title: Renoprotective effects of VPI versus ACEI in normotensive nephrotic rats on different sodium intakes.
abstract: BACKGROUND
  Control of blood pressure (BP) and optimal reduction of proteinuria (Uprot) are necessary for long-term renoprotection. Unfortunately, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) antagonists are not effective during sodium repletion. Vasopeptidase inhibitors (VPI) cause dual inhibition of ACE and neutral endopeptidase, the latter resulting in decreased atrial natriuretic peptide (ANP) breakdown and thus enhanced natriuresis. Therefore, in contrast with ACEI, VPI may be effective during high sodium intake.
  
  
  METHODS
  To test this hypothesis, the renoprotective actions of the new VPI gemopatrilat (GEM) were studied during low (0.05% NaCl) and high (3.0% NaCl) sodium diets in normotensive Wistar rats with established adriamycin nephrosis. The ACEI lisinopril (LIS) was used as control. Rats received either GEM (0.3 mg/g chow), an equihypotensive dose of LIS (75 mg/L drinking water), or vehicle (VEH) from week 6 (that is, established Uprot) until sacrifice. The effect of therapy was monitored by measuring systolic BP and Uprot (weekly) and structural renal damage at the end of study (week 16).
  
  
  RESULTS
  During low sodium, GEM effectively reduced Uprot (-48 +/- 4%), but LIS was more effective (-80 +/- 2%), while Uprot slightly increased in VEH (+23 +/- 2%). The focal glomerulosclerosis (FGS) score after GEM (38 +/- 14) was lower than in the VEH group (79 +/- 27), although this was not significant. LIS (18 +/- 6) reduced FGS significantly. Remarkably, on high sodium, GEM was completely ineffective in reducing BP, Uprot and structural renal injury, just like LIS.
  
  
  CONCLUSIONS
  The renoprotective actions of VPI depend on dietary sodium intake in normotensive nephrotic rats: therapeutic efficacy is fully blunted by a high sodium diet. During a low sodium diet, gemopatrilat was renoprotective, but less effective than lisinopril. Whether higher doses of the VPI could improve its renoprotective efficacy remains to be elucidated.
authors.affiliation: Department of Medicine, Groningen University Institute of Drug Exploration (GUIDE), University of Groningen, The Netherlands. gd_laverman@hotmail.com
authors.forename: Gozewijn D
authors.initials: GD
authors.lastname: Laverman
authors.forename: Harry
authors.initials: H
authors.lastname: Van Goor
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.forename: Paul E
authors.initials: PE
authors.lastname: De Jong
authors.forename: Dick
authors.initials: D
authors.lastname: De Zeeuw
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D009401:Nephrosis / Q000188:drug therapy* / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D012982:Sodium, Dietary / Q000494:pharmacology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001381:Azepines; D004791:Enzyme Inhibitors; D012982:Sodium, Dietary; D003404:Creatinine; D017706:Lisinopril; D015260:Neprilysin; C478302:gemopatrilat