We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT 2 R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT 2 R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP 3 R) and protein kinase C⑀ (PKC⑀) proteins. We assessed AT 2 R, angiotensin II type 1 receptor (AT 1 R),

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... P 3 R, and PKC⑀ protein expression (Western blots) and AT 2 R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (nϭ6) were exposed to no IR, no IRϩPD (0.3 mol/L), IR, and IRϩPD. Compared with no IR and no IRϩPD, IR decreased (PϽ0.05) functional recovery and AT 2 R mRNA and protein, as well as AT 1 R mRNA (not protein) and IP 3 R and PKC⑀ proteins. Compared with IR, PDϩIR improved LV functional recovery (PϽ0.05) and markedly increased AT 2 R mRNA and protein (PϽ0.001). However, PD did not change AT 1 R mRNA or protein. More importantly, PDϩIR markedly increased IP 3 R and PKC⑀ proteins. The downregulation of AT 2 R mRNA and protein with IR and their upregulation with PD indicate that the effects of PD are AT 2 R specific. The overall results suggest that the cardioprotective effect of acute PD treatment on LV functional recovery after IR in the isolated working rat heart is specifically due to AT 2 R blockade and is associated with enhanced downstream IP 3 R and PKC⑀ signaling. (Hypertension. 2000;35:506-510.