Hypertensive Dahl Salt‐Sensitive Rats Demonstrate a Reduction in Central Blood Pressure Following the Short‐Term Treatment with Ivabradine and Spironolactone

Abstract

IntroductionA proper management of central blood pressure (cBP) has been recently recognized as a novel therapeutic target to reduce cardiovascular risks among hypertensive (HT) patients. Considering that the hypotensive action of most antihypertensive drugs does not persist after treatment interruption, the search for compounds which would permanently reduce the level of cBP remains vital. It has been previously reported that a mineralocorticoid receptor antagonist spironolactone (SL) as well as a “pure” heart rate lowering drug ivabradine (IVA) can both affect the level of cBP and cardiac structure in hypertension.HypothesisIt was hypothesized that combined treatment with SL and IVA could permanently reduce cBP in chronically HT animals via alterations in myocardial properties.MethodsSelf‐sustaining hypertension was induced in 20 male (seven‐week‐old) Dahl salt‐sensitive rats by feeding them a high‐salt (HS) diet (8% NaCl) for 7 weeks. Then all HT rats were switched back to a normal‐salt (NS) diet (0.3% NaCl) and randomized in two experimental groups to receive ether a combined treatment (HT‐T) with IVA (10 mg/kg/day) and SL (20 mg/kg/day) or the vehicle alone (HT‐V) for 8 weeks via intraperitoneal ALZET osmotic pumps. The ten age‐matched male rats fed a NS diet only were used as normotensive controls (NT‐C). Heart rate and peripheral blood pressure were evaluated every week in conscious rats using a CODA tail‐cuff plethysmography system. One week following treatment termination, the central (aortic) and cardiac hemodynamic parameters were assessed in anesthetized rats using an intravascular/intracardiac Millar micro‐tip pressure catheter and a PowerLab data acquisition system. Subsequently, rats were euthanized, and their hearts were excised, weighed and processed to paraffin for histology and quantitative morphology.ResultsAfter 7 weeks on a HS diet, all experimental rats had markedly elevated mean arterial pressure (MAP) and heart rate. Subsequent replacement of a HS diet with a NS diet did reduce the level of MAP by ~12%, but in both HT groups it remained significantly higher than in NT‐C rats throughout the rest of the study on average by ~27% (P≤0.001). On the other hand, during eight weeks of treatment, heart rate was persistently reduced only in HT‐T rats on average by ~38% and ~27% (P≤0.001) compared to HT‐V and NT‐C groups, respectively. At the end of the study, the invasive hemodynamic measurements showed that although cBP remained markedly elevated in all HT rats compared to a NT‐C group, the level of cBP in HT‐T rats was significantly lower than that in HT‐V group (149.4±4.3 vs. 167.5±3.3 mmHg in MAP, P≤0.01). Moreover, a reduction in cBP among HT‐T rats was associated with decreased left ventricular (LV) contractility and delayed active relaxation as compared to HT‐V rats. At the same time, histological examination of the hearts has confirmed that sustained hypertension caused significant LV hypertrophy (P≤0.001) and myocardial fibrosis (P≤0.01) in both HT groups. Most important, compared to a HT‐V group, the HT‐T rats had thicker LV free wall (3.20±0.06 vs. 2.94±0.11 mm, P≤0.05) and a markedly higher myocardial density of monocytes/macrophages (228.8±12.5 vs 62.4±7.1 CD68‐positive cells/mm2, P≤0.0001).ConclusionOur findings demonstrated that concurrent treatment of chronically HT rats with IVA and SL led to a sustained reduction in cBP and that such hypotensive effect was associated with ongoing myocardial remodeling in treated animals.