trandolapril and Glomerulosclerosis--Focal-Segmental

Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists.. 5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague-Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks.. Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR.. SNX caused a significant (P < 0.01) increase of systolic blood pressure (170 +/- 8.6 mmHg) compared to sham operated controls (131 +/- 5.3 mmHg). Blood pressure was significantly (P < 0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153 +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg). Compared to sham operated rats (0.03 +/- 0.01) glomerulosclerosis index (GSI) was significantly (P < 0.01) higher in the untreated SNX group (0.9 +/- 0.15). Significantly lower GSI was found in Trandolapril treated (0.29 +/- 0.04), BMS 182874 treated (0.36 +/- 0.05), and Ro 46-2005 treated animals (0.45 +/- 0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P < 0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P < 0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower.. Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists interfere with development of glomerulosclerosis by mechanisms which are, at least in part, independent of systemic blood pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Base Sequence; Blood Pressure; Dansyl Compounds; DNA Primers; Endothelin Receptor Antagonists; Endothelins; Glomerulosclerosis, Focal Segmental; Hypertrophy; Indoles; Kidney Glomerulus; Male; Molecular Sequence Data; Nephrectomy; Polymerase Chain Reaction; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; RNA, Messenger; Sulfonamides

Previous studies have demonstrated differences in the progression to glomerulosclerosis with the use of calcium channel blockers (CCB). The results with angiotensin-converting enzyme (ACE) inhibitors are more consistent. Moreover, only two studies have examined the combined effects of these drug classes on the development of glomerulosclerosis. The aim of the study presented here was to test the hypothesis that nonhypotensive doses of the combination (VT) of a nondihydropyridine CCB, verapamil (V), and an ACE-inhibitor, trandolapril (T), will slow the development of glomerulosclerosis better than either agent alone in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were randomized to treatment in one of three groups with nonhypotensive doses of these agents; a fourth group served as control (C). The control rats developed significant increases in proteinuria compared with the other groups (C, 190 +/- 35 mg.kg-1.d-1 versus VT, 19 +/- 12 mg.kg-1.d-1; P < 0.05). This finding correlated with the degree of glomerulosclerosis (mean severity grading for C, 3.31 +/- 0.21 versus VT, 1.6 +/- 0.51; P < 0.05). Moreover, there was no significant reduction in arterial pressure between these groups (C, 282 +/- 5 versus VT, 259 +/- 13 mm Hg; P = 0.12). Despite persisting hypertension, the rise in proteinuria was also attenuated in both the V group (57 +/- 21 mg.kg-1.d-1) and the T group (43 +/- 24 mg.kg-1.d-1). However, compared with the control rats, kidney morphology was unchanged. Lastly, creatinine clearance was better preserved in the VT group compared with the control group (C, 0.57 +/- 0.01 versus VT, 0.74 +/- 0.06 mL.min-1.100 g-1; P < 0.05). It was concluded that the combination of nonhypotensive doses of VT attenuates the rise in proteinuria and progression to glomerulosclerosis. This study supports the concept that VT may have effects on the glomerulus that are independent of blood pressure reduction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Creatinine; Disease Progression; Disease Susceptibility; Drug Synergism; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Hypertension; Indoles; Kidney; Male; Metabolic Clearance Rate; Proteinuria; Rats; Rats, Inbred SHR; Verapamil