Abstract 2523: Azelnidipine Enhances Beneficial Effects of Olmesartan on Left Ventricular Remodeling During the Development of Hypertension-induced Heart Failure
Objective: This work was undertaken to investigate the comparative effect of angiotensin II type 1 receptor blocker (ARB) and a combination of ARB and calcium channel blocker (CCB) on left ventricular (LV) remodeling during the development of hypertensive heart failure (H-HF).
Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n = 10 for each group) with
hydralazine (5 mg/kg/d),
olmesartan (OLM, 5 mg/kg/d), or
combined OLM and azelnidipine (AZE, 2mg/kg/d) for 8 weeks.
The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins were localized in cardiac myocytes (CMCs), and Cat-dependent activities were increased by 4.1-fold in the LV of H-HF rats (n = 8, P< 0.001) and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of H-HF rats (H-HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n = 6, P< 0.0±1; control 22±2.1%). OLM suppressed not only macrophage infiltration but also levels of NADPH oxidase components (p22phox, gp91 phox, and p47 phox) concomitant with decreased NADPH activity and O2- production in LV tissues of H-HF rats. Along with its comparable anti-inflammatory effect, add-on AZE further improved all of these parameter changes by OLM. Furthermore, combination therapy significantly enhanced the improvement of LV fibrosis, hypertrophy, stiffness, and dysfunction by OLM. In vitro, H2O2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with the antioxidants such as MnTmPyp (50 μmol/L) and N-acetylcysteine (5 mmol/L) as well as a NADPH oxidase inhibitor apocynin (100 μmol/L) in culture CMCs, SMCs, and macrophages (n = 6, P< 0.01).
Conclusions: OLM and a combination of OLM and AZE exerted cardioprotective effects in hypertensive HF, via elastolytic Cat activation inhibition by the reduction of NADPH oxidase-dependent superoxide anion production. AZE enhanced the cardioprotective effects of OLM. Thus, the combination of ARB with CBB is a promising potential therapeutic strategy for H-HF.