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.
Benz
Kerstin
K
Department of Pediatrics, University of Erlangen, Erlangen, Germany. amann@patho.imed.uni-erlangen.de <amann@patho.imed.uni-erlangen.de>
Orth
Stephan R
SR
Simonaviciene
Aurelia
A
Linz
Wolfgang
W
Schindler
Ursula
U
Rütten
Hartmut
H
Amann
Kerstin
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000819:agonists / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013995:Time; D062367:ortho-Aminobenzoates / Q000494:pharmacology* / Q000627:therapeutic use
D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C515616:5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide