AT<sub>1</sub>receptor blockade limits myocardial injury and upregulates AT<sub>2</sub>receptors during reperfused myocardial infarction

Jugdutt, Bodh I.; Menon, Vijayan

doi:10.1023/b:mcbi.0000026062.29029.d4

Cited by 29 publications

(20 citation statements)

References 44 publications

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“…32 Our data are consistent with a report that valsartan increases AT 2 R expression in the heart after ischemia-reperfusion injury, which is important in limiting infarct size. 33 Previous reports have shown that AT 2 R-dependent events involve increased B 2 R signaling, including renal natriuresis, 28 regulation of blood pressure, 34 and vascular relaxation. 9,11,13 An important signaling mechanism for the AT 2 R is crosstalk with bradykinin via increased bradykinin generation, presumed because of inhibition of the Na ϩ -H ϩ exchanger causing intracellular acidosis and activation of kininogenase activity, which generates bradykinin.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 2 Receptor Expression After Vascular Injury

et al. 2006

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Abstract-It has been suggested that the effects of angiotensin II type 1 receptor (AT 1 R) blockers are in part because of angiotensin II type 2 receptor (AT 2 R) signaling. Interactions between the AT 2 R and kinins modulate cardiovascular function. Because AT 2 R expression increases after vascular injury, we hypothesized that the effects on vascular remodeling of the AT 1 R blocker valsartan and the ACE inhibitor benazepril require AT 2 R signaling through the bradykinin 1 and 2 receptors (B 1 R and B 2 R). To test this hypothesis, Brown Norway rats were assigned to 8 treatments (nϭ16): valsartan, valsartanϩPD123319 (AT 2 R inhibitor), valsartanϩdes-arg 9 -[Leu 8 ]-bradykinin (B 1 R inhibitor), valsartanϩHOE140 (B 2 R inhibitor), benazepril, benazeprilϩHOE140, amlodipine, and vehicle. After 1 week of treatment, carotid balloon injury was performed. Two weeks later, carotids were harvested for morphometry and analysis of receptor expression by immunohistochemistry and Western blotting. Valsartan and benazepril significantly reduced the intima:media ratio compared with vehicle. Blockade of AT 2 R, B 1 R, or B 2 R in the presence of valsartan prevented the reduction seen with valsartan alone. B 2 R blockade inhibited the effect of benazepril. Injury increased AT 1 R, AT 2 R, B 1 R, and B 2 R expression. Treatment with valsartan but not benazepril significantly increased intima AT 2 R expression 2-fold compared with vehicle, which was not reversed by inhibition of AT 2 R, B 1 R, and B 2 R. Functionally, valsartan increased intimal cGMP levels compared with vehicle, and this increase was inhibited by blocking the AT 2 R, B 1 R, and B 2 R. Results suggest that AT 2 R expression and increased cGMP represent a molecular mechanism that differentiates AT 1 R blockers, such as valsartan, from angiotensin-converting enzyme inhibitors like benazepril. Key Words: valsartan Ⅲ angiotensin Ⅲ AT 2 R Ⅲ restenosis Ⅲ rat A ngiotensin II (Ang II) exerts its effects primarily through 2 functionally distinct receptors, the angiotensin type 1 receptor (AT 1 R) and angiotensin type 2 receptor (AT 2 R). The AT 1 R is widely distributed in adults, whereas the AT 2 R is only highly expressed in the fetus. 1 However, AT 2 R expression increases in pathological conditions, such as vascular injury. 2 These 2 receptors exert effects that are generally considered antagonistic. Blocking Ang II activity with angiotensin-converting enzyme (ACE) inhibitors reduces the risk of mortality in patients at high risk for cardiovascular events. 3 Recently, AT 1 R blockers (ARBs) have been shown to be effective in reducing stroke in patients with left ventricular hypertrophy 4 and mortality in heart failure patients. 5 Kinins exert diverse physiological actions, including vasodilation, 6 increased capillary permeability, and inflammation. 7 The major kinins, which are agonists at the bradykinin type 2 receptor (B 2 R), are metabolized to produce the des-Arg 9 -kinins, which are agonists at bradykinin type 1 receptors (B 1 Rs). Although the B 2 R is widely...

