Effects of an atrial natriuretic peptide receptor antagonist on glomerular hyperfiltration in diabetic rats

Previous studies from this laboratory implicated atrial natriuretic peptide (ANP) as a possible mediator of glomerular hyperfiltration in diabetic rats. In this study, the potential of HS-142-1 (HS), a novel polysaccharide compound with ANP receptor antagonist properties, to ameliorate glomerular hyperfiltration in diabetic rats was assessed. Initially, it was confirmed that a bolus iv injection of HS blocked both diuretic and natriuretic responses to exogenous ANP in normal Munich-Wistar rats. The acute effects of HS in moderately hyperglycemic diabetic rats with glomerular hyperfiltration and hyperperfusion were then determined. In diabetic rats, HS (20 mg/kg bolus iv) lowered GFR by approximately 46% from hyperfiltering (1.86 +/- 0.06 mL/min) to normal (1.13 +/- 0.13 mL/min) levels, whereas GFR in vehicle-treated diabetic rats remained unchanged (1.92 +/- 0.08 mL/min to 1.77 +/- 0.09 mL/min). In nondiabetic euvolemic rats, GFR was reduced by 20% after HS, whereas GFR in vehicle-treated controls was unchanged. In contrast, HS had no effect on GFR in hydropenic rats. Effective RPF was not significantly reduced in either diabetic or normal euvolemic rats in response to HS; consequently, significant reductions in filtration fraction were observed in both groups. Urine flow and sodium excretion rates were significantly reduced after HS in both diabetic and nondiabetic groups but not in hydropenic or vehicle-treated groups. These data show that HS ameliorates glomerular hyperfiltration in diabetic rats, further supporting the hypothesis that intrarenal actions of natriuretic peptides contribute significantly to glomerular hyperfiltration in experimental diabetes mellitus.