Reduction in Blood Pressure Observed in Hypertensive Dahl Salt-Sensitive Rats After Cotreatment with Ivabradine and Spironolactone Coincides with Myocardial Inflammation

Introduction: Blood pressure-lowering medications can reduce or even reverse left ventricular (LV) hypertrophy and myocardial fibrosis induced by chronically elevated blood pressure. However, in patients with resistant hypertension (HPT), high blood pressure often remains unresponsive to anti-hypertensive treatment. Therefore, the search for novel therapeutic strategies that would help preserve or restore myocardial properties and, hence, LV function even under the effect of persistently elevated blood pressure has remained of significant importance. Hypothesis: Considering that a competitive mineralocorticoid receptor antagonist spironolactone (SL) could alleviate HPT-induced myocardial fibrosis, whereas a treatment with a heart rate-lowering drug ivabradine (IVA) was shown to mitigate the scale of concentric hypertrophy and LV dysfunction, it has been hypothesized that a combination of these two compounds might benefit myocardial properties and cardiac function even in the presence of chronically elevated blood pressure. Methods: Twenty male, 7-week-old Dahl salt-sensitive (DSS) rats were placed on a high-salt diet (8% NaCl) for 7 weeks to induce chronic, self-sustaining HPT. Then all HPT rats were switched back to a normal-salt diet (0.3% NaCl) and randomized in two experimental groups to receive ether a combined treatment (HPT-T) with IVA (10 mg/kg/day) and SL (20 mg/kg/day) or the vehicle only (HPT-V) for 8 weeks via intraperitoneal ALZET osmotic pumps. Ten age-matched male DSS rats fed a normal-salt diet only were used as control. Heart rate and peripheral blood pressure were evaluated every week in conscious rats for the duration of the study using a CODA tail-cuff plethysmography system. At the end of an experimental period, osmotic pumps were removed to terminate the treatment, and 1 week later, central (aortic) and cardiac hemodynamic parameters were assessed in isoflurane-anesthetized rats using a Millar micro-tip pressure catheter attached to a PowerLab data acquisition system. Subsequently, rats were euthanized, and their hearts were excised, weighed and processed to paraffin for histology and quantitative morphology. Statistical analysis was performed using Prism 6 software. Results: During 8 weeks of treatment, mean arterial pressure (MAP) had remained persistently elevated in both groups of HPT rats by ~27% (P≤0.001) compared to control, whereas heart rate had been solely reduced in HPT-T rats by ~38% (P≤0.001) and ~27% (P≤0.001) compared to HPT-V and control rats, respectively. After cessation of treatment, heart rate became similar in all rats, while the level of MAP remained significantly higher in HPT groups. The assessment of aortic (central) and cardiac hemodynamics revealed a marked reduction in central MAP (149.4±4.3 vs. 167.5±3.3 mmHg, P≤0.01) and peak systolic LV pressure (169.8±6.5 vs. 187.2±5.4 mmHg, P≤0.01) in rats from HPT-T group compared to HPT-V rats. Surprisingly, a decrease in central blood pressure detected in HPT-T animals coincided with an evident decline in LV contractility. The morphologic examination of the hearts revealed that chronic HPT did induce relatively comparable scale of LV hypertrophy (P≤0.001) and myocardial fibrosis (P≤0.01) in two HPT groups. However, in contrast to HPT-V group, the rats in HPT-T group showed a marked increase in myocardial density of CD68-positive monocytes/macrophages (228.8±12.5 vs 62.4±7.1 cells/mm 2 , P≤0.0001). Conclusion: Our findings demonstrate that a cotreatment of chronically HPT rats with IVA and SL did not improve myocardial tissue properties but led to a sustained decrease in LV and central blood pressure that was corresponded with myocardial inflammation and reduction in LV contractility. Supported by Camden Health Research Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.