α_1A-Subtype adrenergic agonist therapy for the failing right ventricle

Abstract

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α-adrenergic receptors (α-ARs), in particular the α-subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α-subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg·day). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α-subtype is a potential therapeutic target to treat the failing RV. Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α-adrenergic receptor subtype agonist A61603. Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the α-subtype is a therapeutic target to treat RV failure.

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

“…Given this lack of data, decreases in CPA in response to Bleo were chosen to match published experimental measurements of CPA in mice with other forms of PH ( Tewari et al, 2013 ; Liu et al, 2015 , 2017a ; Wang et al, 2018 ). RV mass was increased to match RV hypertrophy reported by Cowley et al (2017) in Bleo mice. For all simulations, blood volume and systemic vascular resistance were adjusted to maintain systolic arterial pressures between 110 and 125 mmHg as done previously ( Tewari et al, 2016b ).…”

“…Bleomycin treatment has been shown to result in pulmonary fibrosis, PH and RVF in ∼2 weeks ( Williams et al, 1992 ; Sato et al, 1993 ; Hemnes et al, 2008 ; Cowley et al, 2017 ). Hemnes et al (2008) characterized the development of PH and RVF in bleomycin (Bleo) treated mice in vivo using right heart catheterization and pressure volume loop analysis.…”

“… Hemnes et al (2008) characterized the development of PH and RVF in bleomycin (Bleo) treated mice in vivo using right heart catheterization and pressure volume loop analysis. Our group has documented the development of RVF following Bleo treatment and demonstrated impaired myocyte force generation ( Cowley et al, 2015 , 2017 ). Table 1 summarizes these experimental results.…”

“…Myocyte maximum force generation has been found to be preserved or increased in some models of PH ( Fan et al, 1997 ; Walker et al, 2011 ; Wang et al, 2018 ), but decreased in others ( Versluis et al, 2004 ; Dai et al, 2006 ; Cowley et al, 2015 , 2017 ). In particular, in RVF secondary to LV failure and RVF due to bleomycin-induced pulmonary fibrosis ( Wang et al, 2010 ; Cowley et al, 2017 ), maximum myocyte force generation (Fmax) decreases. Changes in passive myocardial mechanics have also been found in human PH as measured in isolated RV trabeculae ( Rain et al, 2013 ) and experimental models of PH associated with myocardial fibrosis ( Rain et al, 2016 ).…”

Updates in the function and regulation of α1‐adrenoceptors

“…Similarly, experimental and clinical trial data have suggested that α 1 ‐adrenoceptor antagonists might worsen some cases of heart failure (Jensen et al, ). It has been suggested that α 1 ‐adrenoceptor agonists could provide cardio‐protection (Jensen et al, ; Perez & Doze, ), particularly those selective for the α 1A subtype (Cowley et al, ). Consistent with this, in transgenic mice adrenergic‐induced ischaemic‐preconditioning is mediated by α1A‐ adrenoceptors (Perez & Doze, ).…”