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.

• Authors: Kerstin Benz, Stephan R Orth, Aurelia Simonaviciene, Wolfgang Linz, Ursula Schindler, Hartmut Rütten, Kerstin Amann
• Journal: Kidney & blood pressure research (Kidney Blood Press Res) Vol. 30 Issue 4 Pg. 224-33 ( 2007) ISSN: 1423-0143 [Electronic] Switzerland
• PMID: 17575468 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2007 S. Karger AG, Basel.

Chemical References

• Receptors, Cytoplasmic and Nuclear
• Sulfonamides
• ortho-Aminobenzoates
• Heme
• Guanylate Cyclase
• Soluble Guanylyl Cyclase
• 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide

Topics

• Animals
• Blood Pressure (drug effects, physiology)
• Disease Models, Animal
• Disease Progression
• Guanylate Cyclase (metabolism)
• Heme (agonists, metabolism)
• Kidney Failure, Chronic (drug therapy, enzymology, pathology)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, Cytoplasmic and Nuclear (agonists, metabolism)
• Soluble Guanylyl Cyclase
• Sulfonamides (pharmacology, therapeutic use)
• Time
• ortho-Aminobenzoates (pharmacology, therapeutic use)