Similar renoprotection after renin‐angiotensin‐dependent and ‐independent antihypertensive therapy in 5/6‐nephrectomized Ren‐2 transgenic rats: are there blood pressure‐independent effects?

Abstract

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.

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

“…We are aware that this is a drawback of all studies employing the tail-cuff method for BP measurements. However, despite this limitation we have demonstrated in pilot experiments with the tail-cuff method that the direct BP measurement by radiotelemetry in 5/6 NX TGR provide similar results [20]. …”

“…In accordance with recommendations for BP measurements in experimental animals [21], this method is adequate for detecting intergroup differences in SBP over time, and therefore is optimal for long-term studies. This method is regularly used in our laboratory [16,17,18,19,20] and was previously validated; a close correlation was found between measurements by tail-plethysmography and direct BP measurements using indwelling catheter in conscious rats. It is important to emphasize that this method does not allow accurate measurements of diastolic BP and mean arterial pressure.…”

“…The dose of atrasentan was adjusted weekly according to actual water intake. The doses of ET A receptor antagonist, ACEi and ARB were chosen on the basis of previous studies that have demonstrated that this dose of atrasentan effectively blocked ET A receptors and this combination of trandolapril and losartan elicited maximal inhibition of RAS [16,20]. Systolic BP (SBP) was measured with automated tail cuff system (Hatteras Instruments, Cary, N.C., USA).…”

“…At the end of the experiment, animals were decapitated and plasma and tissue ANG II and tissue ET-1 levels were measured as described and validated previously [16,17,18,19,20,22]. This approach was used because we previously showed that plasma and tissue ANG II concentrations in anesthetized animals are higher than those obtained from decapitated conscious rats, and that normotensive animals exhibit a greater increase in renin secretion in response to anesthesia and surgery than ANG II-induced hypertensive intrarenal renin-depleted animals [23].…”

“…Studies were started in 2-month-old male TGR and their transgene-negative controls (HanSD), in which 5/6 nephrectomy (NX) was carried out under anesthesia (tiletamine + zolazepam, Virbac SA, Carros Cedex, France, 8 mg/kg, and xylazine, Spofa, Czech Republic, 4 mg/kg intramuscularly), as described previously [20]. Animals were treated either with a combination of the ACEi trandolapril (Gopten, Abbott, Prague, Czech Republic, 6 mg/l in drinking water) and the ARB losartan (Lozap, Zentiva, Prague, Czech Republic, 100 mg/l in drinking water), or with the ET A receptor blocker atrasentan (5 mg kg –1 day –1 , Abbott, USA in drinking water), or with the combination of ACEi + ARB + ET A blocker for 20 weeks.…”