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Contrasting Effects of Ang II Receptors Following Ischemia‐Reperfusion in Ang II‐preconditioned Rat Hearts

Ang II‐preconditioning (APC) significantly improves post‐ischemic recovery of cardiac function although its cardioprotective mechanisms remain largely unknown. To evaluate the role of the Ang II receptors in APC, isolated‐perfused rat hearts were pre‐treated (15 min) with losartan (AT1R blocker, 10µM) and/or PD123319 (AT2R blocker, 1µM) prior to 4 cycles (5 min each) of Ang II (10nM) with or without drugs, followed by 30 min of global ischemia and 90 min of reperfusion (IR, n=4/group). The drugs were absent during the reperfusion period. Left‐ventricular developed pressure (LVDP), the first derivative of developed pressure (+dP/dt), the rate pressure product (RPP) and LDH release were monitored and infarct size was evaluated at the end of reperfusion. Losartan significantly reduced cardiac function compared to APC during the pre‐ischemic (PI) and post‐ischemic (PO) periods (35%, P<0.05). PD123319 did not affect cardiac function during PI but abolished the AT1R‐dependent component when co‐infused with losartan. PD123319 also increased cardiac function 2‐fold (P<0.05) during PO with or without losartan, indicating that the effect of AT2R blockade was independent of APC. These actions of AT1R and AT2R blockade were associated with significant reductions in infarct size (64%, P<0.05) and LDH release (72%, P<0.05) compared with controls. Both blockers also reduced LDH release (45%, P<0.05), but only losartan inhibited infarct size (64%, P<0.05) compared with APC. These findings suggest that whereas AT1Rs promote cardiac function and are critical for APC, AT2Rs suppress cardiac function after IR. Supported by: RCMI Program grant G12MD007600, the Univ. of Puerto Rico, and NIH grant SCIHL118669 (SJ).