RESEARCH ARTICLE Heart Failure: Novel Therapeutic Pathways Emerging from Basic Science (cid:2) 1A -Subtype adrenergic agonist therapy for the failing right ventricle

of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by (cid:2) 1 -adrenergic receptors ( (cid:2) 1 -ARs), in particular the (cid:2) 1A -subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the (cid:2) 1A -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 (cid:3) 1 ·day (cid:3) 1 ). 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 (cid:2) 1A -subtype is a potential therapeutic target to treat the failing RV. mouse bleomycin of a Chronic A61603 multiple of 1A the bleomycin RV failure model had a beneﬁcial effect on RV contraction and on multiple markers of RV injury. This study suggests that in the context of pulmonary ﬁbrosis, the (cid:2) 1A -subtype is a novel therapeutic target to treat RV failure by improving RV function and decreasing RV injury. RV injury model and A61603 therapy. Adult male C57BL/6J mice (Jackson Laboratory) were used (age: 10–14 wk, body weight: (cid:4) 28 g at the beginning of the experiment). We used a RV-speciﬁc heart failure model. The ﬁbrogenic antibiotic bleomycin (Sigma-Aldrich, St. Louis, MO) was introduced into the lungs by endotracheal instil- lation (0.075 units bleomycin in 100 (cid:5) l saline), which leads to pulmonary ﬁbrosis, pulmonary hypertension, and RV failure in ~2 wk (12). Animals were harvested after 10–14 days. Control animals were instilled with saline. Concurrently, mice were chronically treated for 2 wk with A61603 (Tocris Bioscience, Bristol, UK), a potent and highly speciﬁc agonist for the (cid:2) 1A -subtype that does not stimulate the other two (cid:2) 1 -AR subtypes ( (cid:2) 1B or (cid:2) 1D ). A subhypertensive dose of A61603 (10 ng·kg (cid:3) 1 ·day (cid:3) 1 ) (20) or saline was given by continuous subcutaneous infusion with an osmotic mini-pump (model 1002, Alzet, Durect) that was implanted between the scapulae under isoﬂu-rane anesthesia. This is a disease prevention study design. In vivo hemodynamics. Echocardiography was performed on conscious, gently restrained mice using an Acuson S2000 (Siemens) with a 5- to 14-MHz multidimensional matrix transducer. RV dimensions were measured using two-dimensional guided M-mode, acquired from ﬁve consecutive cardiac