Opposite Effects of Angiotensin AT ₁ and AT ₂ Receptor Antagonists on Recovery of Mechanical Function After Ischemia-Reperfusion in Isolated Working Rat Hearts

Abstract

This is the first demonstration that short-term treatment with a selective AT1 versus AT2 antagonist exerts different effects on recovery of mechanical function after ischemia-reperfusion: the AT2 antagonist was cardioprotective, whereas the AT1 antagonist was not. These data suggest that AT2 antagonists and AT1 agonists may offer novel approaches for the treatment of mechanical dysfunction after ischemia-reperfusion.

AT1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts

“…Although our findings with AT 2 R blockade during acute ischemia-reperfusion in this study and others (7,8) suggest that acute increase in AT 2 R expression and potential AT 2 R activation might be harmful, this does not necessarily conflict with the postulated beneficial role of the mild-to-modest AT 2 R stimulation during chronic AT 1 R blockade. This concept (16,17,33) assumes that during chronic AT 1 R blockade, shunting of ANG II to AT 2 Rs induces AT 2 R activation and unopposed AT 2 R effects involving bradykinin, PGs, and NO, but data on AT 2 R protein or mRNA or downstream signaling are needed.…”

“…As reviewed by Jalowy et al (16), AT 1 R blockade is not universally beneficial in all models of ischemiareperfusion in all species (7,8) or in other models (22,30,32), as is often assumed (9,16,17,40,41). Although the beneficial effects of long-term AT 1 R blockade after infarction (9) support the role of AT 1 R during cardiac remodeling after infarction, AT 2 Rs are likely involved (12,20,38).…”

“…All rats were housed and treated according to the guidelines of the Canadian Council on Animal Care and the American Physiological Society. As described previously (7,8), male Sprague-Dawley rats (250-300 g), which had been acclimatized and fed ad libitum, were anesthetized with intraperitoneal pentobarbital sodium (50 mg/kg). Hearts were rapidly excised and placed in ice-cooled Krebs-Henseleit solution (pH 7.4, gassed with 95% O 2-5% CO2).…”

“…In the same model, acute treatment (from the onset of ischemia) with the AT 1 R antagonist losartan attenuated the postischemic mechanical dysfunction (40) and pretreatment (4-6 h before ischemia) with losartan blocked the increase in AT 1 R binding but did not affect AT 1 R protein or mRNA after ischemia-reperfusion (41). In the isolated working rat heart (19), we previously showed that the AT 2 R antagonist PD-123319 enhanced (7), whereas losartan worsened (7,8), functional recovery after ischemia-reperfusion. We hypothesized that during ischemia-reperfusion in working hearts, AT 2 R is downregulated and AT 2 R blockade induces AT 2 R upregulation and cardioprotection.…”

AT1-receptor blockers: differences that matter

“…1,2 The AT 2 -receptor subtype is also activated by angiotensin II, and has been shown in experimental studies to counteract the detrimental effects of AT 1 -receptor stimulation. 3,4 Selective blockade of the AT 1 receptor thus represents a rational therapeutic target in hypertension and cardiovascular disease. 5 Since the introduction of the prototype AT 1 -receptor blocker, losartan, in 1994 five others have been introduced into clinical practice: candesartan, eprosartan, irbesartan, telmisartan and valsartan; a number of others are currently undergoing develop-effect, and this finding is supported by the results of comparative clinical trials.…”