Abstract
Hypertension is endemic worldwide, afflicting up to 40% of the global population over the age of 25. Haemodynamic stretch stress from raised blood pressure is a driver for organ damage in the heart and kidney, contributing to potentially fatal conditions. Aldosterone activated mineralocorticoid receptors have also been shown to contribute to cardiorenal damage in a hypertensive state. This study compared the effects of spironolactone, a mineralocorticoid receptor antagonist (MRA), and amlodipine, a calcium channel blocker, when administered in a chronic hypertensive Cyp1a1-Ren2 transgenic rat model. Cyp1a1-Ren2 rats characteristically develop hypertension in a dose-dependent manner in response to dietary indole-3-carbinol (I3C). Male rats (19 week old) were assigned to either standard or I3C (0.167% w/w) diet, 2 weeks prior to experimental day 0. At experimental day 40, rats in both dietary groups were assigned into three drug treatment groups (n=4/group): spironolactone (8.82 mg/kg/day), amlodipine (0.44 mg/kg/day) or vehicle control oral dosing until termination at experimental day 85.
Systolic blood pressures recorded at day 0 and day 85 were significantly higher in the I3C diet group compared to standard diet. Spironolactone and amlodipine did not reduce systolic blood pressure at day 85 compared to control groups. Urine volume, proteinuria, left ventricular wall thickness, glomerulosclerosis, renal fibrosis and renal populations of both macrophages and myofibroblasts were increased in the I3C dietary group compared to standard diet; however none of these variables were significantly reduced with either spironolactone or amlodipine treatment compared to the control group in the I3C diet group. A reduction in renal fibrosis and renal cortex macrophage infiltration was observed with spironolactone treatment compared to control in the I3C diet group; however this was not statistically significant. A blood pressure independent reduction in proteinuria was seen in the spironolactone treated rats compared to control, but was also not statistically significant.
The trends identified with spironolactone treatment in this study were consistent with many other published works; however these studies suggest spironolactone has been shown to have many other protective characteristics unidentified in this study. Internal validity issues arose from initial stress-related difficulties, compromising intra-group comparisons. This and the underpowered nature of this study limit the interpretation of the study’s results. Therefore this study came to no conclusion in regards to blood pressure independent benefits of addition of spironolactone to a systemic hypertensive situation