Opposite Effects of Angiotensin AT 1 and AT 2 Receptor Antagonists on Recovery of Mechanical Function After Ischemia-Reperfusion in Isolated Working Rat Hearts

Abstract

Background Angiotensin II type 1 (AT ₁ ) receptor antagonists, when given over the long term, reduce the deleterious consequences of ischemia-reperfusion injury. Whether short-term administration of AT ₁ or angiotensin II type 2 (AT ₂ ) receptor antagonists is cardioprotective has not been investigated. Methods and Results The effects of short-term administration of selective AT ₁ and AT ₂ receptor antagonists on the recovery of mechanical function during reperfusion after 30 minutes of global, no-flow ischemia were studied in left atrium–perfused isolated working rat hearts. Control hearts (n=8) showed incomplete recovery of left ventricular minute work (LV work) and cardiac efficiency during reperfusion to 51±15% and 61±19% of preischemic levels, respectively. Compared with control hearts, the selective AT ₂ receptor antagonist PD123,319 (0.3 μmol/L) given before ischemia (n=7) improved the recovery of LV work and efficiency to 82±4% and 98±7% of preischemic levels, respectively ( P <.01). In contrast, the selective AT ₁ antagonist losartan (1 μmol/L) blocked the recovery of LV work and depressed efficiency to 0±0% and 1±0% (n=7) of preischemic levels, respectively ( P <.01; n=7). Neither antagonist altered coronary vascular conductance. Conclusions This is the first demonstration that short-term treatment with a selective AT ₁ versus AT ₂ antagonist exerts different effects on recovery of mechanical function after ischemia-reperfusion: the AT ₂ antagonist was cardioprotective, whereas the AT ₁ antagonist was not. These data suggest that AT ₂ antagonists and AT ₁ agonists may offer novel approaches for the treatment of mechanical dysfunction after ischemia-reperfusion.