Reichelt, Melissa E., Willems, Laura, Peart, Jason N., Ashton, Kevin J., Matherne, G. Paul, Blackburn, Michael R., and Headrick, John P. (2007) Modulation of ischaemic contracture in mouse hearts: a ‘supraphysiological’ response to adenosine. Experimental Physiology, 92 (1). pp. 175-185.

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Abstract

While inhibition of ischaemic contracture was one of the first documented cardioprotective actions of exogenously applied adenosine, it is not known whether this is a normal function of endogenous adenosine generated during ischaemic stress. Additionally, the relevance of delayed contracture to postischaemic outcome is unclear. We tested the ability of endogenous versus exogenous adenosine to modify contracture (and postischaemic outcomes) in C57/Bl6 mouse hearts. During ischaemia, untreated hearts developed peak contracture (PC) of 85 ± 5 mmHg at 8.9 ± 0.8 min, with time to reach 20 mmHg (time to onset of contracture; TOC) of 4.4 ± 0.3 min. Adenosine (50 μm) delayed TOC to 6.7 ± 0.6 min, as did pretreatment with 10 μm 2-chloroadenosine (7.2 ± 0.5 min) or 50 nm of A1 adenosine receptor (AR) agonist N6-cyclohexyladenosine (CHA) (6.7 ± 0.3 min), but not A2AAR or A3AR agonists (20 nm 2-[4-(2-carboxyethyl) phenethylamino]-5′ N-methylcarboxamidoadenosine (CGS21680) or 150 nm 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (Cl-IB-MECA), respectively). Adenosinergic contracture inhibition was eliminated by A1AR gene knockout (KO), mimicked by A1AR overexpression, and was associated with preservation of myocardial [ATP]. This adenosine-mediated inhibition of contracture was, however, only evident after prolonged (10 or 15 min) and not brief (3 min) pretreatment. Ischaemic contracture was also insensitive to endogenously generated adenosine, since A1AR KO, and non-selective and A1AR-selective antagonists (50 μm 8-sulphophenyltheophylline and 150 nm 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), respectively), all failed to alter intrinsic contracture development. Finally, delayed contracture with A1AR agonism/overexpression or ischaemic 2,3-butanedione monoxime (BDM; 5 μm to target Ca2+ cross-bridge formation) was linked to enhanced postischaemic outcomes. In summary, adenosinergic inhibition of contracture is solely A1AR mediated; the response is ‘supraphysiological’, evident only with significant periods of pre-ischaemic AR agonism (or increased A1AR density); and ischaemic contracture appears insensitive to locally generated adenosine, potentially owing to the rapidity of contracture development versus the finite time necessary for expression of AR-mediated cardioprotection.

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