Protective effects of CGS 30440, a combined angiotensin-converting enzyme inhibitor and neutral endopeptidase inhibitor, in a model of chronic renal failure.

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Abstract

The purpose of these studies was to compare the effects of CGS 30440 (CGS), a dual angiotensin-converting enzyme inhibitor (ACEI)/neutral endopeptidase inhibitor (NEPI) to benazepril (BZ), an ACEI, in a model of five-sixths nephrectomy. The doses of BZ and CGS 30440 tested were 6.5 micromol/kg/day and 2.2 micromol/kg/day. Drugs or vehicle (V) were administered subcutaneously for 6 weeks with dosing initiated 1 week after renal mass reduction. At 6 weeks of receiving drug (7 weeks after five-sixths nephrectomy), CGS/6.5 and BZ/6.5 and CGS/2.2 maintained systolic blood pressures (SBP) at presurgical values. BZ/2.2 did not reduce SBP and was similar to the V group. Urinary protein excretion increased >10-fold in the V-treated group. BZ, at either dose, reduced the proteinuria slightly. CGS/6.5 and CGS/2.2 caused significant (p < 0.05) reductions in proteinuria. Creatinine clearance (Cr(cl)), was reduced by 82% in V, 65 and 61% in the CGS/6.5 and CGS/2.2 groups, and by 69 and 74% in the BZ/6.5 and BZ/2.2 groups, respectively. Both CGS treatments improved the fractional excretion of Na+ (%FE(Na)) significantly from the BZ and V groups. The %FE(Na) for BZ at either dose did not differ from that of V. Elevated urinary cyclic guanosine monophosphate (cGMP), an indicator suggesting increased intrarenal levels of atrial natriuretic peptide (ANP), was observed only in the CGS groups. Histologic examination indicated that BZ/6.5 reduced glomerular sclerosis and the extent of tubular dilation, whereas BZ/2.2 had little effect. CGS, especially at the high dose, virtually normalized the glomerular and tubular pathology. Compared with BZ, CGS 30440 treatment further diminished tubular dilation and proteinaceous cast formation. These tubular effects are consistent with some of the renal actions of ANP. The results from these studies indicate that CGS 30440, a combined ACEI/NEPI, conferred a greater renal protective effect than did ACE inhibition alone.

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Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

W Border, S Kagami, Joan W. Miller … (1994)

Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-beta plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease/protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-beta. Ang II treatment of rat mesangial cells in culture increased TGF-beta and matrix components biglycan, fibronectin, and collagen type I at both the mRNA and protein levels in a time- and dose-dependent manner. Saralasin, a competitive inhibitor of Ang II, prevented the stimulation. Ang II also promoted conversion of latent TGF-beta to the biologically active form. Coincubation of mesangial cells with Ang II and neutralizing antibody to TGF-beta blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-beta and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of TGF-beta expression. This mechanism may well contribute to glomerulosclerosis in vivo.

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Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.

Annie S. Anderson, H Rennke, Caroline T. Meyer … (1985)

Micropuncture and morphologic studies were performed in four groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 3 received no specific therapy. Groups 2 and 4 were treated with the angiotensin I converting enzyme inhibitor, enalapril, 50 mg/liter of which was put in their drinking water. All rats were fed standard chow. Groups 1 and 2 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure difference and glomerular plasma flow rate. In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained the mean glomerular transcapillary hydraulic pressure gradient at near-normal levels without significantly compromising SNGFR and the glomerular capillary plasma flow rate, as compared with untreated group 1 rats. Groups 3 and 4 were studied 8 wk after renal ablation. Untreated group 3 rats demonstrated persistent systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and segmental sclerosis. In group 4 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 8-wk period and significantly limited the development of proteinuria and glomerular lesions. These studies suggest that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further support the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced.

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Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy.

Shigeto Ishidoya, Jeremiah J Morrissey, Ruth McCracken … (1996)

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF-beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy.