The effect of an allosteric modulator of the adenosine A 1 receptors was investigated using an ischaemia-reperfusion protocol in murine isolated hearts. Isolated hearts were perfused with Kreb-Henseleit solution gassed with carbogen gas (95% O 2 and 5% CO 2) in Langendorff mode and electrically paced at 480 bpm. Following 20 min equilibration and 20 min global normothermic ischaemia, the allosteric modulator VCP333 (1 μM) or the adenosine A 1 receptor partial agonist VCP102 (10 μM) were infused after 5 min of reperfusion for 15 min. Upon termination of the drug treatment, reperfusion continued for a further 40 min. At the end of 60 min reperfusion, treatment with VCP333 or VCP102 improved the recovery of the left ventricular developed pressure when compared to control group responses ( p < 0.05). Neither compound affected end diastolic pressure, coronary flow rates or dP/dt max values when compared to control tissues during reperfusion ( p > 0.05). The infusion of VCP102 or VCP333 during reperfusion reduced cardiac troponin I efflux to 6.7% and 25% respectively of control heart efflux ( p < 0.05). This data indicates that the allosteric modulator of the adenosine A 1 receptor (VCP333) has similar characteristics to the adenosine receptor partial agonist VCP102 as it improves cardiac function and reduces myocardial cell death following an ischaemic episode.
References
[1]
Belardinelli, L.; Linden, J.; Berne, R.M. The cardiac effects of adenosine. Prog. Cardiovasc. Dis. 1989, 32, 73–97, doi:10.1016/0033-0620(89)90015-7.
Ross, A.M.; Gibbons, R.J.; Stone, G.W.; Kloner, R.A.; Alexander, R.W. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J. Am. Coll. Cardiol. 2005, 45, 1775–1780, doi:10.1016/j.jacc.2005.02.061.
[6]
Mubagwa, K.; Flameng, W. Adenosine, adenosine receptors and myocardial protection: An updated overview. Cardiovasc. Res. 2001, 52, 25–39, doi:10.1016/S0008-6363(01)00358-3.
[7]
Moser, G.H.; Schrader, J.; Deussen, A. Turnover of adenosine in plasma of human and dog blood. Am. J. physiol. 1989, 256, C799–C806.
[8]
Auchampach, J.A.; Bolli, R. Adenosine receptor subtypes in the heart: Therapeutic opportunities and challenges. Am. J. physiol. 1999, 276, H1113–H1116.
[9]
Matherne, G.P.; Linden, J.; Byford, A.M.; Gauthier, N.S.; Headrick, J.P. Transgenic A1 adenosine receptor overexpression increases myocardial resistance to ischemia. Proc. Natl. Acad. Sci. USA 1997, 94, 6541–6546.
[10]
Lohse, M.J.; Klotz, K.N.; Schwabe, U.; Cristalli, G.; Vittori, S.; Grifantini, M. 2-Chloro-N6-cyclopentyladenosine: A highly selective agonist at A1 adenosine receptors. Naunyn Schmiedebergs Arch. Pharmacol. 1988, 337, 687–689.
Valant, C.; Aurelio, L.; Urmaliya, V.B.; White, P.; Scammells, P.J.; Sexton, P.M.; Christopoulos, A. Delineating the mode of action of adenosine A1 receptor allosteric modulators. Mol. Pharmacol. 2010, 78, 444–455.
[16]
Christopoulos, A. Allosteric binding sites on cell-surface receptors: Novel targets for drug discovery. Nat. Rev. Drug Discov. 2002, 1, 198–210, doi:10.1038/nrd746.
Soudijn, W.; van Wijngaarden, I.; IJzerman, AP. Allosteric modulation of G protein-coupled receptors: Perspectives and recent developments. Drug Discov. Today 2004, 9, 752–758, doi:10.1016/S1359-6446(04)03220-9.
[20]
Mizumura, T.; Auchampach, J.A.; Linden, J.; Bruns, R.F.; Gross, G.J. PD 81,723, an allosteric enhancer of the A1 adenosine receptor, lowers the threshold for ischemic preconditioning in dogs. Circ. Res. 1996, 79, 415–423, doi:10.1161/01.RES.79.3.415.
Thornton, J.D.; Liu, G.S.; Olsson, R.A.; Downey, J.M. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation 1992, 85, 659–665, doi:10.1161/01.CIR.85.2.659.
[23]
Lasley, R.D.; Rhee, J.W.; Van Wylen, D.G.; Mentzer, R.M., Jr. Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. J. Mol. Cell. Cardiol. 1990, 22, 39–47.
[24]
Zhao, Z.Q.; McGee, S.; Nakanishi, K.; Toombs, C.F.; Johnston, W.E.; Ashar, M.S.; Vinten-Johansen, J. Receptor-mediated cardioprotective effects of endogenous adenosine are exerted primarily during reperfusion after coronary occlusion in the rabbit. Circulation 1993, 88, 709–719, doi:10.1161/01.CIR.88.2.709.
[25]
Lagerstrom, M.C.; Schioth, H.B. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov. 2008, 7, 339–357, doi:10.1038/nrd2518.
[26]
Elzein, E.; Zablocki, J. A1 adenosine receptor agonists and their potential therapeutic applications. Expert Opin. Investig. Drugs 2008, 17, 1901–1910, doi:10.1517/13543780802497284.
[27]
May, L.T.; Leach, K.; Sexton, P.M.; Christopoulos, A. Allosteric modulation of G protein-coupled receptors. Ann. Rev. pharm. Toxicol. 2007, 47, 1–51, doi:10.1146/annurev.pharmtox.47.120505.105159.
[28]
Sanjani, M.S.; Teng, B.; Krahn, T.; Tilley, S.; Ledent, C.; Mustafa, S.J. Contributions of A2A and A2B adenosine receptors in coronary flow responses in relation to the KATP channel using A2B and A2A/2B double-knockout mice. Am. J. Physiol. Heart Circ. Physiol. 2011, 301, H2322–H2333, doi:10.1152/ajpheart.00052.2011.
[29]
Flood, A.; Headrick, J.P. Functional characterization of coronary vascular adenosine receptors in the mouse. Br. J. Pharmacol. 2001, 133, 1063–1072, doi:10.1038/sj.bjp.0704170.
[30]
Amoah-Apraku, B.; Xu, J.; Lu, J.Y.; Pelleg, A.; Bruns, R.F.; Belardinelli, L. Selective potentiation by an A1 adenosine receptor enhancer of the negative dromotropic action of adenosine in the guinea pig heart. J. Pharmacol. Exp. Ther. 1993, 266, 611–617.
