Effect of a novel partial adenosine A₁ receptor agonist VCP102 in reducing ischemic damage in the mouse heart

Investigations into the use of A 1 adenosine receptor (A 1 AR) agonists in reducing post‐ischemic damage to the heart have been of significant interest to cardiovascular research. The present study examined the cardioprotective effects of the partial A 1 AR agonist, N 6 ‐[4‐[1,1,3,3‐tetramethylisoindolin‐2‐yloxyl‐5amido]ethyl]phenyl]adenosine (VCP102) and the full A 1 AR agonist, N 6 ‐cyclopentyl adenosine (CPA), in murine isolated hearts perfused in Langendorff mode. Following 30‐min ischemia, hearts were treated with the A 1 AR agonists during early reperfusion for 15 min (IR protocol). Significant increases in left ventricular developed pressure (LVDP) and contractility (dP/dt max ) were observed at the final reperfusion values for VCP102 (100 nM)‐treated hearts, as compared with the control tissues ( P <0.05). EDP values in VCP102‐treated hearts were also lower than control tissues ( P <0.05). The A 1 AR antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 10 nM) and the A 3 AR antagonist 3‐ethyl‐5‐benzyl‐2‐methyl‐4‐pheylethynyl‐6‐phenyl‐1,4‐(±)‐diphydropyridine‐3,5‐dicarboxylate (MRS1191, 200 nM) attenuated the protective actions of 15 min VCP102 during IR ( P <0.05). An improvement in functional recovery was not observed with CPA (100 nM, P >0.05). Infarct size was also significantly reduced in VCP102‐ or CPA‐treated hearts as compared with control tissues ( P <0.05). DPCPX and MRS1191 attenuated VCP102‐induced decreases in infarct size ( P <0.05), but did not alter the responses to CPA ( P >0.05). Significant reductions in cardiac troponin I release and expression of the pro‐apoptotic zymogen caspase‐3 were observed in both treatment groups ( P <0.05). In summary, both A 1 ARs and A 3 ARs may play a role in mediating cardioprotection and improving functional recovery in the IR heart with VCP102. Furthermore, treatment with the partial agonist appeared to confer improved functional cardiac protection when compared with CPA. Drug Dev Res 68:529–537, 2007.