Renoprotective effects of VPI versus ACEI in normotensive nephrotic rats on different sodium intakes

Abstract

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. 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). 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. 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.