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

Abstract

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.

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat

“…Notably, this was achieved at doses of BI 703704 (0.3, 1, and 3 mg/kg) that did not significantly reduce MAP. This is consistent with a previous report indicating that treatment with the sGC activator HMR1766 can reduce urinary albumin excretion in the rat 5/6 nephrectomy model of chronic renal failure without affecting blood pressure (Benz et al, 2007). Thus, although BI 703704 is capable of reducing blood pressure, significant hemodynamic effects are not required to induce robust proteinuria reductions in ZSF1 rats.…”

“…* ,# Significant P , 0.05 versus vehicle and enalapril, respectively, using one-way analysis of variance. rat 5/6 nephrectomy model of chronic renal failure (Kalk et al, 2006;Benz et al, 2007). This model is characterized by surgically-induced impaired renal function, but lacks the diabetic milieu and its impact on renal molecular pathways.…”

Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence

“…Dahl rats fed a high-salt diet (JP Stasch et al, unpublished). In a low-NO/high-renin rat model of hypertension, vericiguat reduced right and left ventricle hypertrophy and mortality, and showed a positive effect on grading of kidney changes, and the incidence and severity of myocardial lesions [49][50][51][52][53]54 ]. The potentially beneficial effects of vericiguat on cardiac function are supported by the findings from recently completed phase I studies, which found that this agent leads to improvement in important cardiologic parameters, including: cardiac output/index, systemic vascular resistance, and stroke volume [49].…”

Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat

“…Inasmuch as impaired autoregulation provides a risk factor for chronic renal failure, particularly in combination with hypertension (5), the findings also suggest safety with regard to chronic renal failure. In addition, cinaciguat and the structurally unrelated sGC activator ataciguat (HMR1766) have been shown to play a beneficial role in chronic kidney disease (4,35), presumably due to nonvascular effects ascribed to NO and cGMP on renal inflammation, fibrosis, and glomerulosclerosis (10,36,63).…”