Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Apr 12;6(4):546-56.
doi: 10.3390/ph6040546.

An allosteric modulator of the adenosine A1 receptor improves cardiac function following ischaemia in murine isolated hearts

Anna Butcher  1 , Peter J Scammells, Paul J White, Shane M Devine, Roselyn B Rose'meyer
Affiliations

An allosteric modulator of the adenosine A1 receptor improves cardiac function following ischaemia in murine isolated hearts

Anna Butcher et al. Pharmaceuticals (Basel). .

Abstract

The effect of an allosteric modulator of the adenosine A1 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% O2 and 5% CO2) 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 A1 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/dtmax 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 A1 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical structures of VCP102 and VCP333.
Figure 2
Figure 2
The effect of 15-min allosteric modulator VCP333 (1 μM) or VCP102 (10 μM) infusion on left ventricular developed pressure (LVDP) in mouse isolated hearts following 20-min of global ischaemia. Values are mean ± SEM, n = 6–10 per group, * p < 0.05 vs control.
Figure 3
Figure 3
The effect of 15-min allosteric modulator VCP333 (1 µM) or VCP102 (10 µM) infusion on end diastolic pressure (EDP) in mouse isolated hearts following 20-min of global ischaemia. Values are mean ± SEM, n = 6–10 per group.
Figure 4
Figure 4
The effect of 15-min allosteric modulator VCP333 (1 μM) or VCP102 (10 μM) infusion on coronary flow (mL/min) in mouse isolated hearts following 20-min of global ischaemia. Values are mean ± SEM, n = 5–9 per group.
Figure 5
Figure 5
The effect of 15-min allosteric modulator VCP333 (1 μM) or VCP102 (10 μM) infusion on contractile function (dP/dtmax) in mouse isolated hearts following 20-min of global ischaemia. Values are mean ± SEM, n = 6–10 per group.
Figure 6
Figure 6
The effect of 15-min adenosine A1 receptor allosteric modulator VCP333 (1 μM) or VCP102 (10 µM) infusion during early reperfusion following 20-min of global ischaemia on cTnI levels. Values are mean ± SEM, * p < 0.05 vs. control.
See this image and copyright information in PMC

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. - DOI - PubMed
    1. Braz J.C., Gregory K., Pathak A., Zhao W., Sahin B., Klevitsky R., Kimball T.F., Lorenz J.N., Nairn A.C., Liggett S.B., et al. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat. Med. 2004;10:248–254. doi: 10.1038/nm1000. - DOI - PubMed
    1. Nayeem M.A., Mustafa S.J. Protein kinase C isoforms and A1 adenosine receptors in porcine coronary smooth muscle cells. Vascul. Pharmacol. 2002;39:47–54. doi: 10.1016/S1537-1891(02)00307-5. - DOI - PubMed
    1. Ho M.F., Rose’meyer R.B. Vascular adenosine receptors; Potential clinical applications. Curr. Vasc. Pharmacol. 2012;10:23140547. - PubMed
    1. 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. - DOI - PubMed