Avosentan is protective in hypertensive nephropathy at doses not causing fluid retention

• Published in: Pharmacological research 2014-02, Vol.80, p.9-13
• Main Authors: Baltatu, Ovidiu C., Zaugg, Christian E., Schumacher, Christoph, Louie, Pat, Campos, Luciana A., Bader, Michael
• Format: Article
• Language: English
• Subjects: Albuminuria - drug therapy; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Angiotensin receptor antagonist; Angiotensinogen - biosynthesis; Angiotensinogen - genetics; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - therapeutic use; Diuresis - drug effects; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin receptor antagonist; Fluid retention; Hematocrit; Humans; Hypertension, Renal - drug therapy; Hypertension, Renal - mortality; Hypertension, Renal - pathology; Hypertensive nephropathy; Kidney - drug effects; Kidney - pathology; Male; Nephritis - drug therapy; Nephritis - mortality; Nephritis - pathology; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - therapeutic use; Rats; Rats, Transgenic; Renin - biosynthesis; Renin - genetics; Tetrazoles - administration & dosage; Tetrazoles - therapeutic use; Valine - administration & dosage; Valine - analogs & derivatives; Valine - therapeutic use; Valsartan
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2013.12.003

Multiple studies indicate that endothelin antagonism may have a protective effect for chronic kidney disease. Despite that, clinical studies using avosentan have been halted due to adverse effects including fluid overload. Therefore, we aimed at investigating whether avosentan may have protective effects against hypertensive nephropathy at doses below those inducing fluid-retention. We used double transgenic rats (dTGR), overexpressing both the human renin and angiotensinogen gene, which develop malignant hypertension. Effects of avosentan alone or in combination with low-dose of valsartan (angiotensin AT1 receptor antagonist) on end-organ damage were studied. Avosentan induced a decrease of diuresis (18.3%) with a consequent decrease in hematocrit (8.3%) only at the highest dose investigated (100mg/kg). Treatment with the combination of avosentan and valsartan (10 and 0.1mg/kg, once daily by gavage, respectively) decreased albuminuria to a greater extent than each compound given alone (avosentan: 19.6mg/24h; valsartan: 12.9mg/24h; avosentan+valsartan: 1.7mg/24h, data are median values). Histological severity score also showed a drastic reduction of kidney damage. Furthermore, avosentan alone or in combination therapy dramatically decreased mortality compared to the 100% in untreated animals. These data support a therapeutic effect of avosentan at doses below those inducing fluid overload.