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Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 2 Receptor Expression After Vascular Injury

et al. 2006

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“…Because the angiotensin AT 2 receptor is implicated in the cardiovascular benefits of the ARB valsartan, [30][31][32] we investigated the effect of coadministration of the AT 2 receptor antagonist PD123319 in the cardioprotective actions of aliskiren, valsartan, and their combination. PD123319 had no effect on myocardial infarct size in vehicle-treated rats but prevented the reduction in myocardial infarct size by all 3 drug treatments ( Figure 1).…”

Section: Aliskiren Reduces Myocardial Infarct Size Via An At 2 Receptmentioning

confidence: 99%

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

2014

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Abstract-Angiotensin-converting enzyme inhibitors and angiotensin AT 1 receptor blockers reduce myocardial ischemiareperfusion injury via bradykinin B 2 receptor-and angiotensin AT 2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B 2 and AT 2 receptors in this effect. Female SpragueDawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B 2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT 2 receptor antagonist PD123319 (30 mg/ kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B 2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B 2 receptor-and AT 2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT 2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT 2 receptor-mediated cardioprotection by valsartan. MethodsDetailed methods are provided in the online-only Data Supplement. Results Effects of Drug Treatment on Systolic BloodPressure, Body Weight, Heart Weight/Body Weight Ratio, and Mean Arterial Blood Pressure During I/R Injury Systolic blood pressure (SBP) of the 12 groups of rats during the 4-week treatment period before I/R injury is shown in the Table. In the present study, we used doses of aliskiren (10 mg/kg per day SC) and valsartan (30 mg/kg per day PO) that have little effect on blood pressure in normotensive Sprague-Dawley rats. Neither aliskiren nor valsartan caused any change in SBP during the 4 weeks (Table). However, SBP in rats receiving the combination of aliskiren plus valsartan was less than that in vehicle-treated rats. In contrast, SBP in rats receiving the B 2 receptor antagonist icatibant (0.5 mg/kg per day SC) alone was higher than that of vehicle-treated rats. Rats treated with aliskiren, valsartan, and the combination of aliskiren plus valsartan had lower SBP during combined treatment with icatibant than that of rats treated with icatibant alone. Treatment with the AT 2 receptor antagonist PD123319 (30 mg/kg per day SC) alone did not affect blood pressure. During combined treatment w...

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“…Jugdutt et al suggested that AT1R blockade combined with up-regulation of AT2R protein expression could contribute to the cardioprotective effects of ATII blockade during reperfused myocardial infarction. 64 However, Ryckwaert et al indicated that only blockade of both AT1 and AT2 receptors improved ventricle function from ischaemia reperfusion. 65 The beneficial mechanism of ATII blockade at ischemia-reperfusion needs further exploration.…”

Section: Drug Therapymentioning

confidence: 99%

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

Kang

Yang

2007

CIM

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Purpose: To review (1) the mechanisms of coronary microvascular reperfusion injury, particularly in the relationships between microvascular endothelium dysfunction, microstructure damage, microemboli and no-reflow phenomena; (2) the no-reflow presentation and management at ischemia-reperfusion to suggest future direction for noreflow therapy in acute myocardial infarction. Sources: Original articles and reviews published between 1997 and 2007 and focusing on the no-reflow phenomenon in MEDLINE and PubMed. The search terms used were "no-reflow", "microvascular injury", "acute myocardial infarction" and "reperfusion injury". All papers identified were English-language, full text papers. In addition, the reference lists of identified relevant articles were also searched. Conclusions:The no-reflow phenomenon is characterised by damage to microvascular function and microstructure at ischaemia-reperfusion. Microemboli contribute to noreflow. Clinical myocardial contrast echocardiography (MCE), scintigraphic and magnetic resonance imaging (MRI) have shown evidence of microvascular damage, eg, perfusion defects are closely related to lack of contractile recovery and irreversible myocyte damage. Clinical agents and devices targeting microvascular injury (especially protection of endothelium and reduction of microemboli) after acute myocardial infarction may be key points to improve no-reflow.

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AT₁receptor blockade limits myocardial injury and upregulates AT₂receptors during reperfused myocardial infarction

Cited by 29 publications

References 44 publications

Angiotensin II Type 2 Receptor Expression After Vascular Injury

Angiotensin II Type 2 Receptor Expression After Vascular Injury

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

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AT1receptor blockade limits myocardial injury and upregulates AT2receptors during reperfused myocardial infarction

Cited by 29 publications

References 44 publications

Angiotensin II Type 2 Receptor Expression After Vascular Injury

Angiotensin II Type 2 Receptor Expression After Vascular Injury

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

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AT₁receptor blockade limits myocardial injury and upregulates AT₂receptors during reperfused myocardial infarction

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism