared to sham; these changes were completely prevented by HMR1766. In untreated SNX, glomerulosclerosis ( 1.02 +/- 0.13) was significantly higher than in sham ( 0.12 +/- 0.04), SNX+ HMR1766 ( 0.27 +/- 0.04) and SNX+ ACE- i ( 0.46 +/- 0.06). Tubulointerstitial changes went in parallel. Increased glomerular cell number after SNX ( 71.5 +/- 14 vs. 60 8 7.3 in sham) was prevented by HMR1766 ( 55.7 +/- 7.3), but not by ACE- i ( 66.6 +/- 9). The results document beneficial BP- independent HMR1766 effects on kidney structure and urinary albumin excretion in a noninflammatory model of renal failure and may argue for a novel therapeutic principle.