Background: Hypertension (HT)-induced accumulation of myocardial collagen stiffens the left ventricular (LV) wall and, hence, promotes diastolic dysfunction. Considering that a competitive aldosterone receptor antagonist spironolactone (SL) as well as a “pure” heart rate-lowering drug ivabradine (IVA) have both been proven to exert an anti-fibrotic effect during cardiac remodeling, we hypothesized that, in combination, these drugs would complement each other in alleviating HT-induced myocardial fibrosis and, therefore, could better preserve diastolic function.

Methods: Sustained HT was induced in 7-week-old male Dahl salt-sensitive rats by feeding them a high-salt (8%) diet for 7 weeks. Then, HT rats were randomly assigned in two experimental groups: 1) IVA (10 mg/kg/day) + SL (20 mg/kg/day)-treated (HT-T) and 2) vehicle only (HT-V). The drugs and the vehicle (a mixture of 50% dimethyl sulfoxide/50% propylene glycol, v/v) were delivered IP by osmotic pumps for 8 weeks. The age-matched rats were used as normotensive controls (NT). Heart rate (HR) and blood pressure (BP) were recorded every other week using a CODA tail-cuff plethysmography system. At the end of the study, the hemodynamic parameters were assessed using a Millar pressure catheter and the hearts were collected for histology and quantitative morphometry. Statistical analysis was performed using Prism 6.

Results: We found that during 8-week treatment period, BP had remained comparably elevated in both HT groups by ~26% (P≤0.01) on average vs. NT rats, whereas HR had been persistently reduced in HT-T group by ~38% and ~27% (P≤0.01) on average vs. HT-V and NT rats, respectively. At the end of the study period, all groups revealed a similar level of LV end-diastolic pressure, suggesting the analogous diastolic stiffness of the myocardium. At the same time, morphological examination of the hearts has confirmed that sustained HT caused significant interstitial and perivascular fibrosis (P≤0.01) in both experimental groups compared to NT rats, and that the treatment did not change the extent of fibrillar collagen accumulation as compared to HT-V rats.

Conclusions: Taken together, our findings confirmed that a combined treatment with IVA and SL could not alleviate HT-induced myocardial fibrosis.