Central Angiotensin (1-7) Enhances Baroreflex Gain in Conscious Rabbits With Heart Failure

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Hypertension (Impact Factor: 6.48). 08/2011; 58(4):627-34. DOI: 10.1161/HYPERTENSIONAHA.111.177600
Source: PubMed


In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of angiotensin (Ang) II, Ang-(1-7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1-7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1-7) on baroreflex control of heart rate and renal sympathetic nerve activity in conscious rabbits with CHF. We hypothesized that central Ang-(1-7) would improve baroreflex function in CHF. Ang-(1-7) (2 nmol/1 μL per hour) or artificial cerebrospinal fluid (1 μL per hour) was infused by an osmotic minipump for 4 days in sham and pacing-induced CHF rabbits (n=3 to 6 per group). Ang-(1-7) treatment had no effects in sham rabbits but reduced heart rate and increased baroreflex gain (7.4±1.5 versus 2.5±0.4 bpm/mm Hg; P<0.05) in CHF rabbits. The Ang-(1-7) antagonist A779 (8 nmol/1 μL per hour) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1-7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline renal sympathetic nerve activity was significantly lower, and baroreflex control of renal sympathetic nerve activity was enhanced in CHF rabbits receiving Ang-(1-7). These data suggest that augmentation of central Ang-(1-7) inhibits sympathetic outflow and increases vagal outflow in CHF, thus contributing to enhanced baroreflex gain in this disease state.

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    • "The presence of Mas in areas, such as the hypothalamus, nucleus tractus solitarii, rostral and caudal ventrolateral medulla, provides the basis for several effects produced by its agonist, Ang-(1–7), in the brain. Modulation of sympathetic activity (Silva et al., 1993; Fontes et al., 1994; da Silva et al., 2011; Kar et al., 2011; Li et al., 2013), increase of vagal tonus (Guimaraes et al., 2012), and improvement of baroreflex sensitivity (Chaves et al., 2000) are some of the effects of Ang-(1–7) that can be blocked by the Mas antagonist A-779. In agreement with these findings, genetic ablation of Mas produces a decrease in baroreflex sensitivity and changes in sympathetic activity (Walther et al., 2000b). "
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    ABSTRACT: The Mas-related G protein-coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as β-alanine, alamandine, adenine, RF-amide peptides, or salusin-β. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1-7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential.
    Pharmacological reviews 10/2014; 66(4):1080-1105. DOI:10.1124/pr.113.008136 · 17.10 Impact Factor
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    • "The higher baroreflex gain induced by angiotensin has been characterized in rats after an intracerebroventricular (ICV) injection. The development of hypertension in DOCA-salt rats and/or the disorders of chronic heart failure (CHF) were both reduced under higher baroreflex [10] [11]. ICV infusion of leptin ameliorated the variability of heart rate (HR) and the baroreflex sensitivity in STZ-induced diabetic rats [12]. "
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    ABSTRACT: Reduced baroreflex sensitivity (BRS) is widely observed in diabetic human and animals. Rosiglitazone is one of the clinically used thiazolidinediones (TZD) known as PPAR γ agonist. Additionally, the klotho protein produced from choroid plexus in the central nervous system is regulated by PPAR γ . In an attempt to develop the new therapeutic strategy, we treated streptozotocin-induced diabetic rats (STZ) with rosiglitazone (STZ + TZD) orally at 10 mg/kg for 7 days. Also, STZ rats were subjected to intracerebroventricular (ICV) infusion of recombinant klotho at a dose of 3 μ g/2.5 μ L via syringe pump (8 μ g/hr) daily for 7 days. The BRS and heart rate variability were then estimated under challenge with a depressor dose of sodium nitroprusside (50 μ g/kg) or a pressor dose of phenylephrine (8 μ g/kg) through an intravenous injection. Lower expression of klotho in medulla oblongata of diabetic rats was identified. Cerebral infusion of recombinant klotho or oral administration of rosiglitazone reversed BRS in diabetic rats. In conclusion, recovery of the decreased klotho in brain induced by rosiglitazone may restore the impaired BRS in diabetic rats. Thus, rosiglitazone is useful to reverse the reduced BRS through increasing cerebral klotho in diabetic disorders.
    02/2014; 2014:309151. DOI:10.1155/2014/309151
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    • "In line with ACE2, I.C.V infusion of Ang-(1-7) caused a significantly increase in baroreflex sensitivity in male Wistar rats [53], and this effect was amplified by co-infusion with bradykinin, suggesting a potential synergistic effect between the two peptides [54]. I.C.V infusion of Ang-(1-7) was also found to enhanced baroreflex function in rabbits with CHF through inhibiting sympathetic outflow and increasing vagal outflow [55]. In addition, infusion Ang-(1-7) into lateral cerebral ventricle of DOCA rats was found to cause an improvement of baroreflex function and a restoration of the sympathetic nerve activity [48]. "
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    ABSTRACT: The renin-angiotensin system (RAS) in brain is a crucial regulator for physiological homeostasis and diseases of cerebrovascular system, such as ischemic stroke. Overactivation of brain Angiotensin-converting enzyme (ACE) - Angiotensin II (Ang II) - Angiotensin II type 1 receptor (AT1R) axis was found to be involved in the progress of hypertension, atherosclerosis and thrombogenesis, which increased the susceptibility to ischemic stroke. Besides, brain Ang II levels have been revealed to be increased in ischemic tissues after stroke, and contribute to neural damage through elevating oxidative stress levels and inducing inflammatory response in the ischemic hemisphere via AT1R. In recent years, new components of RAS have been discovered, including ACE2, Angiotensin-(1-7) [Ang-(1-7)] and Mas, which constitute ACE2-Ang-(1-7)-Mas axis. ACE2 converts Ang II to Ang-(1-7), and Ang-(1-7) binds with its receptor Mas, exerting benefical effects in cerebrovascular disease. Through interacting with nitric oxide and bradykinin, Ang-(1-7) could attenuate the development of hypertension and the pathologic progress of atherosclerosis. Besides, its antithrombotic activity also prevents thrombogenic events, which may contribute to reduce the risk of ischemic stroke. In addition, after ischemia insult, ACE2-Ang-(1-7)-Mas has been shown to reduce the cerebral infarct size and improve neurological deficits through its antioxidative and anti-inflammatory effects. Taken together, activation of the ACE2-Ang-(1-7)-Mas axis may become a novel therapeutic target in prevention and treatment of ischemia stroke, which deserves further investigations.
    Current Neuropharmacology 03/2013; 11(2):209-17. DOI:10.2174/1570159X11311020007 · 3.05 Impact Factor
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