Stimulation of Cyclic GMP Production via AT
            <sub>2</sub>
            and B
            <sub>2</sub>
            Receptors in the Pressure-Overloaded Aorta After Banding

Hiyoshi, Hiromi; Yayama, Katsutoshi; Takano, Masaoki; Okamoto, Hiroshi

doi:10.1161/01.hyp.0000128022.24598.4f

Cited by 47 publications

(45 citation statements)

References 25 publications

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“…25,[27][28][29] Many previous studies have shown interaction between the B 2 and AT 2 receptors. [33][34][35][36][37][38] Siragy et al 35 showed that PD123319 suppressed basal bradykinin levels and prevented valsartan-induced increase in bradykinin levels in renal interstitial fluid. Our study is the first to examine this question in the heart.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…However, Ang II also induced apoptosis of VSMCs mediated by the AT-2 receptor in a mouse model of aortic banding-induced hypertension [57].…”

Section: Part II -Role Of the Renin-angiotensin-aldosterone System Onmentioning

confidence: 96%

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Raimondo¹,

Tuttolomondo²,

Buttà³

et al. 2012

CPD

108

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Abstract:The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosteron system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Recpetor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflmmatory effect of drugs bocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.

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“…The mechanism of AT 2 receptor-induced dilation in the pressure-overload model is BK-dependent, because the contractile response was restored with PD or icatibant in mice. 17 Ang II invoked a 9-fold increase in aortic cGMP that was abolished by either PD or icatibant. Functional vasodilator AT 2 receptors also have been demonstrated in the fetal aorta, where AT 2 receptor expression is extremely high.…”

Section: Vasodilation Mediated By Bk No and Cgmpmentioning

confidence: 96%

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

2005

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T he renin-angiotensin system is a coordinated hormonal cascade of major importance in cardiovascular and renal regulation. The principle effector of this system is the octapeptide angiotensin II (Ang II), which acts at 2 cell membrane receptors, AT 1 and AT 2 . The majority of the actions of Ang II have been demonstrated to be mediated by the AT 1 receptor, including growth promotion, vasoconstriction, antinatriuresis, aldosterone secretion, salt appetite, thirst, sympathetic outflow and inhibition of renin biosynthesis, and secretion. 1 The AT 2 receptor has been less well understood. Past studies, however, clearly demonstrated that the AT 2 receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT 1 receptor. 2 Studies in the mid to late 1990s demonstrated that AT 2 receptor stimulation engenders an autacoid vasodilator cascade composed of bradykinin (BK), nitric oxide (NO), and guanosine cyclic 3Ј, 5Ј-monophosphate (cGMP). [3][4][5] This discovery turned attention to the possibility that the AT 2 receptor may mediate vasodilation, opposing the vasoconstrictor actions of Ang II at the AT 1 receptor. 6 Parallel cell signaling studies indicated that the AT 2 receptor is G-proteincoupled (through Gi␣) and that receptor stimulation is accompanied by an increase in phosphotyrosine phosphatase activity and an inhibition of MAP kinase enzymes (p42 and p44) composing the extracellular signal-related kinase (ERK1/2). AT 2 receptor-mediated inhibition of the extracellular signal-regulated kinase pathway opposed the actions of Ang II, resulting in extracellular signal-regulated kinase phosphorylation via the AT 1 receptor. 1,2,6,7 Work during the late 1990s through 2002 suggested that the AT 2 receptor might serve as a vasodilator counterforce to the AT 1 receptor. 2,6,7 However, vasorelaxation was difficult to elicit in some experimental models, attributed to the relatively low level of AT 2 receptor vascular expression compared with that of the AT 1 receptor. 1,6 To unmask the vasodilator action of the AT 2 receptor, experiments began to focus on eliminating the vasoconstrictor action of the AT 1 receptor with an AT 1 receptor blocker before and during AT 2 receptor stimulation. These studies demonstrated that AT 2 receptor activation by Ang II clearly dilated blood vessels and reduced blood pressure. 8,9 Studies also demonstrated that at least part of the depressor action of AT 1 receptor blockade is mediated by AT 2 receptor stimulation, in acute and chronic experimental models. 10,11 The vasodilator action of the AT 2 receptor was easier to detect during conditions in which the renin-angiotensin system was upregulated, such as sodium restriction, Ang II infusion, or renal vascular hypertension. 6,10,11 Most studies pointed to the role of BK, NO, and cGMP in mediating the observed vasodilator response via the AT 2 receptor. 6,7 So, is there anything new about the AT 2 receptor during the past 2 years? Yes, in many ways these have been "banner years" in promoting our underst...

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Stimulation of Cyclic GMP Production via AT ₂ and B ₂ Receptors in the Pressure-Overloaded Aorta After Banding

Cited by 47 publications

References 25 publications

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

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

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

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Stimulation of Cyclic GMP Production via AT 2 and B 2 Receptors in the Pressure-Overloaded Aorta After Banding

Cited by 47 publications

References 25 publications

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

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

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

Contact Info

Product

Resources

About

Stimulation of Cyclic GMP Production via AT ₂ and B ₂ Receptors in the Pressure-Overloaded Aorta After Banding

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

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