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Efficacy of Pretreatment With the Angiotensin II Type 1 Receptor Blocker UP269-6 and Losartan in the Dog: Effect on Hemodynamics and Ischemia-Reperfusion

Background: Whether pretreatment with the novel oral angiotensin II (AngII) type 1 receptor (AT,R) antagonist UP269-6 (UP) can produce more effective AT,R blockade than losartan (LN) for cardioprotection during ischemia-reperfusion (IR) in the dog has not been deter mined. Methods and Materials: We compared the effect of UP (n = 5) and LN (n = 5) on serial in vivo hemodynamics, AngII pressor responses, and left ventricular (LV) volumes and function (echocardiograms) during escalation to optimal oral dosage over 7 days (day 0 to day 6), and acute IR (15 minutes ischemia, 30 minutes reperfusion) and ex vivo AT,R protein (Western immunoblots) with additional sham (n = 5) and IR (n = 5) controls on day 6. Compared with LN, UP produced greater vasodepression and decrease in diastolic volume during dose escalation and greater inhibition of the AngII pressor response over the range of escalating concentrations (0.05, 0.10, 0.25, and 0.50 μg/kg) on day 6. Acute IR after UP pretreatment resulted in less increase in LV filling pressure and LV diastolic and systolic volumes and greater ejection fraction, although UP and LN had similar effects on AT,R protein. Conclusion: Pretreatment with UP269-6 over 7 days produces more effective pharmacologi cal AT,R blockade and cardioprotection after acute IR than LN in the dog.