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 +/- 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.