Long-term use of low-dose spironolactone in spontaneously hypertensive rats: Effects on left ventricular hypertrophy and stiffness

Abstract

The aim of the present study was to evaluate the effect of low-dose spironolactone initiated during the early stages of hypertension development and to assess the effects of chronic pressure overload on ventricular remodeling in rats. Male spontaneously hypertensive rats (SHRs) (4 weeks) were randomized to receive daily spironolactone (20 mg/kg) or vehicle (mineral oil) from 4 weeks to 8 months of age. Systolic blood pressure was measured non-invasively by tail-cuff pletysmography at baseline, 4 and 8 months. Hemodynamic assessment was performed at the end of treatment by arterial and ventricular catheterization. An in situ left ventricular pressure-volume curve was created to evaluate dilatation and wall stiffness. Systolic blood pressure at 1 month of age was higher in SHRs than in the Wistar group; it increased throughout the follow-up period and remained elevated with treatment (Wistar: 136 ± 2, SHR: 197 ± 6.8, SHR-Spiro: 207 ± 7.1 mmHg; p < 0.05). Spironolactone reduced cardiac hypertrophy (Wistar: 1.25 ± 0.03 SHR: 1.00 ± 0.03, SHR-Spiro: 0.86 ± 0.02 g; p < 0.05) and left ventricular mass normalized to body weight (Wistar: 2.51 ± 0.06, SHR: 2.70 ± 0.08, 2.53 ± 0.07 mg/g; p < 0.05). Moreover, the left ventricular wall stiffness that was higher in SHRs was partially reduced by spironolactone treatment (Wistar: 0.370 ± 0.032; SHR: 0.825 ± 0.058; SHR-Spiro: 0.650 ± 0.023 mmHg/ml; p < 0.05). Our results show that long-term spironolactone treatment initiated at the early stage of hypertension development reduces left ventricular hypertrophy and wall stiffness in SHRs.

Early Spironolactone Treatment Attenuates Heart Failure Development by Improving Myocardial Function and Reducing Fibrosis in Spontaneously Hypertensive Rats

“…Treatment with spironolactone did not change arterial blood pressure. This result is in accordance with other authors showing that the spironolactone dose used in this study can induce beneficial cardiac effects without modifications in blood pressure [14,23,45,46]. As blood pressure remained unchanged, it was possible to exclude the influence of hemodynamic effects on our results.…”

Aldosterone Blockade Reduces Mortality without Changing Cardiac Remodeling in Spontaneously Hypertensive Rats

“…This result is in agreement with previous studies in SHR using similar spironolactone doses [45,46]. As arterial pressure was unchanged by the treatment, we were able to exclude the influence of hemodynamic effects on the cardiac remodeling process and mortality.…”

“…In SHR, the aldosterone blockade was evaluated during the cardiac remodeling process but not during heart failure development. In young [45,56,57,58,59] and mature [20,46] SHR, treatment with aldosterone blockers have resulted in improved or unchanged LV hypertrophy and myocardial fibrosis. The conflicting results after aldosterone blockers treatment suggest that their role in the remodeling process and heart failure development are not completely understood but are probably influenced by treatment period and experimental cardiac injury model.…”

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

“…29 Increased oxidative stress, inflammation, and fibrosis are evident in several animal models of cardiac and renal diseases (eg, rats post-MI, dogs with HF, and uninephrectomized diabetic rats). 18,[38][39][40] Furthermore, MR activation stimulates apoptosis and causes vasoconstriction and reduced blood flow in the animal heart and kidneys. 8,18,41,42 Reduced endothelium-dependent vasodilatation is thought to be caused by an aldosterone-mediated decrease in the bioavailability of nitric oxide.…”