Downregulation of Angiotensin II Receptor Type 1 in Heart Failure

Kurabayashi, Masahiko; Yazaki, Yoshio

doi:10.1161/01.cir.95.5.1104

Cited by 17 publications

(9 citation statements)

References 30 publications

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“…[13][14][15][16][17] Our data corroborate these findings by demonstrating that AT 2 blockade causes a decrease in LV cGMP content in intact hearts stimulated by Ang II. In addition, AT 2 blockade amplified PKC translocation in hypertrophied hearts stimulated with Ang II.…”

Section: Discussionsupporting

confidence: 85%

“…In addition, several authors proposed that AT 2 receptor activation may enhance apoptotic cell death. 17,24 These hypotheses merit future studies in the present aortic stenosis model of chronic LV hypertrophy and failure.…”

Section: Discussionmentioning

confidence: 92%

“…11,12 Several studies have proposed that downstream signaling related to the AT 2 receptor differs strikingly from signaling of the AT 1 receptor and involves kinin/cGMP signaling rather than the PKC pathway. [13][14][15][16][17] Transgenic experiments suggest that the AT 2 receptor signaling cascade has distinct biological roles compared with AT 1 receptor-mediated signaling. 18,19 Consistent with this hypothesis, recent studies in vascular smooth muscle cells 20 and endothelial cells 21 demonstrated that the AT 2 receptor exerts antiproliferative effects counteracting the growth-promoting effects of the AT 1 receptor.…”

mentioning

confidence: 99%

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Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts

et al. 1999

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Background-We have previously shown that the acute molecular growth response of new protein synthesis and protein kinase C activation in response to angiotensin II (Ang II) is altered in left ventricular (LV) hypertrophy compared with normal hearts. We have also shown an upregulation of Ang II type 2 (AT 2 ) receptors in hypertrophied hearts relative to controls. Activation of AT 2 receptors is proposed to counteract growth effects of AT 1 receptor in response to Ang II. Thus, we tested the hypothesis that in hypertrophied hearts, the AT 2 receptor mediates inhibitory effects on the new cardiac protein synthesis in response to acute Ang II stimulation. Methods and Results-Flaccid buffer-perfused adult normal and hypertrophied rat hearts were perfused with Ang II 10

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts

et al. 1999

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“…Although early experiments have used animal models, evidence is increasing indicating that both AT 1 and AT 2 receptors are present in humans. 4,28,29 Moreover, the beneficial hemodynamic effects of combined ACE inhibition and AT 1 receptor blocker have been demonstrated in patients with heart failure. 30 Preliminary studies in patients with heart failure who were treated with combined administration of the ACE inhibitor lisinopril and valsartan produced improvement in those individuals compared with individuals treated with the ACE inhibitor alone.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP

et al. 2001

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Abstract-Angiotensin (Ang) receptor blockers (ARBs) increase bradykinin (BK) by antagonizing Ang II at its type 1 (AT 1 ) receptors and diverting Ang II to its counterregulatory type 2 (AT 2 ) receptors. Because the effect of ARBs on BK is constrained by the short half-life of BK and because ACE inhibitors block the degradation of BK, this study was designed to test the hypothesis that an ACE inhibitor can potentiate ARB-induced increases in renal interstitial fluid (RIF) BK levels. We used a microdialysis technique to recover BK and cGMP in vivo from the RIF of sodium-depleted, conscious Sprague-Dawley rats infused for 60 minutes with the AT 1 receptor blocker valsartan (0.17 mg/kg per minute), with the active metabolite of the ACE inhibitor benazepril (benazeprilate, 0.05 mg/kg per minute), or with the specific AT 2 receptor blocker PD 123,319 (50 g/kg per minute) alone or combined. Each animal served as its own control. RIF BK and cGMP levels increased significantly over 1 hour in response to valsartan, benazeprilate, or both but not to a vehicle control (PϽ0.01). The combined benazeprilate-valsartan effect was greater than the sum of their individual effects, suggesting potentiation rather than addition, and was abolished by PD 123,319. We demonstrate for the first time that an ACE inhibitor (benazepril) and an ARB (valsartan) potentiate each other, and we postulate that such combinations may be beneficial in clinical states marked by Ang II elevation, such as chronic heart failure, postinfarction left ventricular dysfunction, and hypertension. Key Words: angiotensin-converting enzyme inhibitors Ⅲ receptors, angiotensin II Ⅲ bradykinin Ⅲ rats Ⅲ cyclic GMP T he renin-angiotensin system (RAS) exerts paracrine and autocrine effects on the heart, vasculature, adrenal glands, kidneys, and brain in addition to its endocrine role in maintaining systemic perfusion and renal function. 1 Prolonged RAS activation in conjunction with other growth promoters may contribute to cardiovascular hypertrophy and hyperplasia. Angiotensin (Ang) II, the principal effector of the RAS, produces both physiological and detrimental effects via its ubiquitously distributed type 1 (AT 1 ) receptors. 2 Although the functions of the less expressed type 2 (AT 2 ) receptors have not been fully elucidated, initial studies have suggested that these receptors mediate counterregulatory homeostatic effects (eg, vasodilation, inhibition of cell proliferation, increased apoptosis, and differentiation) in a yinyang relationship with the AT 1 receptors. 3,4 Studies from our laboratory have indicated that AT 2 receptor stimulation is associated with increased bradykinin (BK), 5 NO,6,7 and cGMP levels in renal interstitial fluid (RIF). 8 BK is a vasoactive peptide hormone that serves as an intermediate in a cascade mediated by AT 2 receptors in opposition to actions initiated at AT 1 receptors. 7 Intrarenal generation of BK modulates NO production, 9 which in turn leads to the activation of cGMP, 10 the final link in the biochemical cascade set in moti...

