Adenosine Receptor Agonists

Markus Wallner, Piotr Ponikowski


Adenosine is a purine nucleoside that binds to adenosine cell surface receptors, which are widely expressed in heart and blood vessel cells as well as in the brain, kidney and adipose tissue.There are 4 subtypes of P1 (adenosine) G protein-coupled receptors (GPCR), named A1, A2A, A2B, and A3, which mediate a variety of cardioprotective and regenerative effects. In the heart, these effects are predominantly mediated through A1 receptors (A1R), which are expressed in atrial and ventricular cardiomyocytes and smooth muscle cells.  Pre-clinical studies have reported multiple potential benefits achievable by modulation of adenyl cyclase with beneficial effects in a variety of pre-clinical models of cardiovascular disease including chronic heart failure (HF). A1R blockade (e.g. rolofylline) was however not successful in the PROTECT trial, where 2033 patients with acute HF and renal dysfunction were randomized to rolofylline or placebo, showed no benefit on renal function, symptoms, rehospitalization, or mortality. Following this attention turned to partial adenosine agonists, capadenoson and neladenoson bialanate hydrochloride, which has two phase II studies underway, PANACHE (HFpEF) and PANTHEON (HFrEF).


Heart Failure; Adenosine Receptor Agonists

Full Text:



Schmidt M, Jacobsen JB, Lash TL, Botker HE and Sorensen HT. 25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study. BMJ. 2012;344:e356.

Investigators S, Yusuf S, Pitt B, Davis CE, Hood WB and Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The New England journal of medicine. 1991;325:293-302.

Group CTS. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The New England journal of medicine. 1987;316:1429-35.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J and Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. The New England journal of medicine. 1999;341:709-17.

Redfield MM, Jacobsen SJ, Burnett JC, Jr., Mahoney DW, Bailey KR and Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA : the journal of the American Medical Association. 2003;289:194-202.

Vaduganathan M, Butler J, Pitt B and Gheorghiade M. Contemporary Drug Development in Heart Failure: Call for Hemodynamically Neutral Therapies. Circulation Heart failure. 2015;8:826-31.

Gheorghiade M, Bohm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, Solomon SD, Baschiera F, Botha J, Hua TA, Gimpelewicz CR, Jaumont X, Lesogor A and Maggioni AP. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA : the journal of the American Medical Association. 2013;309:1125-35.

Maggioni AP, Anker SD, Dahlstrom U, Filippatos G, Ponikowski P, Zannad F, Amir O, Chioncel O, Leiro MC, Drozdz J, Erglis A, Fazlibegovic E, Fonseca C, Fruhwald F, Gatzov P, Goncalvesova E, Hassanein M, Hradec J, Kavoliuniene A, Lainscak M, Logeart D, Merkely B, Metra M, Persson H, Seferovic P, Temizhan A, Tousoulis D and Tavazzi L. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. European journal of heart failure. 2013;15:1173-84.

Bayeva M, Gheorghiade M and Ardehali H. Mitochondria as a therapeutic target in heart failure. Journal of the American College of Cardiology. 2013;61:599-610.

Wilcox JE, Fonarow GC, Ardehali H, Bonow RO, Butler J, Sauer AJ, Epstein SE, Khan SS, Kim RJ, Sabbah HN, Diez J and Gheorghiade M. “Targeting the Heart” in Heart Failure: Myocardial Recovery in Heart Failure With Reduced Ejection Fraction. JACC Heart failure. 2015;3:661-9.

Greene SJ, Sabbah HN, Butler J, Voors AA, Albrecht-Kupper BE, Dungen HD, Dinh W and Gheorghiade M. Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure. Heart failure reviews. 2016;21:95-102.

Fredholm BB, AP IJ, Jacobson KA, Linden J and Muller CE. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacological reviews. 2011;63:1-34.

Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ and Freeman TC. Tissue distribution of adenosine receptor mRNAs in the rat. British journal of pharmacology. 1996;118:1461-8.

Burnstock G. Purinergic Signaling in the Cardiovascular System. Circulation research. 2017;120:207-228.

Linden J. Adenosine in tissue protection and tissue regeneration. Molecular pharmacology. 2005;67:1385-7.

Musser B, Morgan ME, Leid M, Murray TF, Linden J and Vestal RE. Species comparison of adenosine and beta-adrenoceptors in mammalian atrial and ventricular myocardium. Eur J Pharmacol. 1993;246:105-11.

Hussain T and Mustafa SJ. Binding of A1 adenosine receptor ligand [3H]8-cyclopentyl- 1,3-dipropylxanthine in coronary smooth muscle. Circulation research. 1995;77:194-8.

Akbar M, Okajima F, Tomura H, Shimegi S and Kondo Y. A single species of A1 adenosine receptor expressed in Chinese hamster ovary cells not only inhibits cAMP accumulation but also stimulates phospholipase C and arachidonate release. Molecular pharmacology. 1994;45:1036-42.

Wang D and Belardinelli L. Mechanism of the negative inotropic effect of adenosine in guinea pig atrial myocytes. The American journal of physiology. 1994;267:H2420-9.

Yuan K, Cao C, Han JH, Kim SZ and Kim SH. Adenosine-stimulated atrial natriuretic peptide release through A1 receptor subtype. Hypertension. 2005;46:1381-7.

Sabbah HN, Gupta RC, Kohli S, Wang M, Rastogi S, Zhang K, Zimmermann K, Diedrichs N and Albrecht-Kupper BE. Chronic therapy with a partial adenosine A1-receptor agonist improves left ventricular function and remodeling in dogs with advanced heart failure. Circulation Heart failure. 2013;6:563-71.

Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JG, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ and Gheorghiade M. Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nature reviews Cardiology. 2017;14:238-250.

Puhl SL, Kazakov A, Muller A, Fries P, Wagner DR, Bohm M, Maack C and Devaux Y. Adenosine A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to alpha1 -adrenoceptor stimulation in vivo. British journal of pharmacology. 2016;173:88-102.

Staehr PM, Dhalla AK, Zack J, Wang X, Ho YL, Bingham J and Belardinelli L. Reduction of free fatty acids, safety, and pharmacokinetics of oral GS-9667, an A(1) adenosine receptor partial agonist. J Clin Pharmacol. 2013;53:385-92.

Kitakaze M, Hori M, Takashima S, Sato H, Inoue M and Kamada T. Ischemic preconditioning increases adenosine release and 5’-nucleotidase activity during myocardial ischemia and reperfusion in dogs. Implications for myocardial salvage. Circulation. 1993;87:208-15.

Shneyvays V, Mamedova LK, Leshem D, Korkus A and Shainberg A. Insights into the cardioprotective function of adenosine A(1) and A(3) receptors. Experimental and clinical cardiology. 2002;7:138-45.

Urmaliya VB, Pouton CW, Devine SM, Haynes JM, Warfe L, Scammells PJ and White PJ. A novel highly selective adenosine A1 receptor agonist VCP28 reduces ischemia injury in a cardiac cell line and ischemia-reperfusion injury in isolated rat hearts at concentrations that do not affect heart rate. Journal of cardiovascular pharmacology. 2010;56:282-92.

Birkenfeld AL, Jordan J, Dworak M, Merkel T and Burnstock G. Myocardial metbolism in heart failure: Purinergic signalling and other metabolic concepts. Pharmacology & therapeutics. 2018.

Vallon V, Muhlbauer B and Osswald H. Adenosine and kidney function. Physiol Rev. 2006;86:901-40.

Ronco C, Haapio M, House AA, Anavekar N and Bellomo R. Cardiorenal syndrome. Journal of the American College of Cardiology. 2008;52:1527-39.

Givertz MM, Massie BM, Fields TK, Pearson LL and Dittrich HC. The effects of KW- 3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. Journal of the American College of Cardiology. 2007;50:1551-60.

Greenberg B, Thomas I, Banish D, Goldman S, Havranek E, Massie BM, Zhu Y, Ticho B and Abraham WT. Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study. Journal of the American College of Cardiology. 2007;50:600-6.

Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, Cleland JG, Givertz MM, Voors A, DeLucca P, Mansoor GA, Salerno CM, Bloomfield DM and Dittrich HC. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. The New England journal of medicine. 2010;363:1419-28.

Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, Miller AB, Pina IL, Thomson S, Varosy PD, Zile MR, Cleland JG, Givertz MM, Metra M, Ponikowski P, Voors AA, Davison BA, Cotter G, Wolko D, Delucca P, Salerno CM, Mansoor GA, Dittrich H, O’Connor CM and Massie BM. The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT. Drug Saf. 2012;35:233-44.

Peleli M, Fredholm BB, Sobrevia L and Carlstrom M. Pharmacological targeting of adenosine receptor signaling. Mol Aspects Med. 2017;55:4-8.

Fredholm BB, AP IJ, Jacobson KA, Klotz KN and Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological reviews. 2001;53:527-52.

Srinivas M, Shryock JC, Dennis DM, Baker SP and Belardinelli L. Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes. Molecular pharmacology. 1997;52:683-91.

Longabaugh JP, Didsbury J, Spiegel A and Stiles GL. Modification of the rat adipocyte A1 adenosine receptor-adenylate cyclase system during chronic exposure to an A1 adenosine receptor agonist: alterations in the quantity of GS alpha and Gi alpha are not associated with changes in their mRNAs. Molecular pharmacology. 1989;36:681-8.

Albrecht-Kupper BE, Leineweber K and Nell PG. Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic signalling. 2012;8:91-9.

Tendera M, Gaszewska-Zurek E, Parma Z, Ponikowski P, Jankowska E, Kawecka-Jaszcz K, Czarnecka D, Krzeminska-Pakula M, Bednarkiewicz Z, Sosnowski M, Ochan Kilama M and Agrawal R. The new oral adenosine A1 receptor agonist capadenoson in male patients with stable angina. Clin Res Cardiol. 2012;101:585-91.

Meibom D, Albrecht-Kupper B, Diedrichs N, Hubsch W, Kast R, Kramer T, Krenz U, Lerchen HG, Mittendorf J, Nell PG, Sussmeier F, Vakalopoulos A and Zimmermann K. Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine A1 Receptor Agonist for the Chronic Treatment of Heart Diseases. ChemMedChem. 2017;12:728-737.

Voors AA, Dungen HD, Senni M, Nodari S, Agostoni P, Ponikowski P, Bax JJ, Butler J, Kim RJ, Dorhout B, Dinh W and Gheorghiade M. Safety and Tolerability of Neladenoson Bialanate, a Novel Oral Partial Adenosine A1 Receptor Agonist, in Patients With Chronic Heart Failure. J Clin Pharmacol. 2017;57:440-451.

Shewan LG, Coats AJS, Henein MY. Authors’ Responsibilities and Ethical Publishing. International Cardiovascular Forum Journal 2018;13:3-4, DOI: 10.17987/icfj.v13i0.525


Copyright (c) 2019 The author(s)

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.