A1 Receptor mediated myocardial infarct size reduction by endogenous adenosine is exerted primarily during ischaemia

OBJECTIVE: The aim was to test the hypothesis that A1 receptor mediated cardioprotection by endogenous adenosine is exerted during ischaemia rather than reperfusion. METHODS: Anaesthetised open chest rabbits were subjected to 30 min regional ischaemia and 120 min reperfusion, and randomised to one of six groups: group I--saline vehicle (VEH) (n = 12) to allow A1 and A2 adenosine receptor interactions during ischaemia and reperfusion; group II--both A1 and A2 receptors were antagonised during ischaemia and reperfusion with 8-p-sulphophenyltheophylline (SPT) (10 mg.kg-1) (SPTIR, n = 14); groups III and IV--the selective A1 adenosine receptor antagonist 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902) was given during ischaemia-reperfusion in low dose (1 mg.kg-1, LA1-IR, n = 11) and higher dose (2 mg.kg-1, HA1-IR, n = 6); group V--KW-3902 (1 mg.kg-1) was given only during reperfusion (A1-R, n = 12); group VI--SPT was given only at reperfusion (SPTR, n = 11). RESULTS: In in vitro studies, (1) KW-3902 completely inhibited negative inotropic effects of the A1 agonist R(-)N6-(2-phenylisopropyl) adenosine (R-PIA) in catecholamine stimulated papillary muscles, and (2) had no effect on concentration dependent vasorelaxation to adenosine or R-PIA. In in vivo studies, transmural myocardial blood flow in the area at risk (determined using 15 microns radiolabelled microspheres) was reduced by 98% in all groups from 139(SEM 15.8) to 2.7(1.1) ml.min-1 x 100 g-1 (p < 0.001). At 120 min of reperfusion, blood flow in the area of necrosis was significantly less in groups LA1-IR 48.6(6.2), HA1-IR 36.1(7.1), SPTIR 35.9(6.4), and SPTR 25.1(5.4) compared to groups VEH 69.1(15.8) and A1-R 77.2(11.8). The area at risk (Ar) was equivalent among groups. SPT treatment during ischaemia-reperfusion in the SPTIR group increased the area of necrosis (An, assessed by triphenyltetrazolium chloride) relative to Ar (An/Ar) to 51(1.9)% v 26.0(1.7)% in VEH group. KW-3902 in LA1-IR and HA1-IR during both ischaemia and reperfusion increased An/Ar to 35.2(2.5)% and 35.2(2.1)% of area at risk, respectively, both of which were significantly less than the SPTIR group. With A1 blockade at reperfusion (A1-R), An/Ar was equivalent to that in VEH 27.0(1.9)%, while an infarct size of 46.7(2.1)% was still observed in SPTR. CONCLUSIONS: While adenosine exerts its predominant modulation of infarct size during reperfusion, the cardioprotection mediated by A1 receptor mechanisms is modest and exerted principally during the ischaemic time period.