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“…15,24,25 The facilitating effect of Ang II being less in CHF-compared with control preparations may be explained by down-regulation or desensitisation/uncoupling of the AT 1 -receptor, which has been described previously. 18,[26][27][28] In general, increased levels of Ang II are assumed to be the main cause of down-regulation. 26,29 Although, in the present study, stimulationinduced release of tritium-label was not different in controls compared with CHF-preparations, changes in function of the sympathetic nerve terminal, as well as changes in the signalling pathway, may possibly play a role in the decreased facilitation by Ang II in CHF-preparations.…”

Section: Discussionmentioning

confidence: 99%

Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model

Belterman

Mathy

Balt

et al. 2003

J Renin Angiotensin Aldosterone Syst

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Congestive heart failure (CHF) is characterised by activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). Both systems are known to interact and to potentiate each other s activities. We recently demonstrated that angiotensin II (Ang II) enhances sympathetic nerve traffic via prejunctionally-located AT1-receptors. At present, little is known about the effects of Ang II at the level of the sympathetic neurones in CHF. Accordingly, we investigated the effect of Ang II in the presence and absence of the AT1-receptor antagonist, eprosartan, on stimulation-induced nerve traffic in isolated thoracic aorta preparations obtained from rabbits suffering from experimentally-induced CHF. Control-preparations were obtained from age-matched animals. Sympathetic activity was assessed by a [3H]noradrenaline spill-over model. Additionally, Ang II constrictor responses were compared between CHF and control vessels in the presence and absence of eprosartan. Additionally, to study postjunctional facilitation, the effects of Ang II on postsynaptic a-adrenoceptor-mediated responses were studied using noradrenaline. Stimulation-evoked SNS-neurotransmission was similar in both groups (CHF versus control). Ang II (0.1 nM 0.1 M) caused a concentration-dependent increase of the stimulation-evoked sympathetic outflow in both groups, with a maximum at 10 nM (control [n=7], FR2/FR1 2.03+0.11 and CHF- preparations [n=7], FR2/FR1 1.71+0.07). The enhancement by Ang II was decreased in CHF- preparations compared with controls (p<0.05). Eprosartan concentration-dependently attenuated the Ang II-enhanced (10 nM) sympathetic outflow in both CHF- and control preparations. The sympatho-inhibitory potency of eprosartan was similar in both groups (control pIC50 8.81 0.31; CHF 8.65+0.42). Ang II (1 nM 0.3 M) concentration-dependently increased the contractile force in control preparations (Emax 21.64+3.86 mN, pD2 7.63+0.02, n=7). Eprosartan (1 nM 0.1 M) influenced the Ang II- contractions via a mixed form of antagonism. In CHF-preparations, Ang II caused impaired vascular contraction. The KCl-induced contraction was decreased in the CHF- compared with control preparations (13.02+0.64 mN versus 30.40+0.89 mN). The relative Ang II contraction (% of KCl) was also decreased (2.3% vs. 58.0%). Concentration-response curves to noradrenaline (%KCl) were similar (control pD2 6.93+0.05, Emax 131.0+2.7; CHF pD2 7.00+0.05, Emax 136.7+2.6) (p>0.05) and were not affected by Ang II. We conclude that Ang II-enhanced sympathetic neurotransmission is mediated by the prejunctional AT1-receptor in both control and CHF-preparations. The decreased facilitation of SNS effects by Ang II may be explained by down-regulation or desensitisation of the neuronal AT1-receptor. Additionally, the aortic contractile capacity in heart failure rabbits appears to be decreased, probably as a result of heart failure-associated neuroendocrine and functional changes.

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Downregulation of Angiotensin II Receptor Type 1 in Heart Failure

Cited by 17 publications

References 30 publications

Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts

Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts

Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP

Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model

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