SAT-332 THE EFFECT OF SPIRONOLACTONE IN A RAT MODEL OF ESTABLISHED HYPERTENSION.

Abstract

Hypertension is one of the leading contributors to cardiovascular and renal disease. Spironolactone (SP) improves cardiac outcomes following injury, but its impact on hypertension-induced kidney fibrosis is uncertain. We aimed to investigate the impact of sustained hypertension with and without daily administration of spironolactone (SP) on the function and injury progression in both heart and kidney, in a transgenic rat model of hypertension. Male, eight week old, Cyp1a1Ren2 rats were randomised to either normal chow or chow with the addition of 0.167% w/w Indol-3-carbinol to induce hypertension (systolic >150mmHg). Hypertensive rats were further divided into those receiving spironolactone daily (human equivalent dose of 50mg), or not, following the establishment of hypertension. Measurement of systolic blood pressure (SBP) and echocardiograms were performed regularly and tissue collected for analyses following termination (after three months). The extent of fibrosis was determined histologically using quantitative pixel count analysis while glomerulosclerosis was scored semi-quantitatively. Induction of chronic hypertension resulted in elevated SBP (196±21 vs 91±13 mmHg (controls)), proteinuria (60±19 vs 14±3 ml.kg-1.hr-1), cortical fibrosis (7±0.4% vs 0.2±0.1%) and glomerulosclerosis index scores (GSI: 2.6±0.3 vs 0.2±0.06) [all variables were significant at p<0.001]. Hypertension also reduced cardiac left ventricular ejection fraction (LVEF, 67±7 vs 80±3%, p<0.001) and myocardial global longitudinal strain (myoGLS, -11±2 vs -17±2%, p<0.001) compared to normotensive animals. Treatment of hypertensive animals with SP resulted in reduced SBP (184±15, p<0.01) and blunted the deterioration of LVEF (72±4, p<0.05) and myoGLS (-13±1, p<0.01) when compared to untreated animals. While SP had no impact on proteinuria, it did result in significant reductions in cortical fibrosis (3±1.3%, p<0.05) and GSI (2±0.1, p<0.05) when compared to untreated hypertensive animals. Prolonged elevation of untreated SBP caused significant and progressive cardiac and renal damage over three months. The addition of spironolactone to established hypertensive animals improved physiological measurements and significantly decreased fibrotic and sclerotic damage in the kidney. Further work aims to explore the relationship between hypertension and renal deterioration.