Spironolactone Prevents Activation of the Intrarenal Renin-Angiotensin System and Increases Survival in (mREN2) 27 Transgenic Rats with Malignant Hypertension.
In transgenic rats [(mRen2)27 TGR+] that overexpress mouse renin, there is a high incidence of malignant hypertension (MH), characterized by high mortality between 8 and 12 weeks of age as a result of stroke, myocardial rupture or renal failure. Spironolactone (SPIRO), an aldosterone antagonist, improves survival in patients with heart failure and in stroke prone rats. To determine the role of aldosterone in MH in TGR+, rats at 5 weeks of age were divided into a treated group which received 50 mg/kg SPIRO per day in powdered food or an untreated group receiving no drug. In the untreated group, MH rats were identified by early death and non-malignant hypertensive (NMH) rats were identified by survival to 14 weeks. SPIRO results in a dramatic increase in survival when compared with rats receiving no treatment. The death rate was 11 of 23 rats in untreated rats compared with 1 of 15 in the SPIRO group (p < 0.01). SPIRO produced an intermediate systolic blood pressure determined by tail cuff compared with untreated MH and NMH animals, but did not lower pressure. Thus, a reduction in pressure is not the primary mechanism by which SPIRO reduces mortality. However, SPIRO prevented the loss of renal concentrating capacity as signified by hypo-osmotic polyuria in MH rats. This was associated with increased urinary excretion of Ang II and Ang-(1-7) in the weeks prior to death in MH rats. SPIRO has been shown to reduce vascular pathology, and as a result, SPIRO may prevent both the loss of concentrating ability and a subsequent inappropriate activation of the intrarenal renin-angiotensin system. (AHA-NC, HL-51952)