Alamandine injected into the paraventricular nucleus increases blood pressure and sympathetic activation in spontaneously hypertensive rats

Shen, Yun-Dun; Chen, Xi-Ru; Yang, Chunxi; Liu, Bo-Xun

doi:10.1016/j.peptides.2018.03.014

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…11) Alamandine has a hypotensive effect when microinjected into the caudal ventrolateral medulla of 2K1C hypertensive rats and has a pressor effect when administered to the rostral ventrolateral medulla of Fisher rats. 18) Shen et al 19) have previously shown that the administration of alamandine to the hypothalamic paraventricular nucleus increased blood pressure and enhanced sympathetic activity via its MrgD receptor and that the cAMP-protein kinase A (PKA) pathway was involved in mediating these effects…”

Section: Discussionmentioning

confidence: 99%

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Hekmat

Zare

Moravej

et al. 2019

Biological & Pharmaceutical Bulletin

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Alamandine is a new member of the angiotensin family. Here, we studied the mRNA and protein expression of cardiac angiotensin-converting enzyme 2 (ACE2) in the chronic phase of a rat model of 2-kidney, 1-clip hypertension (2K1C), and the effects of 2-week alamandine infusion on blood pressure, cardiac indices, and ACE2 mRNA and protein expression in the hearts. The rats were subjected to to sham-operation or placement of plexiglass clips around the left renal artery. Alamandine, at a dose of 600 µg/kg/d, was administered for 2 weeks via an osmotic mini-pump. At 18 weeks, after induction of hypertension, blood pressure and cardiac indices of contractility were measured using a Powerlab Physiograph system. The ACE2 mRNA and protein levels were determined using real time-PCR and Western blotting, respectively. In the hypertensive rats, alamandine caused a significant decrease in systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), left ventricular end-diastolic pressure (p < 0.001) and, left ventricular systolic pressure (p < 0.001) and increase in the maximum rate of pressure change in the left ventricle (dP/dt(max)) (p < 0.05). Also, the ACE2 mRNA expression in the heart increased in the hypertensive rats compared to the normotensive rats (p < 0.05), and alamandine restored this to normal values, although these changes were only seen at the mRNA and not the protein level. Histological analysis of cardiac tissue confirmed that alamandine decreased cardiac fibrosis and hypertrophy in 2K1C hypertensive rats. Our results indicate that alamandine, which acts as a depressor arm of the renin-angiotensin system, could be developed for treating hypertension.

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Section: Discussionmentioning

confidence: 99%

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Hekmat

Zare

Moravej

et al. 2019

Biological & Pharmaceutical Bulletin

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“…Similar to Ang-(1-7), central alamandine infusion improves baroreflex sensitivity for control of heart rate [17]. Alamandine, however, also has site-specific cardiovascular actions by acting at MrgD within the CVLM and RVLM to produce vasodilation and decrease blood pressure [16], and by acting in the PVN to increase blood pressure and renal sympathetic nerve activity [62].…”

Section: Ang-(1-7) Pathwaysmentioning

confidence: 99%

“…Some studies have shown neutral effects of ACE inhibitors and ARBs on measures of sympathetic tone such as plasma norepinephrine and muscle sympathetic nerve activity in clinical populations [72,73,37,[74][75][76]. The collective literature, however, suggests that the beneficial effects of these therapies on blood pressure are, at least in part, due to cardiovascular autonomic mechanisms (Table 2) [62]. ACE inhibitors and ARBs reduce central sympathetic neural discharge as well as reduce norepinephrine spillover rates and improve tissue clearance at peripheral nerve terminals in essential hypertension [65].…”

Section: Ace Inhibitors and Angiotensin Receptor Blockersmentioning

confidence: 99%

The renin–angiotensin system in cardiovascular autonomic control: recent developments and clinical implications

2018

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Complex and bidirectional interactions between the renin-angiotensin system (RAS) and autonomic nervous system have been well established for cardiovascular regulation under both physiological and pathophysiological conditions. Most research to date has focused on deleterious effects of components of the vasoconstrictor arm of the RAS on cardiovascular autonomic control such as renin, angiotensin II, and aldosterone. The recent discovery of prorenin and the prorenin receptor have further increased our understanding of RAS interactions in autonomic brain regions. Therapies targeting these RAS components, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are commonly used for treatment of hypertension and cardiovascular diseases, with blood pressure lowering effects attributed in part to sympathetic inhibition and parasympathetic facilitation. In addition, a vasodilatory arm of the RAS has emerged that includes angiotensin-(1-7), ACE2, and alamandine and promotes beneficial effects on blood pressure in part by reducing sympathetic activity and improving arterial baroreceptor reflex function in animal models. The role of the vasodilatory arm of the RAS to cardiovascular autonomic regulation in clinical populations, however, has yet to be determined. This review will summarize recent developments in autonomic mechanisms involved in effects of the RAS on cardiovascular regulation, with a focus on newly discovered pathways and therapeutic targets for this hormonal system.

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“…In vivo , participation of the G i signaling pathway in an alamandine effect could be shown after microinjection of alamandine in the paraventricular nucleus of normotensive Wistar Kyoto (WKY) rats and SHR rats. Blood pressure as well as sympathetic outflow increased in both groups upon activation of MrgD receptor dependent on cAMP and protein kinase A (PKA), while the increase in SHR rats was larger than in the control group (21).…”

Section: G Protein Couplingmentioning

confidence: 99%

Alamandine and Its Receptor MrgD Pair Up to Join the Protective Arm of the Renin-Angiotensin System

Schleifenbaum

2019

Front. Med.

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Only a few years ago, alamandine was found to be a member of the protective arm of the renin-angiotensin system. It turned out to be an endogenous ligand of the G protein-coupled receptor MrgD. So far, MrgD had predominantly been studied in a neuronal context. The expression of the receptor in non-neuronal tissue showed hitherto unknown effects mediated by MrgD, most strikingly alamandine-induced vasodilation. Alamandine being a part of the non-classical renin-angiotensin system, a protective role of receptor activation seemed natural. This review summarizes the different effects of MrgD activation by alamandine in vasculature, in the central nervous system, and in organs as kidney and heart. Alamandine and MrgD are promising novel drug targets to protect the kidney and heart through anti-hypertensive actions.

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Alamandine injected into the paraventricular nucleus increases blood pressure and sympathetic activation in spontaneously hypertensive rats

Cited by 22 publications

References 25 publications

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

The renin–angiotensin system in cardiovascular autonomic control: recent developments and clinical implications

Alamandine and Its Receptor MrgD Pair Up to Join the Protective Arm of the Renin-Angiotensin System

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