Abstract
Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.
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Abbreviations
- A1R:
-
A1 receptor
- ATP:
-
Adenosine triphosphate
- AV:
-
Atrioventricular
- CAD:
-
Coronary artery disease
- cAMP:
-
Cyclic adenosine monophosphate
- FFA:
-
Free fatty acid
- GLUT:
-
Glucose transporter
- HF:
-
Heart failure
- HFpEF:
-
Heart failure with preserved ejection fraction
- HFrEF:
-
Heart failure with reduced ejection fraction
- IS:
-
Infarct size
- KATP :
-
ATP-sensitive potassium channel
- LV:
-
Left ventricular
- LVEF:
-
Left ventricular ejection fraction
- MPTP:
-
Mitochondrial permeability transition pore
- ROS:
-
Reactive oxygen species
- SERCA2a:
-
Sarcoplasmic reticulum calcium-ATPase 2a
- SR:
-
Sarcoplasmic reticulum
- TAL:
-
Medullary thick ascending limb
- TG:
-
Triglyceride
- UPC:
-
Uncoupling protein
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Dinh, W., Albrecht-Küpper, B., Gheorghiade, M., Voors, A.A., van der Laan, M., Sabbah, H.N. (2016). Partial Adenosine A1 Agonist in Heart Failure. In: Bauersachs, J., Butler, J., Sandner, P. (eds) Heart Failure. Handbook of Experimental Pharmacology, vol 243. Springer, Cham. https://doi.org/10.1007/164_2016_83
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