Effects of Combined Endothelin A Receptor and Renin-Angiotensin System Blockade on the Course of End-Organ Damage in 5/6 Nephrectomized Ren-2 Hypertensive Rats

Abstract

Our previous studies in rats with ablation nephrectomy have shown similar cardiorenal protective effects of renin-angiotensin system (RAS)-dependent treatment (combination of angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker) and RAS-independent treatment (combination of α- and β-adrenoreceptor antagonist and diuretics). Moreover, selective blockade of endothelin (ET) receptor type A (ET_A) improved survival rate and attenuated hypertension and organ damage in Ren-2 transgenic rats. Therefore, we were interested in whether ET_A receptor blockade could have additive effects to the classical blockade of the RAS. Transgenic rats underwent 5/6 renal ablation at the age of 2 months and were treated for 20 weeks with RAS blockers alone (angiotensin II receptor blocker – losartan, and angiotensin-converting enzyme inhibitor – trandolapril), ET_A receptor blocker alone (atrasentan) or with the combination of RAS and ET_A receptor blockade. RAS blockade normalized blood pressure and improved survival. It decreased cardiac hypertrophy and proteinuria as well as tissue angiotensin II and ET-1 levels. In contrast, ET_A receptor blockade only partially improved survival rate, reduced blood pressure, attenuated the development of cardiac hypertrophy and transiently reduced proteinuria. However, no additive cardio- and renoprotective effects of ET_A and RAS blockade were noted at the end of the study.

Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats

“…These findings are in accordance with previous studies showing that heterozygous TGR without any intervention (e.g. high salt or 5/6 NX) exhibit high resistance to the development of hypertension‐induced renal damage . In contrast, untreated 5/6 NX TGR exhibited significantly lower creatinine clearance (especially 8 weeks after 5/6 NX, just before the first rats began to die) compared with sham‐operated TGR.…”

“…However, it is clear that different renal diseases exhibit common pathomorphological signs, such as tubulointerstitial fibrosis and tubular atrophy, followed by glomerulosclerosis . The studies using the 5/6 NX model have demonstrated that hypertension and inappropriately activated renin–angiotensin system (RAS) are two critical determinants of the progression rate of CKD to ESRD . In addition, both experimental and clinical studies have shown that RAS blocking agents, such as angiotensin‐converting enzyme inhibitors (ACEI) and angiotensin (Ang) II receptor blockers (ARBs), are highly effective inhibitors of the progression of CKD (renoprotective action) .…”

Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME

“…Tubulointerstitial injury was defined as tubular dilatation, atrophy, cast formation and sloughing of tubular epithelial cells or thickening of tubular basement membrane and scaring as follows grade 0, no injury; grade 1, tubulointerstitial injury in less than 25%; grade 2, (25–50%); grade 3, (>50%). This approach is now routinely used in our laboratory and allows comparison of the present results with those of our previous and also future studies evaluating the pathophysiology of hypertension-associated end-organ damage [7,9,13,20,25,27]. …”

Cardiac and Renal Effects of Atrasentan in Combination with Enalapril and Paricalcitol in Uremic Rats

“…Atrasentan improved the survival rate, reduced blood pressure, attenuated the development of cardiac hypertrophy, and transiently reduced proteinuria. Combination therapy did not provide additive protection [25]. …”