Beneficial Effect of the Long-Term Treatment with the Combination of an ACE Inhibitor and a Calcium Channel Blocker on Renal Injury in Rats with 5/6 Nephrectomy

Abstract

The effects of the addition of a calcium channel blocker, verapamil (20 mg/kg/day) to an ACE inhibitor, trandolapril (0.7 mg/kg/day) in a 6-month treatment on renal insufficiency development in rats with 5/6th nephrectomy, were studied. Every month we measured heart rate and arterial pressure by the tail-cuff method. Renal function studies were performed in metabolic cages. At the end of the study, renal tissue was prepared for light microscope analysis. Renal lesions were assessed by semiquantitative scores in a blind fashion. Corpuscular section area, intraglomerular and tubulointerstitial fibrosis were determined by digital image analysis with a specific software (Fibrosis HR^®) on syrium red-stained renal sections. Trandolapril markedly increased the survival ratio that after 6 months reached 87% in comparison with 61% in untreated rats. No mortality was observed in rats treated with the combination of verapamil and trandolapril. Trandolapril treatment prevented the development of hypertension. The combination verapamil-trandolapril did not induce further reduction on blood pressure. The untreated group showed a marked proteinuria, that in the trandolapril group showed an important reduction. The verapamil + trandolapril group showed a proteinuria significantly smaller than that of all the other groups. Light microscopy semiquantitative studies of the renal injury showed that the trandolapril and verapamil + trandolapril groups had a marked reduction in glomerular and tubulointerstitial alterations, compared with untreated animals. Quantitative determinations of glomerular and interstitial fibrosis performed on syrium red-stained renal sections demonstrated that fibrosis was reduced when rats when treated with trandolapril and even more with verapamil + trandolapril when they were compared to untreated animals’ values. In conclusion, long-term treatment with verapamil given in addition to trandolapril produces additional protection against progressive renal injury associated to subtotal nephrectomy.