Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

Abstract

Background Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF). Methods and Results 12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP. Conclusion In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.

GPCR signaling and cardiac function

“…However, A1 receptor activation causes bradycardia via G i/o protein signaling, an effect therapeutically exploited in treatment of certain supraventricular arrhythmias with adenosine (Headrick et al, 2013). Of note, a partial A1 receptor agonist, capadenoson, has been shown to improve cardiac function and to prevent adverse remodeling in heart failure dogs, indicating that the A1 receptor may also be involved in regulation of contractility, in addition to regulation of heart rate (Sabbah et al, 2013). Although the exact underlying signaling mechanism (s) mediating these effects of capadenoson remain to be elucidated, this finding suggests targeting of the cardiac A1 receptor might be of value for heart failure therapy.…”

Current and future G protein-coupled receptor signaling targets for heart failure therapy

“…However, activation of A1R, which primarily couples to (inhibitory or other) G i/o proteins, also slows HR, which is therapeutically exploited in treatment of certain supraventricular arrhythmias, but, in the context of chronic HF, it might constitute an undesirable effect, as it can lead to bradycardias and atrioventricular blocks 61. A partial A1R agonist, capadenoson,62 was very recently shown to improve LV function and prevent progressive cardiac adverse remodeling in a canine chronic HF model 63. Importantly, improvement of LV systolic function seemed to occur early after treatment initiation with capadenoson, and, since the compound is not a full agonist at the A1R, it appears devoid of the HR-lowering complications with which full A1R agonism is hampered 63.…”

“…A partial A1R agonist, capadenoson,62 was very recently shown to improve LV function and prevent progressive cardiac adverse remodeling in a canine chronic HF model 63. Importantly, improvement of LV systolic function seemed to occur early after treatment initiation with capadenoson, and, since the compound is not a full agonist at the A1R, it appears devoid of the HR-lowering complications with which full A1R agonism is hampered 63. Although the precise signaling mechanism(s) that mediate these beneficial effects of partial A1R agonism in chronic HF remain to be worked out, this study strongly indicates that A1R-selective (partial) agonists might have a place in the chronic HF drug armamentarium in the future (Table 1).…”

New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation

“…[6,7] Nitroxyl enhances myocardial contractility and relaxation, properties that have led to clinical trials of HNO-donating drugs for congestive heart failure. [8,9,10] Nitroxyl reacts with thiols to give an N -hydroxysulfenamide intermediate that can further react with excess thiol to give the corresponding disulfide and hydroxylamine or rearranges to a sulfinamide. [11,12] For example, HNO directly influences myofilament function through modification of key cysteine residues in actin, myosin and tropomyosin and oxidizes cysteine residues present in the transmembrane domain of phospholamban (PLN) that ultimately regulates Ca +2 re-uptake into the sarcoplasmic reticulum.…”