Opposite effects of angiotensin AT1 and AT2 receptor antagonists on recovery of mechanical function after ischemia-reperfusion in isolated working rat hearts
Ford, W.R.; Clanachan, A.S.; Jugdutt, B.I.
Circulation 94(12): 3087-3089
1996
ISSN/ISBN: 0009-7322 PMID: 8989113 Document Number: 459873
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 mu-mol/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 lt .01). In contrast, the selective AT-1 antagonist losartan (1 mu-mol/L) blocked the recovery of LV work and depressed efficiency to 0+-0% and 1+-0% (n=7) of preischemic levels, respectively (P lt .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.