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

The aim was to test the hypothesis that A1 receptor mediated cardioprotection by endogenous adenosine is exerted during ischaemia rather than reperfusion.

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).

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.

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.