Characterization of Cardioprotection Mediated by AT2 Receptor Antagonism After Ischemia-Reperfusion in Isolated Working Rat Hearts

Abstract

Background: Whether cardioprotection induced by the angiotensin II (AngII) type 2 receptor (AT ₂R) antagonist PD123,319 (PD) after ischemia-reperfusion (IR) is influenced by the concentration of PD, presence of AngII, timing of exposure, or inhibition of proton produc tion from glucose metabolism is not known.

Methods and Results: We examined these factors in isolated working rat hearts subjected to IR injury, no treatment (control), or treatment with N6-cyclohexyl adenosine (CHA, 0.5 μmol/L), an adenosine A₁ receptor agonist that induces cardioprotection by decreasing pro tons ("positive" control). Compared with control, 1 μmol/L PD present throughout IR im proved recovery of left ventricular work (73 ± 5 vs. 40 ± 8%) to the level with CHA (82 ± 5%), but 0.1 μmol/L PD did not (58 ± 6 vs. 40 ± 8%). AngII (1 nmol/L) did not effect postischemic recovery associated with 1 μmol/L PD (73 ± 7%) but improved that associated with 0.1 μmol/L PD (86 ± 3%). PD (1 μmol/L), present solely during reperfusion, enhanced postischemic left ventricular recovery to 72 ± 5%. Also, PD (1 μmol/L) did not affect glycolytic rates or proton production in nonischemic or IR hearts.

Conclusion: PD-induced cardioprotection is 1) PD concentration-dependent, 2) AngII- sensitive, 3) mediated during reperfusion, and 4) independent of proton production, suggest ing that reduction in IR injury and indirect AT ₁R stimulation might be involved.