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Lee, H. Thomas, and Charles W. Emala. Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A1 and A3 receptors. Am. J. Physiol. Renal Physiol. 278: F380–F387, 2000.—Renal ischemia and reperfusion during aortic and renal transplant surgery result in ischemic-reperfusion injury. Ischemic preconditioning and adenosine infusion before ischemia protect against ischemicreperfusion injury in cardiac and skeletal muscle, but these protective phenomena have not been demonstrated in the kidney. Rats were randomized to sham operation, 45-min renal ischemia, ischemic preconditioning with four cycles of 8-min renal ischemia and 5-min reperfusion followed by 45-min renal ischemia, systemic adenosine pretreatment before 45-min renal ischemia, or pretreatments with selective adenosine receptor subtype agonists or antagonists before 45-min renal ischemia. Forty-five minutes of renal ischemia followed by 24 h of reperfusion resulted in marked rises in blood urea nitrogen and creatinine. Ischemic preconditioning and adenosine pretreatment protected renal function and improved renal morphology. A1 adenosine receptor activation mimics and A1 adenosine antagonism blocks adenosineinduced protection. In addition, A3 adenosine receptor activation before renal ischemia worsens renal ischemic-reperfusion injury, and A3 adenosine receptor antagonism protects renal function. We demonstrate for the first time that rat kidneys can be preconditioned to attenuate ischemic-reperfusion injury and adenosine infusion before ischemic insult protects renal function via A1 adenosine receptor activation. Our data suggest that an A1 adenosine agonist and A3 adenosine antagonist may have clinically beneficial implications where renal ischemia is unavoidable.