There is significant interest in the therapeutic application of adenosine A_2A receptor agonists, however, headache is a potential side effect which warrants consideration. It has previously been reported that adenosine A_2A receptors are responsible for the vasodilatation of human middle cerebral arteries induced by the non-selective adenosine agonist 5’-(N-ethylcarboxamido)-adenosine (NECA) (Root et al., 2004). Here we report an extension of these studies to the human meningeal artery, dilatation of which is proposed to contribute to the pain of certain types of headache (Cumberbatch et al., 1999).

Human middle meningeal arteries were obtained from 3 donors (2 female, 1 male, aged between 61 and 90) at post mortem (PM) with the informed consent of next of kin, and with the approval of local ethics committees. Tissue s were placed in PBS at 4°C, and transported overnight for use the following day, the mean ( ± s.e.m.) PM delay was 6.3 ± 0.4 hours. Rings of middle meningeal artery were mounted under isometric conditions and an initial tension of 5mN, in 10ml tissue baths containing gassed (95% O₂/5% CO₂) Krebs solution with indomethacin (3µM) at 37°C. The integrity of the endothelium in each case was not established. After 60 minutes equilibration, a cumulative concentration-effect curve to phenylephrine was constructed. After washing, the selective adenosine A_2A antagonist ZM241385 (Ongini et al., 1999), or vehicle (DMSO), was added at 100nM or equivalent and left in contact with the tissues for 30 minutes. Vessels were constricted with an approximate EC_50-70 concentration of phenylephrine (1 – 10 µM) and responses allowed to plateau, after which the selective adenosine A_2A agonist 2-p-(2-carboxyethylphenethylamino-5’-ethylcarboxamido-adenosine), (CGS21680, 1nM – 100µM) was added by cumulative application. After addition of the final concentration of CGS21680, prostacyclin (1µM) was administered to induce a standard relaxation. The Gaddum Schild equation (log₁₀ (concentration ratio – 1) = – (log₁₀ [antagonist])) was used to estimate pA₂ values from these single concentrations.

Cumulative administration of CGS21680 to pre-constricted arteries in the absence of antagonist resulted in a concentration-dependent vasodilatation (pEC₅₀ of 6.8 ± 0.4, n=3) . The adenosine A_2A antagonist ZM241385 produced a significant rightward shift of the concentration-effect curve to CGS21680 (pEC₅₀ of 4.6 ± 0.6, pA 2 of 9.2 ± 0.03). The estimated pA₂ value for ZM241385 compares well with its published affinity (pK i=9.1) for human recombinant adenosine A_2A receptors (Ongini et al., 1999).

In conclusion, adenosine A_2A receptors are present in human middle meningeal arteries and when stimulated cause vasodilatation.

Cumberbatch, M.J. et al., (1999). Br. J. Pharmacol., 126,1478-86
ngini, E., et al. (1999). Naunyn-Schmiedeberg's Archives of Pharmacology, 359, 7-10
Root, J.A., et al. (2004). Br. J. Pharmacol., In press