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

Abstract

. AT 1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts. Am J Physiol Heart Circ Physiol 282: H1206-H1215, 2002; 10.1152/ajpheart.00839.2000.-We assessed ANG II type 1 (AT 1) and type 2 (AT2) receptor (R) expression and functional recovery after ischemia-reperfusion with or without AT1R/AT2R blockade in isolated working rat hearts. Groups of six hearts were subjected to global ischemia (30 min) followed by reperfusion (30 min) and exposed to no drug and no ischemia-reperfusion (control), ischemia-reperfusion and no drug, and ischemia-reperfusion with losartan (an AT 1R antagonist; 1 mol/l), PD-123319 (an AT 2R antagonist; 0.3 mol/l), N 6 -cyclohexyladenosine (CHA, a cardioprotective adenosine A1 receptor agonist; 0.5 mol/l as positive control), enalaprilat (an ANG-converting enzyme inhibitor; 1 mol/l), PD-123319 ϩ losartan, ANG II (1 nmol/l), or ANG II ϩ losartan. Compared with controls, ischemia-reperfusion decreased AT 2R protein (Western immunoblots) and mRNA (Northern immunoblots, RT-PCR) and impaired functional recovery. PD-123319 increased AT 2R protein and mRNA and improved functional recovery. Losartan increased AT 1R mRNA (but not AT1R/AT2R protein) and impaired recovery. Other groups (except CHA) did not improve recovery. The results suggest that, in isolated working hearts, AT 2R plays a significant role in ischemia-reperfusion and AT2R blockade induces increased AT2R protein and cardioprotection.angiotensin II; angiotensin II type 1 receptor; angiotensin II type 2 receptor THE RENIN-ANGIOTENSIN SYSTEM (RAS) is upregulated during myocardial ischemia, infarction, and ischemia-reperfusion injury (5,14). ANG II, the major effector molecule of the RAS, binds to two main receptor subtypes (6, 29), the ANG II type 1 (AT 1 ) and the type 2 (AT 2 ) receptor (R) to exert its physiological effects, several of which enhance ischemia-reperfusion injury. One strategy for cardioprotection is therefore to decrease ANG II formation and receptor stimulation with ANG-converting enzyme (ACE) inhibitors, although their efficacy in ischemia-reperfusion is debated (27). A second strategy is to directly reduce ANG II receptor stimulation by using selective AT 1 R or AT 2 R antagonists. In the nonworking rat heart, pretreatment (1 wk before ischemia) with the AT 1 R antagonist TCV-116 reduced reperfusion injury and improved function (43). 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...

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Inhibition of angiotensin‐converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin‐angiotensin system

“…Interestingly, we observed a higher expression of AT 2 receptors after ACE inhibition, however, no difference in AT1 receptor expression. Whereas different studies have shown that Ang II down-regulates its own receptors (Iwai et al, 1991;Iwai and Inagami, 1992), there are conflicting reports about the regulation of the AT1 and AT2 receptors after ACE inhibition (Ouali et al, 1997;Zhu et al, 1999;Xu et al, 2002).…”

Estrogen prevents intestinal inflammation after trauma-hemorrhage via downregulation of angiotensin II and angiotensin II subtype I receptor

“…Ultimately, Ang II causes vascular injury and organ damage. In fact, several lines of evidence have implicated that inhibition of Ang II may protect against ischemia-reperfusion-induced tissue injury in the heart, brain, liver, kidney, and small intestine (1,5,17,42). Previous studies have shown that the increase in Ang II is more prominent in the splanchnic circulation than in the systemic circulation during major aortic surgery and hypovolemia (44).…”